The experienced questioner brings up several important issues in relationship to critical bleeding, especially in the obstetric setting. I agree with Bruce Spiess’ comments, challenging and provocative as they are. However, the reality is that there are many dilemmas and challenges if we are to improve the management of critically bleeding patients, not the least of which is the nature and quality of the blood products. Obstetric haemorrhage has several unique characteristics, not the least of which is the remarkable ability of young women to survive the insults of massive haemorrhage and transfusion if the bleeding can be brought under control. My observations have been similar to those of the questioner, that frequently older blood (?incorrectly stored) has been responsible for significant problems and the fresher the blood the fewer the problems. There is no immediate answer the question of the quality of blood components and it is certainly a challenge for the blood supply sector and warrants significant research funding. Universal prestorage leukoreduction has probably helped to some extent.

I think it should be emphasized that debate surrounding inappropriate blood transfusion has not been in the settings posed by the questioner who should be reassured that clinical expertise is what saves the patients he refers to. Much of the recent data on the effectiveness of resuscitation with stored red cells indicates that they sustain the macrocirculation and, although the stored red cells may not be immediately effective in delivery of oxygen to the tissues, functional capillary density (FCD) and blood flow is maintained in the microcirculation with the patients remaining red cell being able to deliver the oxygen.

As an aside a recent report from the US raises serious concerns regarding the increase in obstetric morbidity and the alarming increase in transfusion rates:

Kuklina EV, Meikle SF, Jamieson DJ, et al. Severe obstetric morbidity in the United States: 1998-2005. Obst & Gyn 2009;113(2 Pt 1):293-9.

RESULTS: The prevalence of delivery hospitalizations (per 1,000) complicated by at least one severe obstetric complication increased from 0.64% (n=48,645) in 1998-1999 to 0.81% (n=68,433) in 2004-2005. Rates of complications that increased significantly during the study period included renal failure by 21% (from 0.23 to 0.28), pulmonary embolism by 52% (0.12 to 0.18), adult respiratory distress syndrome by 26% (0.36 to 0.45), shock by 24% (0.15 to 0.19), blood transfusion by 92% (2.38 to 4.58), and ventilation by 21 % (0.47 to 0.57). In logistic regression models, adjustment for maternal age had no effect on the increased risk for these complications in 2004-2005 relative to 1998-1999. However, after adjustment for mode of delivery, the increased risks for these complications in 2004-2005 relative to 1998-1999 were no longer significant, with the exception of pulmonary embolism (odds ratio 1.30) and blood transfusion (odds ratio 1.72). Further adjustment for payer, multiple births, and select comorbidities had little effect. CONCLUSION: Rates of severe obstetric complications increased from 1998-1999 to 2004-2005. For many of these complications, these increases were associated with the increasing rate of cesarean delivery.

The questioner also asks about transfusion related immunomodulation (TRIM). It is clear that allogeneic blood transfusion is immunomodulatory, the issue is its clinical significance in terms of adverse patient outcomes. There is minimal data in the obstetric area, most evidence is in relationship to surgery and trauma. It is also difficult to examine the issues of TRIM and the storage lesions separately and it likely that significant TRIM is related to the storage due to cytokine accumulation. The following reference may be of assistance and if the question would like to contact me directly I can provide the papers.

Vamvakas EC, Blajchman MA. Transfusion-related immunomodulation (TRIM): An update. Blood reviews 2007;21(6):327-48.

Zimrin AB, Hess JR. Current issues relating to the transfusion of stored red blood cells. Vox sanguinis 2009;96(2):93-103.

Bosman GJ, Werre JM, Willekens FL, Novotny VM. Erythrocyte ageing in vivo and in vitro: structural aspects and implications for transfusion. Transfusion medicine (Oxford, England) 2008;18(6):335-47.

The points made are valid and real. I too believe when a patient is suddenly loosing massive amounts of blood.  Blood is probably the best thing to give back. Especially in obstetrics when you cannot anticipate how much longer the horrific hemorrhage is going to last.  It is probably not the right thing to do to give fluids (crystalloid and colloid) wait 24 hours to watch the hemoglobin settle out to some very anemic level. That being said, this is of course where clinical judgement comes on in. None of us want to second guess such life saving situations, yet we really do want to raise awareness and get people thinking about " do I need to  just top her up" or let's just give he a unit because....."  What you have described are situations wherein I think not only were units justified but you ran into some of the most dreaded complications.  

There is no doubt that older blood has a higher potassium level as well as cytokines, and a number of other changes all of which are bad. So, there are very real challenges on the table for blood bankers. The pharmaceutical industry has made fantastic drugs to manipulate all kinds of human physiology. Just in the last 5 years a few groups are working on techniques to preserve red cell function. Unfortunately even the best of the best solutions today manage to advance the red cell 2,3 DPG storage to about 10 days to 14 days. That means that the average unit of blood transfused (16-21 days) still has zero 2,3 DPG.
Therefore, we have a long way to go. But, these kinds of discussions along with government awareness could well provide the money and impetus for research and pharmaceutical houses to invest and find solutions.

Perhaps the other side of the coin needs to be investigated. By that I mean we need to have high level discussions about the very core of how we do business. The idea of taking a unit of blood and shoving it in the refrigerator and then using the oldest first just so that the blood bankers regulatory numbers don't look bad is putting the wrong message out there. If we care about our patients (we are all patients some day) then we ought to ask the tough questions and have society fix them. So, we need to completely overhaul how we get store and use blood. Wow, that is huge.  Wouldn't it be great if you knew for a critically ill patient you could get fresh whole blood immediately, or that some other product with the that oxygen carrying capacity were available. I suppose my main message today is to say: "Take a look at the data and it will scare you. We have just assumed that blood from t he blood bank is good. It is not! So, know if you know it is really bad then we have to start the much harder task of studying that problem and fixing it." I really do not have all the answers.

As to the poor woman who got the ST- segments, probably elevated potassium and maybe also decreased oxygen delivery to the myocardium, an arrest and then an unfortunate occurrence with her IV infiltrating, I wonder how she would feel about really becoming a spokesperson for change in the transfusion world. That might be a whole lot more productive than just suing. I do believe she was owed something for pain and suffering etc. But, wouldn't it be nice to have such people get to the root cause of what happened and have them demand change to society.That is improvement in  patient safety. That is what medicine should be doing.

Just some thoughts. Thanks for your wonderful questions and insightful analysis.

Bruce Spiess, MD, FAHA

I was invited into this debate after ordering a 2 unit transfusion post emergency CS with blood loss around 1500ml. The patient had a preop Hb around 110 and showed evidence of volume depletion intraop. I was told about a "no transfusion overnight" policy next morning. She eventually got her second unit and her Hb on discharge was 82. I think senior clinicians should be able to judge accurately how much blood is likely to be needed to keep the Hb above 80 minimum post CS. I'd like to see more evidence of the immunomodulation phenomenon.

I'm dismayed by the increasing reports of blood approaching its use-by date and the increased morbidity. I've certainly had experience of this. Does this mean than shelf life should be shortened or storage procedures improved?

I've had quite a few transfusion problems in the last 20 years. Mostly in the one rural hospital. One patient needed a post  NVD hysterectomy because of intractable bleeding from a cervical tear (post cone biopsy). She had four units of almost expired blood before the anaesth would start. I noticed the T waves peaking as she was going from ICU to theatre. She arrested on the table with a K+ of 7.8. She then developed an anterior compartment syndrome in her right arm after probable extravasation of adrenaline and/or calcium. We saved her life but she got $700,000 for the 20% contracture in her arm after the decompression.

Another patient had bacteraemia/septicaemia from Yersinia enterocolitica post transfusion.
The one I remember best was the multi three who probably had a small amniotic fluid embolus in labour. I noticed the blood wasn't clotting as soon as I started the CS after a "funny turn" and fetal bradycardia. She spent 6 hours on the table and we were giving her fresh uncrossmatched Oneg still warm from the donors at the end of that time. She survived and did well.

I think obstetrics, being the one area outside acute trauma and AAA's where you can lose 10% of your blood volume a minute, needs special consideration in transfusion medicine. We depend on the blood but it needs to be fresh.

Phil Watters O&G

Dear Experts, I was at a transfusion conference in Melbourne and there was an excellent presentation on emerging risks in transfusion. The three that were discussed were immunomodulatory effects, CJD and now Dengue fever. My understanding from the conference was that there was no screening test for Dengue and that is was only prevented from entering the blood supply by excluding donors who were in Dengue prone areas. I further understand that as the Northern Territory is now a Dengue prone area that at certain times of the year when mosquitos are active there is no blood collection occuring.  This is a worrying new and emerging risk with the spread of Dengue to the whole of Australia being inevitable. Am I right to feel alarmed. I have down loaded and copied signs and symptoms and diagnosis of Dengue for those who are not familiar with the disease. I would suspect in a very sick patient if we infected them with Dengue it would be catastrohpic? I would welcome your opinions on this

http://en.wikipedia.org/wiki/Dengue

DENGUE Fever

Signs and symptoms

This is manifested by a sudden onset of severe headache, muscle and joint pains (myalgias and arthralgias—severe pain gives it the name break-bone fever or bonecrusher disease), fever, and rash.^[3] The dengue rash is characteristically bright red petechiae and usually appears first on the lower limbs and the chest; in some patients, it spreads to cover most of the body. There may also be gastritis with some combination of associated abdominal pain, nausea, vomiting, or diarrhea.

Some cases develop much milder symptoms which can be misdiagnosed as influenza or other viral infection when no rash is present. Thus travelers from tropical areas may pass on dengue in their home countries inadvertently, having not been properly diagnosed at the height of their illness. Patients with dengue can pass on the infection only through mosquitoes or blood products and only while they are still febrile.

The classic dengue fever lasts about six to seven days, with a smaller peak of fever at the trailing end of the disease (the so-called biphasic pattern). Clinically, the platelet count will drop until the patient's temperature is normal.

Cases of DHF also show higher fever, variable haemorrhagic phenomena, thrombocytopenia, and haemoconcentration. A small proportion of cases lead to dengue shock syndrome (DSS) which has a high mortality rate.

 Diagnosis

The diagnosis of dengue is usually made clinically. The classic picture is high fever with no localising source of infection, a petechial rash with thrombocytopenia and relative leukopenia.

The WHO definition of dengue haemorrhagic fever has been in use since 1975; all four criteria must be fulfilled:^[4]

1. Fever, bladder problem, constant headaches, severe dizziness and loss of appetite.
2. Hemorrhagic tendency (positive tourniquet test, spontaneous bruising, bleeding from mucosa, gingiva, injection sites, etc.; vomiting blood, or bloody diarrhea)
3. Thrombocytopenia (<100,000 platelets per mm³ or estimated as less than 3 platelets per high power field)
4. Evidence of plasma leakage (hematocrit more than 20% higher than expected, or drop in haematocrit of 20% or more from baseline following IV fluid, pleural effusion, ascites, hypoproteinemia)

Dengue shock syndrome is defined as dengue hemorrhagic fever plus:

• Weak rapid pulse,
• Narrow pulse pressure (less than 20 mm Hg)
• Cold, clammy skin and restlessness.

Serology and polymerase chain reaction (PCR) studies are available to confirm the diagnosis of dengue if clinically indicated.

Treatment

The mainstay of treatment is timely supportive therapy to tackle shock due to haemoconcentration and bleeding. Close monitoring of vital signs in critical period (between day 2 to day 7 of fever) is vital. Increased oral fluid intake is recommended to prevent dehydration. Supplementation with intravenous fluids may be necessary to prevent dehydration and significant concentration of the blood if the patient is unable to maintain oral intake. A platelet transfusion is indicated in rare cases if the platelet level drops significantly (below 20,000) or if there is significant bleeding. The presence of melena may indicate internal gastrointestinal bleeding requiring platelet and/or red blood cell transfusion.

Aspirin and non-steroidal anti-inflammatory drugs should be avoided as these drugs may worsen the bleeding tendency associated with some of these infections. Patients may receive paracetamol preparations to deal with these symptoms if dengue is suspected.^[5]

Emerging treatments

Emerging evidence suggests that mycophenolic acid and ribavirin inhibit dengue replication. Initial experiments showed a fivefold increase in defective viral RNA production by cells treated with each drug.^[6] In vivo studies, however, have not yet been done. Unlike HIV therapy, lack of adequate global interest and funding greatly hampers the development of treatment regime.

The entry by bruce speiss is right on the ball. The orthopaedic surgeons keep detailed information on joint replacement infections. What percentage of these patients received allogeneic transfusions compared to non transfused patients prior to diagnosis of infection. Does dose of blood influence the successful management of the joint infection?  The evidence suggests that it is around healthcare associated infection as well as joint infection.

Another interesting paper around this area that asks more questions than it answers. 

Healing After Hip Replacement Surgery: Effects on Duration of Hospitalization

I would add to the papers that James Ibister cited that you should look up the fine work by Neil Blumberg, MD. If you go to Google or to a medical search engine and type in his name a raft of great work will flow to you regarding transfusion and infection. I have no doubt that the effect is real. There are profound associations in cardiac, most recently pointed out by the group at Cleveland Clinic. They looked at over 15,000 patients and saw a dose dependent effect. Neil-Laval has also shown the same effect about 5 years ago in caridac. The effect in othropedics has also been widely reported and of note it is less with autologous blood than with allogeneic blood. But it is dramaticlly reduced with no blood transfusion at all. There is great work showing that if one takes the plasma from a unit of blood and exposes leukocytes in tissue culture they will cease to opsonize bacteria or plastic particles. Also the donors white cells get transplanted to the recipient. A recent paper looked at World Ward II veterans who are still surviving and were known to have been transfused (fresh whole blood, non whit ecell reduced) during the conflict. About 20% of them carried multiple peoples DNA and were therefore chymeras!! The implications of this are important! when transfused you recieve some level of donor white cells and we really do not know what they do. Data in non-white cell reduced blood shows that for at least 14 days, maybe a year and now from these WW II vets it may be permanent. that means your immune system now carries the cellular memory of more than one individual. Can rare genetic diseases be transmitted this way? Maybe. Is there a definite short term immunosuppresion-absolutely. A few blood bankers still refuse to believe this arguement. But then so did blood bankers refuse to believe that AIDS and hepatitis had anything to do with their product. The best thing to do is to think of every transfusion as a liquid transplantation!

Bruce Spiess, MD 

Below are a few references, most supporting the concern that allogeneic transfusion is an indepent risk factor post op infections and poorer outcomes.

Steinitz, D., E. J. Harvey, et al. (2001). "Is homologous blood transfusion a risk factor for infection after hip replacement?" Can J Surg 44(5): 355-8.

Murphy, P., J. M. Heal, et al. (1991). "Infection or suspected infection after hip replacement surgery with autologous or homologous blood transfusions." Transfusion 31(3): 212-7.

Vamvakas, E. C., S. B. Moore, et al. (1995). "Blood transfusion and septic complications after hip replacement surgery." Transfusion 35(2): 150-6.

Bierbaum, B. E., J. J. Callaghan, et al. (1999). "An analysis of blood management in patients having a total hip or knee arthroplasty." J Bone Joint Surg Am 81(1): 2-10.

In orthopaedic joint surgery is there evidence that blood transfusion is an independant predictor of infection, I understand that is the case in the cardiac surgery literature?