DuraSeal™ Sealants vs. Tisseel™ Fibrin Sealant

TRALI - further evidence to minimize transfusion

TRALI 

Transfusion-Related Acute Lung Injury (TRALI) is a syndrome characterized by acute respiratory distress following transfusion. All plasma-containing blood products have been implicated including rare reports of IVIG and cryoprecipitate. It is a rare complication of allogeneic blood transfusion but the incidence has not been well established due to difficulty in defining the syndrome and to variable reporting mechanisms worldwide. Various studies have estimated the overall frequency of TRALI to be between 1/1,120 and 1/57,810 units transfused. However, there is wide discrepancy in the literature with the reported frequency is as low as 1/557,000 RBC units and as high as 1/432 platelet units.

TRALI is associated with a high morbidity with the majority of patients requiring ventilatory support. However, the lung injury is generally transient with PO2 levels returning to pretransfusion levels within 48 -96 hours and CXR returning to normal within 96 hours. TRALI is associated with a significant mortality rate, often approximated at 5 to 10%. Given the gains in safety made within the blood component production industry, particularly with respect to transmission of infectious diseases, TRALI is now among the three leading causes of transfusion related fatalities along with ABO incompatibility and bacterial contamination.

Transfusion-related acute lung injury and pulmonary edema in critically ill patients: a retrospective study.

Rana R, Fernández-Pérez ER, Khan SA, Rana S, Winters JL, Lesnick TG, Moore SB, Gajic O.

Source

Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.

Abstract

BACKGROUND:

Using the recent Consensus Panel recommendations, we sought to describe the incidence of transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) in critically ill patients.

STUDY DESIGN AND METHODS:

Consecutive patients at four intensive care units (ICUs) who did not require respiratory support at the time of transfusion were identified with custom electronic surveillance system that prospectively tracks the time of transfusion and onset of respiratory support. Respiratory failure was defined as the onset of noninvasive or invasive ventilator support within 6 hours of transfusion. Experts blinded to specific transfusion factors categorized the cases of pulmonary edema as permeability edema (suspected or possible TRALI) or hydrostatic edema (TACO) according to predefined algorithm. In a nested case-control design, transfusion variables and lung injury risk factors were compared between the TRALI cases and controls matched by age, sex, and admission diagnosis.

RESULTS:

There were 8902 units transfused in 1351 patients of whom 94 required new respiratory support within 6 hours of transfusion. Among 49 patients with confirmed acute pulmonary edema, experts identified 7 cases with suspected TRALI, 17 patients with possible TRALI, and 25 cases with TACO. The incidence of suspected TRALI was 1 in 1271 units transfused; possible TRALI, 1 in 534 per unit transfused; and TACO, 1 in 356 per unit transfused. When adjusted for sepsis and fluid balance in a stepwise conditional logistic regression analysis, patients who developed acute lung injury (suspected or possible TRALI) received larger amount of plasma (odds ratio 3.4, 95% confidence interval 1.2-10.2, for each liter infused; p = 0.023).

CONCLUSION:

In the ICU, pulmonary edema frequently occurs after blood transfusion. The association between infusion of plasma and the development of suspected or possible TRALI may have important implications with regards to etiology and prevention of this syndrome.

Link: http://www.ncbi.nlm.nih.gov/pubmed/16965572

Revealed - UK NHS tests for Transfusion related vCJD. US California new cases.

In More Bad news for purveyors of Bovine derived products and transfusion supporters, thousands of NHS patients could be secretly monitored by the Government for symptoms of the human form of mad cow disease amid concerns that there could be another wave of infections.

Experts advising the Department of Health believe patients who have received more than 80 blood transfusions are most at risk of developing the fatal brain disease because it can be passed on through infected blood.

They say monitoring these patients could give vital clues about the way the disease develops and is transmitted from person to person and could help work out whether there are likely to be further deaths. 

Thousands of NHS patients could be secretly monitored by the Government for symptoms of the human form of mad cow disease amid concerns that there could be another wave of infections

It could also inform officials whether the risk from blood donations needs to be treated more seriously.

But they are considering conducting their surveillance secretly because they fear that informing patients they are at risk and are being monitored will cause unnecessary alarm.

The proposals have been discussed by a powerful panel of leading scientists and doctors, which advises the Government on the disease, known as variant CJD.

More...

• Blood test for mad cow disease used in UK for the first time
• Flesh-eating bug that you can catch on the bus or train is spreading in the UK

The panel's report, published online, suggests conducting 'covert health surveillance' of around 30,000 patients known to have received a high number of blood transfusions.

Experts would expect to see at least 150 cases of vCJD in this group of patients, based on scientific evidence that between one in 4,000 and one in 20,000 of the population may be infected.

Experts believe patients who have received more than 80 blood transfusions are most at risk of developing the fatal brain disease as it can be passed on through infected blood

But this has so far not been seen and may either mean the risk is lower than previously thought, or that it is taking longer for cases to develop.

The 'highly transfused' group includes people suffering life-threatening illnesses including acute leukaemia, aplastic anaemia and the blood disorder thalassemia - as well as those with multiple injuries due to road accidents, or heavy blood loss from aneurysms. 

The report acknowledges that following patients without their consent is 'ethically problematic'.

But the panel, a subcommittee of the Advisory Committee on Dangerous Pathogens, has asked the Health Protection Agency to set out the various options for monitoring these patients based on seeking their consent or not. 

Chris James, chief executive of the Haemophilia Society, said: 'We are shocked to learn there was ever any suggestion of non-consensual monitoring. 

'Given the history of contaminated blood in the 1970s and 1980s, the maintenance of medical ethics is especially important to the haemophilia community.

'Any proposed framework must be reviewed by an ethics committee and open to challenge from individuals and organisations such as ourselves through a formal consultation process.' 

Latest official figures show seven NHS patients have died from vCJD after having blood transfusions.

Four are known to have been given blood from people who were infected with fatal vCJD, and the other three had previously had transfusions although it is not known whether the blood was contaminated.  

Since the first vCJD cases emerged in the mid-1990s, 175 people in Britain have died from the brain wasting disease, which is linked to eating beef infected with BSE.

Experts predicted that hundreds more could die after receiving blood infected with the disease. But they now admit they are baffled as to why these cases have failed to emerge. 

One theory is that some people have a genetic advantage and may only carry the disease without developing symptoms. However, they can still infect others if they give blood.

In one case, a patient is known to have been exposed to vCJD in a blood transfusion and is still alive 24 years later. 

A memorial plaque to victims of Human BSE on the Riverside Walk near Westminster Bridge, London

At the moment, patients are only informed that they are at increased risk of developing vCJD if they have been exposed to blood from more than 80 donors and if they are about to have brain, spinal or complex eye surgery.

But this threshold may now be raised to only inform patients if they are exposed to 300 or more blood donors because the lack of vCJD cases so far may indicate that the risk of catching vCJD in blood may be lower than previously suspected. 

Judy Kenny, of the CJD Support Network, whose husband Deryck died aged 69 in 2003 after being given contaminated blood, said: 'If the authorities are going to do any monitoring, patients should be aware of it. 

'There is no grey area - if they are thinking about unconsented monitoring, then it is wrong.'

CJD occurs when nerve-tissue proteins called prions (illustration above) turn 'bad' and gradually destroy the brain

Professor Chris Bunce, science director of charity Leukaemia and Lymphoma Research, said: 'The extent of the risk [of vCJD] to patients who receive regular blood transfusions as part of their treatment is as yet uncertain. 

'One way to ascertain the risk would be to monitor the distribution of the pathogen among people in this group. 

'But with that comes the moral question of whether patients should be informed or not, and this is the dilemma of the Health Protection Agency.'

A Department of Health spokesman said: 'No decisions have been taken on any unconsented follow-up of highly transfused patients.

'No unconsented follow-up has taken place and none would without appropriate ethical approval and on the basis of legal advice.


Meanwhile Stateside...
(Sacramento, CA) 
Friday, February 10, 2012

The Marin County Public Health Officer, Dr. Craig Lindquist, says one person who was diagnosed with a brain disorder similar to Mad Cow Disease has passed away, but that the person did not contract the disease from contaminated beef.  That makes it the classic form of the disease and not the varient form.   

There is another resident still living with Creutzfeldt Jacob Disease or CJD.  Lindquist says there is no evidence it is of the varient variety either. 

CJD is very rare, but always fatal.  It attacks the memory, hand eye coordination and vision before killing the victim within a year. 

The Mad Cow variant of the disease can be spread only by contact with the brain tissue or nervous system tissue of someone or something that is afflicted.  Twenty five years ago, nearly 170 people died of the variant form of the disease in Europe.

Doctor Richard Breitmeyer runs the lab at UC Davis that  tests  Mad Cow disease in sheep and cattle.  

BREITMEYER:  "The current science believes in the United Kingdom that was the cause of Varient CJD in people in that they had consumed meat products that were contaminated with the bovine form."

Breitmeyer's lab is one of six in the nation.

Cattle fed with bovine bone meal was found to be a significant cause of the spread of the disease in Europe.  Of the 40,000 animals tested each year in the United States since, only two tested positive.

In humans, 85 percent of those afflicted with classic CJD had no known risk factors.  Five to ten percent had a genetic history of the disease.

Baxter Announces FDA Approval of Expanded Indication for TISSEEL

DEERFIELD, Ill., Jan 30, 2012 (BUSINESS WIRE) -- Baxter International Inc. announced today that the U.S. Food and Drug Administration (FDA) has approved TISSEEL [Fibrin Sealant] to include general hemostasis in surgery when control of bleeding by standard surgical techniques is ineffective or impractical. TISSEEL is effective in heparinized patients. TISSEEL mimics the final stages of the body's own blood clotting cascade, creating a clot that adheres to the wound surface and helps achieve hemostasis.

"The expanded indication for TISSEEL offers more surgeons an effective tool for controlling bleeding across a wider variety of surgical procedures," said Sibu Saha, M.D., Professor of Surgery, University of Kentucky. "This includes patients who have been treated with heparin who may have unique treatment challenges, which was the case for some of the patients involved in Baxter's clinical trials."
A Phase III clinical study assessed the safety and efficacy of TISSEEL in peripheral vascular surgery compared with manual compression, a standard of care, in 140 evaluable patients (70 patients per treatment arm). In the study, TISSEEL was shown to be statistically significantly better than manual compression in achieving hemostasis. These study results complement a clinical data package showing the safety and effectiveness of the use of TISSEEL as an adjunct to hemostasis.
"TISSEEL and its multiple application devices make it well-suited for a variety of surgical situations, such as open and laparoscopic procedures, reinforcing Baxter's commitment to supporting solutions to the surgical community," said Prof. Hartmut J. Ehrlich, M.D., vice president of global research and development in Baxter's BioScience busines

Important Risk Information

For Topical Use Only. Do not inject TISSEEL directly into the circulatory system or into highly vascularized tissue. Intravascular application of TISSEEL can lead to intravascular coagulation, may result in life-threatening thromboembolic events and may increase the likelihood of acute hypersensitivity reactions in susceptible patients. Exercise caution to minimize the risk of intravascular application when using TISSEEL in surgery.

Do not use TISSEEL in individuals with a known hypersensitivity to aprotinin.

Do not use TISSEEL for the treatment of severe or brisk arterial or venous bleeding. In these situations, TISSEEL will be washed away in the flow of blood before hemostasis can be attained.

Hypersensitivity or allergic/anaphylactoid reactions may occur with the use of TISSEEL. Such reactions may especially be seen if TISSEEL is applied repeatedly over time or in the same setting, or if systemic aprotinin has been administered previously.

Aprotonin is known to be associated with anaphylactic reactions. Even in the case of strict local application of aprotinin, there is a risk of anaphylactic reactions to aprotinin, particularly in the case of previous exposure.

Discontinue administration of TISSEEL in the event of hypersensitivity reactions. Remove remaining product from the application site.

Air or gas embolism has occurred when fibrin sealant was administered using pressurized gas. This may occur if a spray device is used at higher than recommended pressures and in close proximity to the tissue surface.

When using the EASYSPRAY device, or an equivalent spray device for open surgical procedures cleared by FDA, TISSEEL must not be sprayed in enclosed body areas and must be sprayed onto only visible application sites.

TISSEEL is denatured when exposing to solutions containing alcohol, iodine or heavy metals. If any of these substances have been used to clean the wound area, the area must be thoroughly rinsed before the application of TISSEEL.

Apply TISSEEL as a thin layer by dripping or spraying using cannula or spray set. Excess clot thickness may negatively interfere with wound healing.

The safety and effectiveness of TISSEEL used alone or in combination with biocompatible carriers in neurosurgical procedures or other surgeries involving confined spaces have not been evaluated; its use in this setting is not FDA approved.

TISSEEL is made from human plasma. It may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

Vascular Solutions Reports Q4

Net sales of hemostat products (mainly consisting of D-Stat(R) Dry, D-Stat Flowable, and D-Stat Radial) were $5.5 million, down 6% from the year-ago fourth quarter and a 4% decline from the September quarter level. "The hemostatic patch market remains intensely competitive and price sensitive," Mr. Root said. "In mid-2011, we launched the new Silver versions of our D-Stat Dry and Thrombix(R) products, which add an antimicrobial agent. We believe these new products will help us maintain our market-leading position in the hemostat patch market in 2012."
Vascular Solutions will host a live webcast starting at 3:30 p.m., Central Time today to discuss the information contained in this press release. The live webcast may be accessed on the investor relations portion of the company's web site at www.vasc.com . An audio replay of the call will be available until Wednesday, February 8, 2012, by dialing             1-888-203-1112       and entering conference ID# 3945548. A recording of the call will also be archived on the Company's web site, www.vasc.com until Wednesday, February 8, 2012. During the conference call the Company may answer one or more questions concerning business and financial developments and trends, the Company's view on earnings forecasts and new product development and financial matters affecting the Company, some of the responses to which may contain information that has not been previously disclosed.

Baxter International's CEO Discusses Q4 2011 - and the International Markets

Robert L. Parkinson
...In our regenerative medicine business, we achieved a number of milestones, including the approval and U.S. launch of ARTISS Fibrin Sealant for use in facial surgery and the U.S. regulatory filing for TISSEEL Fibrin Sealant for vascular surgery providing a broad hemostasis label. As we've previously mentioned, we're very pleased with the publication of data from Baxter's Phase II chronic myocardial ischemia adult stem cell program, which was published in the scientific journal Circulation Research....
Third, we recently announced the definitive agreement to acquire Synovis, an acquisition that complements and expands Baxter's regenerative medicine and biosurgery franchise, including a number of devices and biological products for hemostasis, tissue sealing and adherence.

Robert J. Hombach

Yes. And so net-net, not much of an impact to speak of on the base of $4.31 of earnings. But as we move into 2012, clearly, we're projecting a much more pronounced impact. And maybe I'll just take a minute here and kind of walk everyone through the drivers because I think this is important. As we've talked about, regularly, Baxter has about 60% of our revenues outside the U.S. We've increasingly highlighted for investors that now slightly more than 20% of our revenues come from emerging markets. And in fact, emerging markets have been growing 2 to 3 times the rate of developed markets over the last 5 years. So the mix of our business certainly has shifted towards emerging markets to a much greater degree. As we've highlighted in the past, for developed markets, we have the ability through natural hedges given our manufacturing footprint, which we have in places like Europe and Canada and Japan, Australia and so on. We have some natural hedges there, but also we utilize financial hedges in those developed markets. Now I would pause here to say, as we've talked about in the past, our pipe policy, we hedge 80% of our projected exposures. And by the nature of hedging, when you're looking 12 to 18 to 24 months out, you have to be careful in your projections to ensure that you don't get yourself in an overhead situation, hence, the 80% with a 20% buffer. But what that does mean is we do have some residual exposure muted but some residual exposure in the developed markets. As we said in the past, with emerging markets, we do not hedge. We do not utilize financial hedges, and we have modest natural hedges in some manufacturing facilities in Latin America, Eastern Europe and so on but nothing near the degree we have in the developed markets. And so our bottom line drop to exposure on the emerging markets is much more leveraged. So to frame that exposure for you then, looking at it by region, so within Latin America, from an operating profit perspective that would be exposed to foreign currency, think of that in terms of $300 million to $400 million of annual profit. And that's primarily Brazil, Colombia and Mexico. For Eastern Europe, which is primarily Russia, Poland and Turkey, again, about $300 million of operating profit on an annual basis. And then in Asia Pacific, and there we would exclude Japan, Australia, New Zealand and China because of the stability of the currency, so all of Asia excluding those 3 is another roughly $300 million of operating profit on an annual basis. So you add that up. That's $900 million to $1 billion of profit exposed to currency in emerging markets. And as you've seen, there's been quite a bit of volatility, and given where we're sitting today and where rates are today relative to where they were on average in 2011, if you assume an 8% to 10% weakening across that basket of emerging market currencies, that's $80 million to $100 million of incremental exposure that we're factoring in here. And you add to that the slight 20% residual impact from the developed markets that goes unhedged, and that's how we get into this kind of $0.15 to $0.18 range of FX exposure. Now, as you would imagine, given the volatility, we've assumed somewhat conservative rates relative to where market rates are today. There's been of bit of a run-up here in the last few days, but given the volatility, I hesitate to call it very conservative. And so that's the picture. But if I step back and think about as a large U.S. multinational corporation in thinking about the long run, being along the emerging markets, whether it's from a growth perspective or currency perspective, is exactly where we want to be. We continue to see great opportunities there, but in times of financial crisis like this, where the correlation between those currencies and the U.S. dollar is all going one way, it creates this kind of outsized exposure that we're having to factor into our guidance here for 2012. So thanks for bearing with me, but I think it's important that people understand the breadth of the issue for us.

David R. Lewis - Morgan Stanley, Research Division

I will -- just maybe one more quick one for Bob Parkinson. And Bob, there's been a lot of concerns here in the quarter regarding European austerity. You've talked a lot about old Europe pressures. I guess we've been surprised about where that pressure's coming from. I think it's a little different than where the investor sees within your plasma business versus your injectable and your nutritional business. Can you just sort of talk to us in the way you're see the pressure and which businesses for Baxter are proving to be more robust? And then where -- which businesses are seeing sort of more pharmaceutical-like pressure?

Robert L. Parkinson

Yes. I mean, so the negative impact of the austerity measures, first of all, is just kind of what I call general softness, David, and underlying demand. But these are the kind of things we see globally. So surgical procedures and things of that nature are somewhat softer than what's been reflected historically. So now we'd run across virtually all our businesses, certainly even our IV business and so on and so forth. But the other pressure that's probably more pronounced and is more associated with our BioScience business would be pricing pressures with governments who clearly are under the gun to implement austerity measures. And given healthcare spend and well-large item that represents on national budgets and so on, we continue to see governments virtually unilaterally implementing various pricing actions, and that impact is more pronounced in things like, say, biosurgery where people are making trade-off decisions in terms of clinical options that they have but also, most of our BioScience products, which are more expensive. So as an example, countries like France implement actions in terms of taking prices down. It's a haircut, David. So it's not as pronounced as what you would see with some of the tender actions, I would say, on hemophilia because encouragingly, we haven't seen the expansion beyond the Anglo markets of the tender activity for hemophilia. But -- so we think we've captured in our guidance for next year those known pricing actions that will be taken on a country-by-country basis. We also think we've reflected kind of the underlying softness of demand. But I think we have to be cognizant of the fact that given the extreme austerity measures and pressures that exist that unlike the U.S. governments in Europe, most notably, really have a history of implementing unilateral actions for which there's not a lot of control. We think we've captured it, but like I say, given the environment, I think, we have to be cognizant that there could be more there. And by the way, this is an ongoing thing. I mean, this is -- it's why I talk about dealing with the new environment in our company, in our culture and so on. This isn't something that's going to pass through this year in -- or through the end of 2012. It's going to be with us....

David H. Roman - Goldman Sachs Group Inc., Research Division

Okay. And then as I look at the Plasma Protein business, the issues about timing of imports in China, I think you had talked about that last quarter, as well a new product, the delay on a large tender for PD Factor VIII in Brazil. Are those issues that we should think about as being ongoing for the next several quarters? Or will those normalize at some point, whereby that business gets back to sort of stable underlying growth on a reported basis?

Robert J. Hombach

Yes. Certainly, Brazil for sure is a timing issue, and we're hoping to continue to accelerate into China. Without them it becomes -- it is a great growth opportunity. So yes, you should see normalized growth rates here in 2012 for that category.

Mary Kay Ladone

Although I would mention, David, that tenders tend to be volatile, and we can see shifts from quarter-to-quarter, so just to highlight that.

Robert L. Parkinson

David, the one thing I would add to the China situation, there's been local action by the Chinese government to further scale back some of their local plasma collection operations in the country. So this importation of albumin in China would appear to be something that is going to be sustainable for the near future, certainly over the next few years, I think, given some of the local issues they manage through.