Diaspirin cross-linked haemoglobin

Journals Reviewed: Anesthesiology March 2000
Abstracted by: Dr S Robertson; MB ChB (Registrar, University of the Witwatersrand)

Summary of abstracts

Enthusiasm has recently been re-kindled for haemoglobin substitutes, especially with the prominence of HIV-associated illness and other blood-borne diseases. Here we look at just one recent study of considerable importance, and briefly review the topic. (The WorldWide Anaesthetist also contains a recent review of blood substitutes. You may wish to briefly browse our editorial comment ).

Haemoglobin solutions

BACKGROUND

Haemoglobin Based Oxygen Carrying (HBOC) systems represent attempts to deliver Oxygen with something other than blood. Interest started in the mid-1900s. Research grew until 1978 when studies showed severe toxicity and the idea was all but abandoned. With the recent resurgence of interest, several studies are now in phase III clinical trials and other case studies show promising results.

PHARMACOLOGY

There are several sources for Haemoglobin.

  • Haemoglobin salvaged from expired blood
  • Recombinant haemoglobin manufactured
  • Bovine haemoglobin

Outside the erythrocyte the Haemoglobin molecule tends to dissociate into dimers. There are several problems with this…

  1. Dimers lack 2,3DPG (which rapidly dissociates from the Haemoglobin) leading to a very high affinity for oxygen.
  2. Dimers are small molecules (approx 32 Daltons) which are readily filtered at the Glomerulus
  3. Dimers have a very short half-life.
  4. Because the Dimers are present in such a great number, they exert a significant colloid osmotic pressure. Dimers can be cross-linked by several mechanisms. In the reviewed study the cross-linking was achieved with bis (3,5-dibromosalicyl) fumarate. This cross-linking solves (at least partially) the above problems

These tetramers have several other pharmacodynamic properties. Below is a list of Pros and Cons in the usage of HBOCs. Omitted are all of the benefits related to improved tissue oxygenation.

PROS

  1. Rapidly available with no need for typing, cross-matching and screening;
  2. Very low infection risk;
  3. Prolonged storage;
  4. Able to replenish iron stores;
  5. Avoids immune and cytotoxic complications of blood transfusion.

CONS

  1. Raised systemic and pulmonary vascular resistance. Causes an increased Mean Arterial Pressure and Pulmonary Arterial Pressure. Related to NO scavenging by the Haemoglobin molecules and to a direct Adrenergic mechanism. Appears to be dose-dependant to a threshold whereafter the effect increases no further (for rHb 1.1 and DCLHb);
  2. Short half-life.

POSSIBLE USES IN CLINICAL MEDICINE

  1. Acute Haemorrhage and Trauma – Rapidly available. Favourable rheology. May also decrease cGMP formation which causes resistance to other pressors
  2. Septic and Cardiogenic shock
  3. Acute myocardial infarction and Stroke
  4. Sickle cell disease
  5. Cardio-pulmonary bypass
  6. Refusal of blood products

A Randomised trial of Diaspirin Cross-linked Hemoglobin

A large study of 209 patients selected from 1956 patients who met the inclusion criteria for blood transfusion in the 24 hour period following cardio-pulmonary bypass. Patients were randomised into two groups after the decision to transfuse had already been made. Group one (104 patients) received 250ml DCLHb solution, and if necessary a further 500ml within the next 24 hours (DCLHb treatment could not be continued for longer than 24 hours) Group two (103 patients) received one unit of PRBCs, and if necessary a further two units of PRBCs

End points were avoidance or a significant decrease in blood usage in the 7 days following cardio- pulmonary bypass.

Results

19% of DCLHb patients needed no blood transfusion. No significant difference in the total number of units of PRBCs transfused to both groups. But the DCLHb group received significantly fewer units on days one and two. Mortality was the same in both groups. More adverse events occurred in the DCLHb than in the PRBC group; these included

  • Hypertension
  • Jaundice
  • Raised liver and pancreatic enzymes
  • Haemoglobinuria

DCLHb was discontinued in seven patients for uncontrolled hypertension (2), myocardial infarction (2), ECG changes, haemorrhage and haematuria. It is not stated if any of these complications occurred in the control group. GIT function was not affected. Reticulocyte counts were higher in th DCLHb group Haemodynamic profiles show increased SVR, MAP, PAP and decreased CO, HR in the DCLHb group. These changes became significant at the time of the third transfusion. Plasma DCLHb concentrations fell to less than half of peak value within 24 hours

Discussion

Only one of the end-points was achieved. Transfusion was delayed but not avoided and this, together with the high incidence of adverse events is the reason that DCLHb treatment cannot be supported in this group of patients. DCLHb is apparently no longer being developed.

Article 1: Randomised trial of Diaspirin Cross-linked Hemoglobin Solution as an alternative to Blood transfusion after Cardiac Surgery
Anesthesiology 2000 92 646-56
Article type: Randomised clinical trial
Author: Lamy ML et al.


Editorial pointers

Although the concept of replacing human blood with artificially 'tweaked' haemoglobin (Hb) molecules is enticing, realisation of this dream seems far away. Initial problems with acellular Hb-based blood substitutes were centred around the greedy fashion in which such molecules bound oxygen, more-or-less solved by engineering molecules with lower affinity, for example rHb 1.1, with a mutation in position 108 of the beta chain, or by creating unusal haemoglobin polymers, for example by cross linking the molecules with diaspirin links. Unfortunately, such elegant solutions (!) only partially address the problems posed by infusing haemoglobin. For example, recently glancing through PubMed, we find that:

  • Haemoglobin scavenges nitric oxide, participates in free-radical reactions, activates the immune system, and is potentially neurotoxic. See:

    Alternative oxygen carriers
    Curr Opin Hematol 1996 Nov;3 (6):492-7
    Hess JR

  • Liposome encapsulated haemoglobin (another smart approach) activates complement.

    Complement-mediated acute effects of liposome-encapsulated hemoglobin
    Artif Cells Blood Substit Immobil Biotechnol 1999 Jan;27 (1):23-41
    Szebeni J, Alving CR

  • And of course, there is the above discouraging article.

Where do we go from here? The short answer appears to be "not far, with diaspirin cross-linked haemoglobin", especially after the results of the study reported in JAMA 1999:

Diaspirin cross-linked hemoglobin (DCLHb) in the treatment of severe traumatic hemorrhagic shock: a randomized controlled efficacy trial.
JAMA 1999 Nov 17;282 (19):1857-64
Sloan EP, et al.

This study showed increased mortality and morbidity in patients with severe haemorrhage managed with DCLHb compared with those given saline (eugh) as a resuscitative solution. Such studies temper the initial enthusiasm generated by a host of pre-clinical studies.

It will probably be some time before any form of haemoglobin solution takes its place on the shelves of the emergency room.

Ed      

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Date of First Publication : 2000-07-29 Date of Last Update : 2006/10/23 Web page author: Click here