Vasoplegia Treatments: The Past, the Present, and the Future

Bruno Levy; Caroline Fritz; Elsa Tahon; Audrey Jacquot; Thomas Auchet; Antoine Kimmoun

Disclosures

Crit Care. 2018;22(52) 

In This Article

Modulation of the Sympathetic System

α2 Agonists

During a shock state, the inappropriate activation of the sympathetic system is associated with receptor desensitization.[65] One innovative approach may be to reduce sympathetic activity. α2 Agonists such as clonidine or dexmedetomidine (200 times more powerful than clonidine) act directly in the locus cœruleus. By binding to presynaptic α2 adrenergic receptors, these agonists also induce a negative feedback on norepinephrine secretion. Known pharmacological effects of this central down-regulation are hypotension, bradycardia, and sedation.[66] However, recent experimental studies in small and large animals have found that administration of α2 agonists, by reducing central sympathetic activity, also restores the response to vasoconstrictors such as α1 agonists or angiotensin II.[67,68] One appealing hypothesis is that the reduction in sympathetic outflow allows a lesser desensitization of peripheral adrenergic receptors as well as a reduction in pro-inflammatory cytokine secretion. Direct vasoconstrictor effects of α2 agonists should also be taken into account.

Selective β1 Blockade

β1 Blockade seemingly restores vascular responsiveness to vasopressors. In 2013, Morelli et al.[69] demonstrated that esmolol, a selective β1 blocker, administered in hemodynamically stabilized septic shock patients, efficiently reduced heart rate without apparent side effects. Of greater interest, the authors observed a decrease in the dose of norepinephrine infused in the esmolol group compared to the placebo group. There are two prevailing hypotheses to explain this unexpected result on norepinephrine dose. First, in 2016, Morelli et al.[70] found that, in septic shock patients under esmolol, the decrease in heart rate was associated with improved arterial elastance, thus restoring ventricular–arterial coupling. Second, our team recently found that in experimental septic shock, esmolol infusion in rats, even at low doses that did not induce a reduction in heart rate, was associated with a better ex vivo vasoreactivity compared to non-treated animals. These beneficial effects appear to be associated with a downregulation of inflammatory pathways in vessels such as NF-κB.[71]

Perspectives in adrenergic modulation could include both central reduction of sympathetic outflow by α2 agonists and peripheral downregulation of β1 adrenergic receptors by selective β1 blocker. Accordingly, Hernandez et al.[72] recently published an experimental study in which they compared the effects of dexmedetomidine and esmolol relative to lipopolysaccharide-control animals on exogenous lactate clearance in a sheep model of early endotoxic shock. The authors found that these two molecules were hemodynamically well tolerated and were associated with better exogenous lactate clearance. Correct dosages and hemodynamic tolerances of the combination of these two molecules nonetheless remain to be explored.

Glucocorticoids

Many experimental studies have demonstrated that administration of glucocorticoids restores vascular responsiveness to vasopressors, likely through a non-genomic inhibition of the arachidonic acid cascade and a genomic inhibition of the nuclear translocation of the NF-κB transcription factor.[73] Moreover, glucocorticoids also inhibit the synthesis of iNOS and COX2.[74,75] Finally, low doses of glucocorticoids appear to restore vascular responsiveness to norepinephrine through an increase in α adrenergic receptor gene expression.[76] A clinical trial demonstrated that administration of low doses of hydrocortisone in septic shock patients tended to normalize the vascular responsiveness to phenylephrine.[73] However, results of a large clinical trial assessing the efficiency of low doses of hydrocortisone on mortality in septic shock patients yielded conflicting findings. Consequently, the SSC recommends against treating septic shock with low intravenous doses of hydrocortisone if hemodynamic fluids and catecholamines are able to restore stability. However, in the case of refractory septic shock, low doses of hydrocortisone (200 mg per day) may be administered.[20] Preliminary results of the APROCCHSS study (NCT00625209; involving hydrocortisone and fludrocortisone) revealed a beneficial effect on 90-day mortality and shock reversal.

Vasopressor Combinations

Depending on the efficacy/risk ratio, optimal vasopressor therapy could thus consist of a combination of agents acting on different receptors while minimizing doses of each agent and therefore possibly increasing overall safety. This paradigm was indirectly tested in both the VAAST and ATHOS-3 studies,[34,53] in which norepinephrine doses were decreased when adding vasopressin or angiotensin II. The combination allowed a decrease in total norepinephrine dose. Unfortunately, this decrease in dosage was not associated with a decrease in adverse events.

Adrenomedullin Blocking

Adrenomedullin is considered as a double-edge sword in septic shock. On the one hand, adrenomedullin supplementation improves endothelial barrier function, attenuates systemic inflammation, and reverses hypodynamic circulation and pulmonary hypertension in ovine endotoxemia. On the other hand, high levels of adrenomedullin are associated with short-term mortality and vasopressor requirement in both septic and cardiogenic shock.[77,78] Finally, adrenomedullin binding has been found to blunt shock-related impairment in energy metabolism as well as to reduce nitrosative stress and attenuate systemic inflammatory response, all of which were ultimately associated with reduced kidney dysfunction and organ injury.[79] One ongoing study (NCT03085758) is currently comparing two doses of ADRECIZUMAB (a humanized murine monoclonal IgG1 antibody specifically binding the N-terminal region of human adrenomedullin) in patients with early septic shock and a high bio-adrenomedullin plasma concentration.

A Role for Genomics and Pharmacogenomics?

Pharmacogenomics could be applied to enhance efficacy and safety of drugs used for sepsis and septic shock, including norepinephrine, epinephrine, vasopressin, and corticosteroids, since known genomic variants intersect with these drugs. For example, Nakada et al.[80] demonstrated that β2 adrenergic receptor gene polymorphism was associated with altered responses to adrenergic agonists and mortality in septic shock. Nevertheless, the variant was only present in 5 to 7 % of the population, thereby rendering the elaboration of a specific test hazardous and likely very expensive.

processing....