Shock - Classification and Pathophysiological Principles of Therapeutics

Abstract

The management of patients with shock is extremely challenging because of the myriad of possible clinical presentations in cardiogenic shock, septic shock and hypovolemic shock and the limitations of contemporary therapeutic options. The treatment of shock includes the administration of endogenous catecholamines (epinephrine, norepinephrine, and dopamine) as well as various vasopressor agents that have shown efficacy in the treatment of the various types of shock. In addition to the endogenous catecholamines, dobutamine, isoproterenol, phenylephrine, and milrinone have served as the mainstays of shock therapy for several decades. Recently, experimental studies have suggested that newer agents such as vasopressin, selepressin, calcium-sensitizing agents like levosimendan, cardiac-specific myosin activators like omecamtiv mecarbil (OM), istaroxime, and natriuretic peptides like nesiritide can enhance shock therapy, especially when shock presents a more complex clinical picture than normal. However, their ability to improve clinical outcomes remains to be proven. It is the purpose of this review to describe the mechanism of action, dosage requirements, advantages and disadvantages, and specific indications and contraindications for the use of each of these catecholamines and vasopressors, as well as to elucidate the most important clinical trials that serve as the basis of contemporary shock therapy.

Keywords: Shock; cardiogenic shock; endogenous catecholamines; exogenous catecholamines; inotropes; septic shock; shock therapy; vasopressors..

Fig. (1)

Simplified scheme of cardiogenic shock.

Fig. (2)

Simplified scheme of septic shock.

Fig. (3)

Schematic of the postulated mechanism of intracellular actions of adrenergic agonists. Alpha-adrenoceptor agonists (α-agonists) bind to α-receptors on vascular smooth muscle and induce smooth contraction and vasoconstriction, thus mimicking the effects of sympathetic adrenergic nerve activation to the blood vessels. The α-adrenergic receptor, activates a different regulatory G protein (Gq), which acts through the IP₃ signal transduction pathway activates the release of calcium from the sarcoplasmic reticulum(SR) which by itself and through the calcium–calmodulin dependent protein kinases(CaMKII) influences cellular processes, which in vascular smooth muscle leads to vasoconstriction.

Fig. (4)

Simplified schematic of postulated intracellular actions of β-adrenergic agonist. β-Receptor stimulation, through a stimulatory Gs-GTP unit activates the adenyl cyclase system, which results in increased concentrations of cAMP. In cardiac myocytes, 1-receptor activation through increased cAMP concentration activates Ca2 channels, which leads to Ca2-mediated enhanced chronotropic responses and positive inotropy by increasing the contractility of the actin-myosin-troponin system. In vascular smooth muscle, Ca2 stimulation and increased cAMP results in stimulation of a cAMP-dependent protein kinase, phosphorylation of phospholamban, and augmented Ca2 uptake by the sarcoplasmic reticulum (SR), which leads to vasodilation.

Fig. (5)

Basic mechanism of action of PDIs. PDIs lead to increased intracellular concentration of cAMP, which increases contractility in the myocardium and leads to vasodilation in vascular smooth muscle.

Fig. (6)

Levosimendan (LEVO) binds to troponin C during systole, increasing the sensitivity of the myocardium to calcium which increases cardiac contractility during systole, but it does not affect diastolic function. Levo leads to an opening of the active sites of troponin C, increasing its sensitivity to calcium. Levo also has a cardioprotective effect because it opens the mitochondrial ATP-sensitive potassium channels in cardiac muscle.

Fig. (7)

The actin–myosin engine and omecamtiv mecarbil. Steps 1 and 2 indicate rapid binding of ATP to the myosin complex allowing the myosin to unbind from actin. Step 3 indicates that, ATP is hydrolyzed into ADP and inorganic phosphate (Pi). This energy allows the myosin head to stretch. Step 4 indicates that, the myosin-ADP-Pi complex bonds to actin in a weakly bound state as it scans for a proper binding site. Step 5 indicates that, once fully attached, the myosin-ADP-Pi strongly bonds to actin, and the release of Pi from the complex causes the myosin head to bend and the actin filament to move. Step 6 indicates that ADP is released and rapidly replaced by ATP, and the cycle is then ready to repeat. Omecamtiv mecarbil accelerates the transition from the weakly bound state to the strongly bound state. (reproduced be permission from Aronson D., et al.) [95].