Icatibant as an early rescue therapy in hypovolemic shock with converting enzyme inhibitor treatment

Activation of the renin-angiotensin system is a key adaptive response to hypovolemia aiming at maintaining mean arterial pressure, cardiac output, and organ perfusion. Angiotensin converting enzyme inhibitor (ACEI) therapy, widely prescribed to treat chronic hypertension, chronic heart disease, or diabetic nephropathy, blunts this adaptive mechanism [1]. These treatments may therefore put patients at risk of life-threatening complications after general anesthesia or hypovolemia [2, 3]. Because the pharmacological effects of ACEI therapy are partly mediated by bradykinin B2 receptor (B2R) activation, we hypothesized that acute B2R blockade would be beneficial in this setting. We previously showed that acute B2R blockade by icatibant, a specific B2R antagonist, significantly improves hemodynamics in a murine model of mild pressure and volume-targeted hemorrhagic shock under ACEI treatment (with 0.3 ml of blood withdrawn) [4]. In the present study, we tested the hypothesis that acute B2R blockade increases survival of ACEI-treated mice in severe hemorrhagic shock. To confirm this hypothesis, we induced severe volume-targeted hemorrhagic shock by 40% blood spoliation (i.e., 0.6 ml).

First, we confirmed our previous results regarding the beneficial effect of icatibant to prevent the deleterious hemodynamic consequences of ACEIs in shocked mice. In fact, the mean arterial blood pressures during shock in the ACEI group were significantly lower compared to the control and ACEI group treated with icatibant (25 [25–75% interquartile range (IQR), 21–29] mmHg vs 38 [25–75% IQR, 33–43] mmHg and 36 [25–75% IQR, 35–38] mmHg, respectively; p < 0.001). Second, we showed that survival in the control and ACEI groups treated with icatibant was significantly higher (81.8 and 90.9%, respectively) than in the ACEI group (36.4%) (p < 0.01). Of note, poor outcome was mostly observed in ACEI-treated mice while control untreated mice had good outcomes. Figure 1 describes the protocol design (Fig. 1a) and shows the survival curve from the beginning of shock to sacrifice (Fig. 1b). The life-saving benefit of B2R blockade was quickly achieved and sustained with a single subcutaneous injection of icatibant. This injection was given only prior to shock. None of the group received conventional vasopressors. However, efficacy of vasopressors has been challenged in this setting [1].

The results of this proof-of-concept study suggest that very early administration of icatibant may limit the consequences of hemorrhagic shock in patients treated with ACEIs before resuscitation could be initiated. Further research is needed with respect to dose and timing of icatibant administration and comparison with conventional vasopressors.