Clinical Needs for Artificial Oxygen Carriers in Anaesthesia
Robert G. Hahn
Summary. Transfusion of blood is associated with high costs in the anaes- thesia department. Immunological testing and/or cross-matching is routinely done before many operations entailing only a small risk of major haemor- rhage. The introduction of artificial oxygen substitutes would save not only the cost of the erythrocytes but also of the extensive blood testing. In opera- tions with an expected large blood loss, competition with donated blood will probably be focused largely on the potential prevention of adverse effects and infection. In the intensive care unit, a beneficial influence on blood rheology is more important than during surgery, and it must be possible to evaluate oxygen delivery after administration of the artificial oxygen substitute. For trauma outside hospital, artificial oxygen substitutes compete with fluid resuscitation as donated blood is rarely an option. Surprisingly, it is currently unclear where and when fluid resuscitation should be provided in the pre- hospital setting. Long transport times and head trauma are currently the most apparent indications. Artificial oxygen substitutes should be available at short notice, i.e., not requiring thawing, in order to be successful products. Here, volume expansion is a desired property along with improvement in oxygen- carrying capacity.
Key words. Artificial oxygen carriers, Hemodilution, Fluid resuscitation, Prehospital care, Red blood cells, Transurethral resection of the prostate
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Department of Anesthesiology, Söder Hospital, S-118 83 Stockholm, Sweden
Introduction
Anaesthesia is a medical speciality in which there is much interest in the development of artificial oxygen carriers. Anaesthetists will certainly be important purchasers of these products regardless of which ones will even- tually appear on the market. The anaesthetist works in four areas, and the focus might be slightly different depending on the country studied. They are:
(1) in the operating theatre, (2) the intensive care unit, (3) on the prehospital scene, and (4) in the pain clinic. The following presentation is focused on explaining the prerequisites for marketing artificial oxygen carriers in the first three of these areas.
Small Risk of Surgical Bleeding
Many surgical operations that are performed today carry only a moderate risk of blood loss requiring transfusion of erythrocytes. In such cases, the cost of the erythrocytes that are eventually given is exceedingly high. The rationale for this view is that all patients at risk need to undergo blood grouping fol- lowed by immunological testing and sometimes cross-matching of each trans- fused bag of erythrocytes (if irregular antibodies are present). The cost of this procedure is substantial, for both analyses and blood sampling, as well as for the involved logistics.
Transurethral resection of the prostate (TURP) can be used as an example.
This operation is still one of the most common operations in the Western world. In a series of 1,034 patients operated on at Söder Hospital, the median blood loss was only 300 ml. However, the bled volume exceeded 1 litre, which is often treated with erythrocytes in elderly males, in 14% of the patients [1]
(Fig. 1). The risk of a blood loss requiring erythrocyte transfusion makes it necessary for the hospital to test all TURP patients as if they were to receive blood. This practice is logical since one never knows who is going to bleed.
However, nearly all of this testing is meaningless as only a few actually benefit from the result. Operations which carry a risk of only 1% for requiring ery- throcytes would not normally require preoperative testing, but operations with a 10% risk do.
An artificial oxygen carrier would be very cost-effective in TURP patients
with excessive bleeding as not only the costs for the transfused erythrocytes
can be saved but also for the blood testing of the vast majority of patients
who do not require erythrocytes.
Expected Major Bleeding
Patients who undergo major surgery are routinely subjected to normo- volaemic haemodilution. This means that the blood loss is treated with infu- sions of salt solutions to maintain the blood volume. Such infusions dilute the blood Hb concentration, and the artificial oxygen carrier then only needs to treat the reduced Hb level without the influence of hypovolaemia. The body has sophisticated compensatory mechanisms to deal with an acute lowering of Hb, the most important one being an increase in stroke volume to main- tain oxygen delivery. Another mechanism consists in an increase in the peripheral extraction of oxygen. At a certain point, however, the compensa- tory mechanisms simply are not sufficient for the body’s needs of oxygen, which limit is called the “anaerobic threshold”. If Hb is further reduced, the delivery of oxygen to the tissues becomes too small, lactate production increases and the patient becomes acidotic.
Fig. 1. The blood loss in 1,034 transurethral prostatic resections. Although the median blood loss is only 300 ml, it exceeded 1,000 ml in 14% of the patients. The existence of transfusion-requiring operations necessitates blood group and immunological testing/
cross-matching in all patients. The use of artificial oxygen carriers saves not only the cost
of the transfused erythrocytes in the small group with extensive haemorrhage, but also
the extensive blood testing in the entire group
Many efforts have been made to find the Hb level that signifies the anaer- obic threshold. This Hb level is called the “transfusion trigger”. Ethical diffi- culties in performing experimental research to find the transfusion trigger on humans are apparent. The truth is that each individual has a different capac- ity to deal with a low Hb. In old age, the cardiac capacity is reduced and this limits the ability to increase the stroke volume. The heart itself might also be susceptible to ischaemia. Young healthy people tolerate a low Hb, even down to 50–55 g/l, much better [2].
The consensus in this field is that the transfusion trigger should range between 60 and 100 g/l (6–10 g/dl) and what the trigger should be in individ- ual patients must be determined by sound clinical judgement [3]. If a lower Hb level is reached, the patient should be transfused with erythrocytes.
A concept in normovolaemic haemodilution is the “allowable blood loss”.
This represents the volume of blood that can be lost before the transfusion trigger is reached. If the Hb concentration is the same in all blood that is lost, the allowable blood loss and the fall in Hb from before surgery to the trans- fusion trigger would be directly proportional. This is not the case, however, because the blood volume is constantly kept normal by infusions of salt solu- tion. The last portion of the bled volume during a haemodilution process will therefore reduce Hb at a slower rate than the first portion. The following log- arithmic equation by Bourke and Smith [4], which is widely used to estimate how large a bleed can be allowed, is based on the estimated blood volume at baseline (BV
o), the Hb level before the operation (Hb
o) and the transfusion trigger (Hb(t)) which is reached at time (t):
This equation assumes that the Hb level is always lowered in direct propor- tion to the blood loss. Erroneous estimations will ensue if the haemodilution does not catch up with the bleeding at all times. This is a very common mistake.
An alternative to the use of the haemodilution equation of Bourke and Smith [4] is to measure Hb in the operating theatre (remember that what we only want to find out is whether the “target” Hb has been reached). Today, good equipment is available at low cost.
One may also compare the results of the haemodilution equation with the loss of Hb molecules in order to estimate how much the blood volume has changed, if at all. Such calculations are based on simple mathematical rela- tionships between blood volume, the amount of Hb lost and the Hb level.
Here, we must involve the Hb mass in the body, which is slightly less than 1 kg [5]:
HB mass
o= BV
o* Hb
oAllowable blood loss = BV
o[ ln Hb
o- ln Hb ( ) t ]
Thus, alterations in blood volume can be estimated from the Hb level in whole blood provided that the loss of Hb through bleeding is known. Such simple equations, which, in contrast to the equation of Bourke and Smith [4], are insensitive to how well the fluid therapy has been managed, can be used to examine whether the haemodilution has indeed been performed in a nor- movolaemic patient [6]. Since hypovolaemia is a serious condition in that it reduces the cardiac output, a low blood volume is certainly a confounder in many (perhaps most) studies attempting to define the transfusion trigger.
Therefore, ideally, studies that draw conclusions about the consequences of haemodilution during surgery should check that the blood volume is normal at the end of the experiments.
The well-controlled environment in which normovolaemic haemodilution is performed puts a slightly different emphasis on the need for artificial oxygen carriers. Here, the arguments for such products are to be found in the profile of adverse effects. Erythrocytes carry a risk of viral infection, and bank blood might impair the microcirculation. Immunomodulation (TRIM) is a known consequence, even to the extent that organ dysfunction (TRALI) may develop. Septic reactions may occur, although such problems are more common when platelets are transfused.
Verification that artificial oxygen carriers entail smaller risks of adverse effects would open up this market. The products will sometimes be used when very large transfusions are required simply because the hospital has run out of blood. However, public opinion is likely to be crucial. If the patients prefer artificial oxygen carriers, the hospitals may have to use them even if they are more expensive than coventional donated blood.
Various erythrocyte-saving techniques are used in the clinic today, but they cannot replace the transfusion of erythrocytes. Predonation of autologous blood which is given back to the patient during the operation emerged during the 1990s, but its use is limited in most countries because of the high cost. In some hospitals, predonation remains a service for the interested. Autotrans- fusion of blood from wounds can indeed be useful during extensive surgery.
The lost blood is suctioned into an apparatus (such as the Cell Saver) where it is anticoagulated, washed, filtrated and retransfused directly in the operat- ing theatre. One problem is the high cost of this technique as well. Just the sterile tubes needed for each operation may cost as much $1,000. Blood that is retransfused without being washed presents the problem of being
“activated”, i.e., it contains high concentrations of cytokines and other sub- stances that may affect the patient [7]. There are also groups of patients, such as cancer patients, in whom retransfusion is unsuitable. These blood-saving BV Hb mass loss of Hb mass
Hb
o t
t t
( ) = -
( )
(-0)
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