Statement for FDA Advisory Panel 7-21-05

Eileen M. Bulger, MD FACS

Co-PI Trauma, Resuscitation Outcomes Consortium

 

 

I am here today on behalf of the Resuscitation Outcomes consortium which is an NIH funded clinical trials network composed of 10 clinical centers in the US and Canada. The mission of this consortium is to conduct clinical trials in cardiac arrest and life threatening trauma. We currently have an IND application under review by CBER to conduct a trial of hypertonic resuscitation following traumatic injury to include patients with hypovolemic shock and severe traumatic brain injury. One arm of this trial will use a 7.5% saline/6% dextran 70 solution, marked by Biophaisia Inc as RescueflowÒ, as the initial resuscitation fluid administered by the prehospital providers. As the discussions here today have implications regarding the need for PromitÒ administration prior to the study fluid in this trial we would like to comment specifically on the risk of anaphylaxis to HSD in trauma patients.

 

We recognize, that the anaphylactoid reactions reported with dextran solutions are associated with dextran-reactive antibodies (DRA), which are believed to be present in most humans in low titers. It is reported that the most serious dextran-induced anaphylactoid reactions (DIAR) are observed in patients with high DRA titers (Berg et al 1991). Generally, only small volumes of dextran need to be infused to elicit a reaction and DIAR usually occurs in the first few minutes after infusion begins (Svensen 2002).

 

Historically, significant allergic reactions have been associated with dextrans of molecular weights >100,000 or those with a greater degree of branching than current clinical dextrans (Kabat and Bezer 1958; Bailey et al 1967; Hedin et al 1976). In general, observations of severe anaphylactic reactions to clinical dextrans with average molecular weights of 75,000 or less are considered rare (Brisman et al 1968), with incidences in the range of 0.013% to 0.024% (Ljungstrom et al 1983).  In comparison to other colloids, the incidence of anaphylactoid reactions related to dextran are about twice the rate for albumin, whereas the incidence of these reactions due to hydroxyethyl starch or gelatin is 2-fold and 6-fold higher, respectively, than for dextran (Barron et al 2004).

 

Based on the proposed mechanism associated with the DIAR, Promit (Dextran 1, MW 1000) was introduced to reduce the incidence of severe reactions. As discussed today, a 10 year study in Sweden reported a 35-fold reduction in the incidence of severe DIAR and a 90-fold reduction in DIAR associated deaths (Hedin and Ljungstrom 1997). Promit had no effect on mild DIAR and was associated with side effects, itself, including bradycardia and arterial hypotension. Nevertheless, use of Promit prior to infusion of Dextran solutions in patients of any type, is considered to make dextran one of the safest colloids to use (Hedin and Ljungstrom 1997).

 

The question has been raised as to whether Promit should be required prior to infusion of HSD in trauma patients. To date with over 900 trauma patients enrolled in clinical trials receiving HSD, no incidences of DIAR have been reported (summarized by Svensen 2002). RescueflowÒ is currently approved in 14 European countries for “use as the initial treatment of hypovolemia with hypotension following traumatic injury”. With >20,000 patients receiving Rescueflow in clinical use, there have been no reports of DIAR (data from Biophausia, Inc, 2005). Laubenthal et al (1987) reported that use of Promit 1 was unnecessary in trauma patients. These authors suggested that the rapid infusion of dextran solutions in trauma patients results in an excess of antigen in the blood and therefore prevents the formation of immune complexes. It has also been suggested that elevated catecholamine levels in trauma patients may be protective for development of DIAR (Maningas et al 1989; Svensen 2002). Whatever the mechanism, it is current medical opinion that trauma patients seem to be protected from development of severe DIAR. It should be noted that the Swedish Physician’s Desk Reference makes no recommendation for using Promit in trauma patients (Svensen 2002).

 

If we can learn from the clinical experience with the use of hypertonic hetastarch (HHS) in Austria, it was observed that 3 of 4 adverse events were attributed to anaphylactoid reactions with an estimate of 18,500-37,000 patients treated with 1-3 units. Patients were treated for hypovolemia in either the ICU or pre-hospital, but the number of actual trauma patients was not listed (Schimetta et al 2002) and it is not stated if the adverse events were in trauma patients, though 2 were over 70. As a worse case scenario we could assume that these patients were trauma victims. The above data would translate to 5-6 anaphylactoid events per 100,000 units of HHS used or 8-16 per 100,000 patients. Since the incidence of such reactions with dextran is half that of hetastarch, then we are looking at an incidence rate of 0.004-0.008% for trauma patients.  It should be noted that hydroxyethyl starch containing products such as Hextend and Hespan have been advocated for treating hypovolemia despite the known risk for anaphylactoid reactions that is greater than that for dextran. Hextend is currently being used by the US military in the Iraq conflict.

 

In summary, we believe that the risk of a severe anaphylactic reaction to HSD in trauma patients is exceedingly small and thus does not warrant pre-medication with Promit in this clinical trial.  One of the reported side effects of Promit administration is arterial hypotension, which has the potential to exacerbate poor tissue perfusion in this patient population. Preclinical studies support the notion that hypertonic solutions will be most effective if administered as the first resuscitation fluid given to a patient in hypovolemic shock, Thus, our proposed clinical trial is based on administration of these fluids by the prehospital care providers. Adding an additional step to pre-medicate these patients could compromise patient care by delaying the paramedic from other critical tasks. In addition, the future use of these fluids, if the trial demonstrates benefit, will likely remain in the prehospital or battlefield environment where pre-medication may not be practical.

 

References

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