This report describes the first steps to investigate the uptake, safety, and influence of AF for suppression of elevated ICP in patients with severe TBI. The parameters for optimal administration/uptake of Salovum® were established within the scope of a pilot study demonstrating an association between an increase of AF levels in blood after rectal administration of Salovum®, with a simultaneous reduction in ICP. In conformity with previous clinical studies investigating the antisecretory and anti-inflammatory actions of AF under various pathological conditions, no systemic side effects that could be attributed to Salovum® treatment were observed in any of the included patients [
10,
20,
27,
28]. The outcomes suggest that AF as an add-on therapy may, directly or indirectly, have some suppressive influence on edema-induced, intracranial hypertension.
Salovum® is enriched with AF peptides, among them AF-16 [
16], which in experimental animal models of focal brain injury has been demonstrated to exert a significant, suppressive effect on cerebral edema with pathologically elevated ICP, and to improve cognitive function [
1,
6,
11]. AF-16 can bypass the blood-brain barrier after iv and intranasal administration and is detected both in cerebral tissue and CSF [
1,
17]. In clinical settings, Salovum® has only been utilized orally in awake patients for treatment of various inflammatory conditions [
10,
27,
28]. The uptake of AF for achieving a clinical response after oral administration is dependent on a functioning gastrointestinal passage [
20]. In the first two patients in which Salovum® was delivered repeatedly via a nasogastric tube, there was an increased gastric retention of the solution due to gastrointestinal dysmotility which often is present in mechanically ventilated, critically ill patients, especially those with intracranial hypertension receiving opioids for analgesia and sedation [
13,
18]. This observation is in line with the recent findings by Cederberg et al. investigating the effects of AF in patients with severe TBI after nasogastric administration of Salovum® [
4]. The retention was stressful to the patients, and no obvious ICP reduction was observed (cf. Table
1). Therefore, in the second patient, we also tested to administer the solution rectally which gave a transient reduction of the elevated ICP (cf. Table
1). The ELISA analysis in the second and third patients showed that blood levels of AF-16 were increased after rectal but not after nasogastric Salovum® administration. Accordingly, the initial strategy for delivery of Salovum® was changed from a nasogastric to a rectal approach with a subsequent increase in plasma concentration of AF-16 which correlated with a statistically significant reduction in ICP. The strategy for rectal delivery was extended from 2 to 3 days in the fourth patient where blood levels of both AF-16 and AF compleasome were significantly increased after rectal Salovum® administration. Merged data from patients 2, 3, and 4 consolidated the statistically significant increase in blood levels of AF-16 after rectal Salovum® administration (
p = 0.02,
n = 14 paired samples).
The small number of included patients is a limitation of the present pilot study. The main purpose of the study was, however, met in that we could identify the optimal means for delivery of Salovum® in order to reduce pathologically elevated ICP in critically ill patients with severe TBI. This has not been investigated previously. Even though the observed reduction in ICP may in part be a consequence of the natural course of the TBI pathophysiology with gradual decrease of edema with time, or could reflect the accumulated effect of other NICU treatments, including thiopental, the influence of AF seems to be of importance based on (i) the correlation between the increase of AF levels in blood with an accompanying reduction in ICP; (ii) the rapid, substantial reduction of ICP to levels < 20 mm Hg within hours after start of rectal Salovum® administration which was observed in the two last patients who both presented with prominent cerebral edema; (iii) the demonstrated, statistically significant difference in mean ICP calculated from hourly registrations before and during the period of rectal administration of Salovum®, irrespective of whether or not the patients were under treatment with thiopental; (iv) the maintenance of ICP reduction at values < 20 mm Hg during most of the course of rectal Salovum® treatment. In addition, the outcomes in patient 2 suggested that AF has no effect on elevated ICP due to hydrocephalus. This observation is in line with previous findings on lack of efficacy in patients with idiopathic normal pressure hydrocephalus [
9]. Thus, AF mainly seems to exert its effects on elevated ICP based on the occurrence of cerebral edema.
The molecular and cellular pathways that contribute to the development of posttraumatic brain edema are multifactorial and need to be more precisely defined in order to bring forth adequate therapies for targeting the edema [
5,
8,
15,
24,
26]. Use of AF may offer a new means to further investigate and affect these events clinically without experiencing the negative side effects seen in treatment with barbiturates. Synthetic AF peptides, which can be administered iv for optimal uptake in a clinical setting, will be available in a near future. This will enable better characterization of AF kinetics with possibility to design randomized trials to further exploit potential AF effects on various types of brain edema.