Trachea Transplants: The Stocholm Story

There are many medical topics that are of an ongoing interest and importance. One of them is the rebuilding or restoration of the trachea caused by tracheal defects. In fact, tracheal defects are one of the most complicated problems found in a person‚Äôs head, neck and chest. People often wonder what exactly a trachea is and what does it do. The trachea is more commonly known as the ‚Äėwindpipe‚Äô. It starts just under the voice box or larynx, runs behind the breastbone and branches off into two smaller tubes (bronchus) that lead into each lung. The trachea is made up of about 20 rings of soft cartilage tissue, along with muscle and connective tissue and moist blood rich linings. When you breathe in oxygen it expands and lengthens slightly to allow the air to inflate the lungs, then returns to its normal size and position when you breathe out. If the trachea is damaged, blocked or destroyed, the normal flow of air slows down or stops all together.

What can damage the trachea and require immediate treatment?

Tracheal Stenosis is a narrowing of the trachea and can be caused by scarring or disease. A tracheoesophageal fistula is where there is an opening between the trachea and the esophagus and food is allowed to pass into the lungs and cause serious lung problems. A foreign body in the trachea happens when food or another foreign substance gets inhaled and lodged in the trachea suddenly cutting off airflow. A soft or non- rigid (floppy) trachea is usually caused by a birth defect, injury or scarring. A tracheal tumor or obstruction is caused by a tumor or other growth that narrows or presses down on the trachea. Any of the above conditions usually require surgery, including a stent or trachea replacement to open the trachea and restore normal breathing. Any surgery on the trachea is complex and should never be viewed as a simple procedure on a tube. Patients with long term trachea issues are usually quite sick and have many complications that require ongoing treatment such as a replacement.

When is replacing trachea considered/safe

Replacing a trachea is considered when the tumor, narrowing or traumatic scarring cannot be removed or repaired safely. In an adult, a safe removal length is considered to be no more than one half of the trachea. For a small child the safe removal length is one third. If more than the safe amount of trachea has to be removed, then the patients airway has to be maintained on an ongoing basis with tubes and stents as the current accepted treatment of choice. Research into a more long-term safe, effective solution has been ongoing because patients with tubes or stents are at a greater risk for major complications and lengthy hospitalizations.

Dr. Paolo Macchiarini

Since 2008, Dr. Paolo Macchiarini from the Karolinska Institute in Stockholm, Sweden, has been replacing parts of airways in patients who either had injuries, cancer or other trachea abnormalities, using experimental procedures with the hope of giving patients a chance at a longer life. Dr. Macchiarini and his team initially have transplanted tracheas from cadavers. He then worked on transplanting patients with artificial or synthetic tracheas. Both the transplanted cadaver and artificial tracheas were treated prior to surgery with stem cells taken from the receiving patients bone marrow. This made the new trachea act like it was the patients own tissues instead of a foreign body that could potentially be rejected after the transplant. These procedures were believed to be hopeful for the field of bioengineering and transplants, especially when he reported that there were no major complications five months after the transplant.

Investigating the study

Unfortunately this potentially productive project has come under serious questioning. The Karolinska Institute has launched two investigations to look into some serious disagreements between published reports and findings of other physicians involved with the specific transplantation cases. The first investigation is being conducted by an expert unaffiliated with the Institute with the investigative report due out in early 2015. This independent expert review looks into three specific transplanted artificial tracheas, performed at the Karolinska Institute by Dr. Macchiarini . The investigation was started after a request was filed by four thoracic surgeons at the Karolinska Hospital. The four physicians, who had treated the involved patients, were concerned because of signifigant discrepancies between the patients medical record and the published report in the well known medical journal The Lancet in 2011. Dr. Macchiarini decided not to answer the specific questions about the discrepancies found to allow a thorough ,unbiased investigation into this accusation of scientific misconduct. In fact, he welcomes this review by an external expert since the charge of scientific misconduct represents a serious violation of the standard rules of scholarly conduct and ethical behavior in scientific research.

What exactly is being called into question in Dr. Macchiarini’s research?

One key discrepancy noted in the investigation request is that three patients who received synthetic tracheas were reported in published articles to have minimal to no complications, while the patients’ medical records show these same patients actually suffered from serious complications. In addition, a claim was made in the same article that synthetic trachea transplants can become a functioning airway. Again this is a claim that appears to not be supported by the patients’ medical record. The investigating doctors also express concern that the published articles contain falsified data or data that has been left out or not addressed at all. Other medical experts, in addition to the four Doctors at Karolinska, have also questioned the ethics of using a synthetic trachea in a human when it has not been tested in a large animal and observed for long term complications and side effects. It is important to note that natural, non-synthetic tracheas have been successfully used in studies involving pigs only. However, the results of the pig study do not accurately predict the results for synthetic tracheas in human beings. There is no readily available evidence of testing being done on large animals before being used in humans, so potential complications or side effects may not be fully known.

The Karolinska Hospital physicians also pointed out that the above issues should have been investigated and questioned during the application process with the Regional Ethical Review Board to get permission to do medical research on human subjects. The physicians report in their investigation request that to the best of their knowledge no such application was applied for or approved by the Regional Ethical Review Board. They also question whether ethical permission would have been granted because of the lack of research results in the large animal model study that is normally done. It is also noted that the patients signed treatment consents for the elective surgical procedure, consents that were not reviewed or approved by the ethics committee bringing up concerns that the patients signed unapproved consents that contained unproven statements about potential complications and side effects. Typically, the ethics committee reviews and approves all consents for accuracy and completeness before they are released for use with patients. There is also concern that one consent, was signed 17 days after the surgery was performed instead of before the procedure. Dr. Macchiarini has stated that the patient signed the consent in his presence before the surgery and he assumes it was some clerical error that caused the difference in dates.

The filed complaint also lists a lack of evidence that the Swedish Medical Products Agency has approved the synthetic trachea for placement in humans as another concern. It is also reported that some medications were used on these patients’, in a manner that was also not approved by the drug manufacturer or the Swedish Medical Products Agency. The Swedish Medical Products Agency is the Swedish national organization that is responsible for the regulation and oversight of the development, production and marketing of drugs and other medical products. Their job is to make sure that patients and health care providers have safe, effective products that are used in a logical and cost effective way.

Another Investigtion from Pierre Delaere (head and neck surgeon, Belgium)

The second investigation involves the Karolinska Institutes Ethics Council coming from a complaint filed in June by Pierre Delaere head and neck surgeon at the University Hospital, KU Leuven, Belgium. This doctor has questions that the published details, regarding the transplants,minimizes the complications faced by patients including the need for stents post transplant. Dr. Macchiarini sent a 15 page response letter to the Karolinska Institute that included an acknowledgement of shortening the discussion of complications at the request of the publishing editor during the normal article review process. The ethics council has been conducting its investigation by interviewing all concerned parties and hopes to have a report and recommendation to the vice-chancellor of the Karolinska Institute by the end of February. Once the report is received and reviewed by Dr. Anders Hamsten, vice-chancellor, a decision will be made in the actions to take next. The Institute has investigated Dr. Macchiarini’s published work two times in the past, when scientific misconduct was reported by other claimants/physicians. The investigations surrounding those 2 claims found no evidence of scientific misconduct. These were done in July 2013 and September 2014. The scientific and medical community are awaiting the outcome of this latest investigation.

Dr. Macchiarini would like to continue his research with synthetic tracheas. He has been doing part time work at the Kuban State Medical University in Krasnodar Russia. However, his clinical trial there was put on hold in September 2014 following the death of a transplant patient. This specific transplant patient had a synthetic trachea placed in June 2012 that began to fail. The patient was given a second transplant in August 2013. Dr. Macchiarini reports this patients cause of death as ‚Äú bilateral acute pneumonia with heart-lung insufficiency‚ÄĚ and unrelated to the trachea transplant as the patient was breathing normal and symptom free two weeks before death. Dr. Macchiarini is considering starting up the clinical trial again now that the actual cause of death has been determined and considered unrelated. He also reports that the most recent tracheal transplant, performed in June, is doing well and is symptom free.

Macchiarini Unsuccessful and ….?

It is interesting to note that six of eight synthetic trachea transplanted patients have died. Their post- transplant life spans range from 3 months to 31 months. The reported causes of death include complications following an accident, another from taking in too much alcohol, and another from respiratory system failure and multiple organ system failures. None of the cases have been directly linked to the transplant itself. It is important to remember that these patients were already very sick before the transplant and the surgery procedure and recovery time weakened them further.

One patient remains in the intensive care unit more than two years after the procedure. Dr. Macchiarini states that this particular patients condition is not a direct result from the transplant as the patients state of health and medical condition was already extremely poor at the time of the transplant surgery. It is documented that her physicians had given her 3-6 months to live before the transplant. Dr. Macchiarini reports that during the transplant the natural airway was far more damaged than anticipated, based on previous examinations before the procedure, and could not have been found before the procedure itself.

In addition to the synthetic trachea procedures, nine patients have received tracheas from cadavers. Dr. Macchiarini released a paper in 2014 that showed 4 of these patients have died from either a recurrence of tumors or from Gastro-intestinal bleeding. There are five patients still living. Four of these patients remain dependent on trachea stents despite the cadaver transplant. One has no need for stents at this time.

The investigations being conducted against Dr. Macchiarini involve very serious accusations, including possible failure to get an informed patient consent and distorting reported data. It is important to remember that Dr. Macchiarini usually operates on seriously ill patients, patients for whom long-term survival is in question and the risks of complications are very great. Therefore a thorough investigation by experts, such as is being done by the Karolinska Institute and the Ethics Council, can hopefully bring answers to these serious questions and help guide additional experimental research in this important bioengineering project and potentially benefit those who are so seriously ill. It will be interesting to read and review the results of both investigations and see where the project goes from here.