Possible Role of Artificial Oxygen Carriers in Shock and Trauma

Possible Role of Artificial Oxygen Carriers in Shock and Trauma

B. Thomas Kjellström

Summary. Trauma is the most common cause of death in young individuals in the industrialized world. One third of all trauma deaths take place within minutes to hours after injury. In this patient group, hemorrhage is a common cause of death. One important part of early treatment in trauma is i.v. admin- istration of crystalloid and/or colloid resuscitation fluids to prevent the development of hemorrhagic/hypovolemic shock. While such fluids can restore blood volume, they cannot transport oxygen to the tissues. Ensuing tissue ischemia leads to anaerobic metabolism and to accumulation of toxic metabolites. This can, in turn, develop into irreversible shock and death. It would thus be advantageous if resuscitation fluids given on the scene not only restored loss of blood volume, but also could carry oxygen and deliver it to the tissues. In hospital blood for transfusion is not always readily avail- able and typing and crossmatching can be time-consuming and costly. Con- sequently, in the hospital setting and during emergency surgery a resuscitation fluid that could deliver oxygen could be of value. Hemospan, a newly designed hemoglobin-based artificial oxygen carrier, has been tested in two different large animal hemorrhagic shock models. Normalization of hemodynamic as well as metabolic parameters was achieved without any signs of the detrimental vasoactivity seen with earlier hemoglobin-based products. Survival time also increased, even in comparison with autologous blood transfusions.

Key words. Artificial oxygen carriers, Shock, Trauma

Department of Defense Medicine, Retzius Väg 8, B1:5, FOI/Karolinska Institutet, SE-17177 Stockholm, Sweden

252

Introduction

In the industrialized world, trauma is the number one cause of death in age groups below 40–45 years of age [1,2]. Approximately half of all trauma deaths occur immediately after the accident; about 30% within a few hours after injury and the last 20% after days to weeks. In the first case, the cause of death is generally severe injuries to vital organs, e.g., the central nervous system, heart or major blood vessels. These patients die within minutes after trauma, and are most often not possible to save regardless of any therapeutic means.

In the second group, hemorrhage is one common cause of death, while late complications, such as infection or multiple organ failure (MOF), cause the death of patients in the third group [3].

The loss of years of life due to trauma amounts to 36 years on an individ- ual basis, which should be compared to the corresponding numbers relating to cancer, 15 years, and to cardiac disease, 12 years [4]. In the USA, about 21 ,000 individuals die annually due to trauma with a resulting annual loss of years of life of approximately 770,000 years. The resulting loss of productiv- ity has been estimated to $6 billion. The annual hospital costs for trauma care in USA are estimated to be $10–15 billion, costs for disability and unemploy- ment not included [5]. In Sweden, a country often considered to have a com- paratively low trauma incidence, 10% of the population has to see a doctor every year after accidents, and approximately 1.5% of the population annu- ally receives hospital care due to trauma [2].

Trauma care can be divided into three major phases: Phase I, the prehos- pital phase, which takes place on the scene of accident and/or during trans- port by ambulance or helicopter to the hospital. The transport time from scene to hospital can be quite variable, from minutes in a city to an hour or more in rural areas. Phase I trauma care will, depending on organization and circumstances, be delivered by paramedics, maybe under supervision of a registered nurse or a physician. Phase II, the hospital or in-hospital phase, by definition starts once the patient enters the hospital emergency room (ER) and is delivered by different members of the hospital staff. The IIIrd, or the late, phase is the rehabilitation phase, consisting of e.g. occupa- tional therapy and physiotherapy, and will not be further dealt with in this paper.

The objectives of Phase I trauma care are to secure respiration, to stop overt

hemorrhage and to counteract development of shock due to hypovolemia. In

this context, development of hypovolemia and hypovolemic shock almost

always is due to hemorrhage [3]. At a certain point, tissue perfusion in shock

becomes inadequate for the oxygen need at the cellular level. Cellular hypoxia

results in anaerobic metabolism, cellular acidosis, lactic acidosis, swelling of

the microvascular endothelium and circulating white cells, blocking of the

microcirculation and impaired organ function. Finally, if the patient survives the first hours to days, MOF may develop; a syndrome with a mortality of 50 %–80% [3,6].

To counteract hypovolemia, resuscitation fluids are administered intra- venously. Such fluids will restore circulating blood volume, but do not carry oxygen and will, consequently, not deliver any oxygen to the hypoxic cells even if the improved circulation per se may, at least transiently and to some extent, increase tissue oxygenation given an unimpaired respiration and micro- circulation [6].

Resuscitation Fluids

Two major categories of i.v. resuscitation fluids have been used over the last decades in the treatment of hemorrhagic/hypovolemic shock, crystalloid or colloid solutions. The former, examples of which are normal saline and Ringer’s lactate, are isotonic compared to blood, while the latter, dextran 70 and hydroxyethyl starch solutions (HES), are hypertonic [7].

In recent years, hypertonic-hyperoncotic resuscitation fluids have been advocated [8,9], registered for clinical use in some countries (for instance Rescue-Flow, Bio-Phausia, Uppsala, Sweden), but also questioned [10]. Crys- talloids freely cross the capillary membrane and equilibrate with the whole extracellular fluid space. Large volumes (up to 5 times the volume deficit) have to be infused, and the intravasal retention is limited. Tissue edema may form [7]. Hypertonic solutions are characterized by high concentrations of e.g.

crystalloids and one of their effects is a transient increase in plasma osmo- lality which, in turn, results in mobilization of intracellular fluid from the ede- matous endothelium and circulating white cells and thus increased blood volume [6]. By combining hypertonic solutions with solutions exerting high oncotic pressure, the increase in circulating volume will be preserved for several (4–8) hours [6].

What beneficial effects these different resuscitation fluids may have in restoring blood volume and supporting macro- and micro-circulation they cannot, however, fulfill one of the most important roles of blood itself, namely to deliver oxygen to tissues and cells.

Artificial Oxygen Carriers

There are, theoretically, three major advantages with artificial oxygen carriers

(AOC) when compared with bank blood [11]:

Artificial oxygen carriers can be sterilized, which blood cannot—no risk of spreading infections like HIV or hepatitis.

Artificial oxygen carriers do not have any blood group antigens—no need for typing and cross-matching.

Artificial oxygen carriers could be stored for a long time, maybe as a stable, lyophilized powder—a great logistic advantage.

Two completely different categories of artificial oxygen carriers, or “artificial blood” exist today, namely hemoglobin-based oxygen carriers (HBOC) and products based on perfluorocarbons (PF) [11]. The latter have the advantage of being chemically manufactured and can thus be produced in large quanti- ties, independently of biological sources. Perfluorocarbons are molecules similar to hydrocarbons, but with fluorine atoms instead of hydrogen atoms.

Perfluorocarbons are excellent carriers of oxygen and carbon dioxide, which are dissolved in the PF liquid and easily extracted by the tissue [12]. At any given partial pressure of oxygen in equilibrium with PF, hemoglobin (Hb), however, binds more oxygen than is dissolved in the PF emulsion. This is one reason why patients in clinical trials with PF often have to breath 70–100%

oxygen in order for the product to carry enough oxygen. Furthermore, com- plement activation, increased body temperature, decreasing platelet counts and prolonged bleeding time have been clinical problems with PF-based products undergoing clinical trials [12,13].

Hemoglobin-based oxygen carriers are based on Hb from different sources, such as outdated blood-bank blood or bovine blood but also human Hb pro- duced by recombinant technology in microorganisms [14]. Hb exists within the red blood cells (RBC) in tetrameric form, but outside the cells each tetramer breaks down into two dimers. These dimers are known to be nephro- toxic, to exert a high oncotic pressure, to induce vasoactivity and to release oxygen at a low p

[11,12,14]. These side effects have been known for decades and consequently much effort has been put down, trying to modify the Hb dimers to alleviate them [11,14]. Cross-linking of the Hb molecules prevent their break-down into dimers. Furthermore, the Hb molecule has been encap- sulated, and also coated (conjugated) with compounds such as dextran and polyethylene glycol (PEG) [14].

Presently, several different AOC products, both HBOC and PF, of the first

and second generation are undergoing clinical trials worldwide. Furthermore,

PF based products are today in clinical use in Russia [15], but hitherto only

one PF based product has been approved in the US for clinical use (in balloon

angioplasty) [13] and one HBOC, in South Africa, for use in patients under-

going surgical procedures [16].

AOC in Shock and Trauma

Phase I and II trauma care aim at the reduction of trauma mortality and mor- bidity by resuscitation from hypovolemia/hypotension and by rapid restora- tion of oxygen delivery to the tissues [17]. From this point of view, it is evident that an ideal resuscitation fluid would be one that could fulfill both these cri- teria, restore circulation and organ perfusion as well as deliver oxygen. Bank blood is, of course, such a fluid, but can hardly be administered during Phase I, and is sometimes not as readily as one could expect during Phase II either [11]. Furthermore, the threat of donor blood shortage may very well become a reality in a not too distant future even in the developed part of the world, just as it already is in other, not so fortunate, areas [11]. Consequently, a lot of work has been dedicated to developing AOC suitable for treatment of trau- matic hemorrhagic shock, and a large, randomized, multicenter study using a diaspirin cross-linked HBOC was conducted in 1997–1998. The study, unfor- tunately, had to be prematurely stopped, due to the fact that mortality was higher for the patients treated with this particular HBOC than for the controls receiving standard therapy. This untoward treatment effect was attributed to the vasopressor effect of the preparation [18,19].

In recent years, PEG-conjugated HBOC have been extensively tested in dif- ferent animal models of exchange transfusion or hemorrhagic shock [20,21].

A novel product, Hemospan (Sangart, San Diego, CA, USA) based on the fol- lowing design principles [22]:

High O

affinity

Viscosity close to the one of blood Hyperonconicity

High molecular volume : mass ratio

has been tested in two different large animal models of hemorrhagic shock [23–25]. Hemospan was demonstrated to lack most of the negative vasoac- tivity effects mentioned above. Furthermore, survival time in a double insult model was longer with Hemospan than with standard hemorrhagic shock treatment (colloids) and even with autotransfusion with the animals’ own shed blood [23]. A related product is currently in clinical Phase II trials in patients undergoing surgical procedures.

Conclusion

Trauma is the dominating cause of death in individuals below 40–45 years of

age in the industrialized world. Much of the mortality and morbidity in

trauma is due to hemorrhagic shock and the following hypoxia on the cellu-

lar level. Shock treatment on the scene of accident often consists of i.v. admin- istration of crystalloid and/or colloid resuscitation fluids. Such fluids can support circulating blood volume, but can not deliver oxygen to hypoxic tissues and cells. At the hospital level, bank blood can be given to treat hem- orrhagic shock. There is in many parts of the world a lack of donor blood.

Even in developed countries blood for transfusion is not always as readily available as one could imagine. Furthermore, there is always a certain risk of transmission of contagious diseases (hepatitis, HIV) inherent in blood trans- fusions. Consequently, there is a place for suitable AOC in treatment of hem- orrhagic shock in trauma, maybe both on scene and at the hospital. Even if there has been disappointment in the outcome of some previous clinical trials, promising novel products have been developed. Some of these are already in clinical trials. Furthermore, a limited number of AOC are approved for clinical use in a couple of countries today.

Conflict of Interest Statement. Dr. B. Thomas Kjellström is a member of the scientific advisory board of Sangart, Inc.

Acknowledgments. Financial support was received from The Swedish Defense Research Agency, Stockholm, Sweden (Grants E 5054 and E 46903) and from Sangart, Inc., San Diego, CA, USA.

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