Noradrenaline (NE) is released from the postganglionic sympathetic nerve fibers and produced directly by the adrenal medulla, stimulating the endothelial alpha receptors of the arterioles and, via a series of mechanisms, promoting the introduction of calcium into the smooth muscle cells of vessels and the passage of calcium into the sarcoplasmic reticulum of the cytosol. The result is that calmodulin (a cytoplasmic protein) binds to four calcium molecules and activates the process of connection between actin and myosin and thus contraction of the smooth muscle fibers of vessels.

The vasoconstrictor effect of NE is therefore not direct but the result of a series of processes triggered by the increase in calcium in the cytosol and culminating in activation of the actin-myosin complex.

At the end of contraction, the expulsion of calcium from smooth muscle cells in the vessels and/or the binding of calcium to the sarcoplasmic reticulum are at the basis of the release process. Sepsis is characterized by specific resistance to NE, and hyperproduction of nitric oxide (NO) is considered the most important cause of this resistance and of the vasodilation that occurs thanks to the production of cyclic GMP. But the increased production of prostacyclin, peroxynitrite, and superoxide anion and the excessive activation of ATP-dependent potassium channels are also clearly relevant in determining the reduced sensitivity of NE and vasodilation. For the above reasons, septic patients require much higher doses of NE than those which are usually capable of causing vasoconstriction in normal subjects. It is therefore not surprising that doses of more than 4 μg/kg/min of NE have been used to obtain mean arterial pressure (MAP) levels that are acceptable in septic shock. Since NO is considered the most important cause of vasodilation and reduced sensitivity to amines in patients with septic shock and since NO is produced from arginine thanks to an enzyme, nitric oxide synthase (NOS), it was expected in the 1980s that vasodilation could be reduced by using an NOS blocker such as N-nitro L-arginine methyl ester (L-NAME). After some apparently favorable experiments, phase III studies were interrupted following evidence of high mortality among treated patients [3]. In fact, the blocker of NO production caused a series of negative effects including impaired microcirculation, reduced bactericidal activity of NO, reduced neutralizing activity of O₂ radicals, reduced modulation of the coagulation cascade, and deterioration of the supply/demand balance in tissues in which oxygenation was already precarious. In conclusion, NO is certainly the largest cause of vasodilation and the poor response to amines in septic patients, but its blockage with L-NAME is not only not advantageous but also dangerous.

Another vasodilator involved in septic shock is prostacyclin (PGI2), which is produced from the interaction with arachidonic acid and cyclooxygenase (COX) and prostacyclin synthase (PGTIS).

PGTIS acts on receptors present in the smooth muscle cells of the vessels resulting in an increase in cyclic MAP which in turn causes vasodilation. Even in this case, it seems acceptable to block the synthesis of prostacyclin with an anti-COX such as ibuprofen, but this approach has also not been effective in humans [4]. Another hyperproduced substance during sepsis is superoxide anion. This anion finds NO (even if it is hyperproduced) and colloids with it without any need for enzyme activation. This results in the production of peroxynitrite [5]. Peroxynitrite is involved in the mechanism that causes reduced sensitivity to amines but is also the only superoxide anion to be involved in this mechanism. This information could open new routes to block the low sensitivity to amines caused by superoxide anion and peroxynitrite by blocking their production. General experiments have been conducted in endotoxinic shock in animals [6], but although they are certainly interesting, no studies of this type in humans have begun yet, at least as far as I know. Another mechanism involved in vasodilation which is typical of septic shock is that of the ATP-dependent potassium channels. When these channels open, potassium (K) leaves the cells causing hyperpolarization of them, resulting in relaxation of the smooth muscle fibers of the vessels and therefore vasodilation. Both NO and peroxynitrite (as well as hyperlactacidemia) can activate the KAPT channels producing vasodilation and a reduced response to amines. An action that contrasts with this mechanism has been demonstrated experimentally by glibenclamide. Even this method of contrasting vasodilation has nevertheless been ineffective in humans [7]. It is useful to remember the possibility of inhibiting the vasodilator effect of NO and the production of it with a substance that has already been used in the past in the treatment of methemoglobinemia: methylene blue. One study in particular drew attention to this substance [8]. This study, the fruit of cooperation between Russian and Norwegian researchers, showed that the administration of a 2 mg/kg bolus of methylene blue, followed 2 h later by a continuous infusion of 0.5–1 mg/kg/h was capable of reducing the vasodilator effect of NO and improving the response to amines. The adverse effects at the doses they used were irrelevant except for a bluish-gray color to the skin that persisted for a few days. The problem is that the effect of this substance does not last long in time, and the authors of the study, afraid of unpredictable accumulative effects, interrupted the study after 6 h. The result was that, eventually, in addition to the very comforting short-term hemodynamic results, the duration of hospitalization and mortality were not statistically affected by the use of methylene blue. This does not mean that in critical moments with a poor response to the infusion of amines and fluids, methylene blue could be attempted at least to address situations that are difficult to manage. To conclude this introductory section, it is clear that for septic shock, although noradrenaline is the amine of choice in the treatment of hypotension, it is often not very effective, especially in terms of its resistance.

As we have seen, antagonizing the mechanisms that are at the basis of vasodilation is anything but simple, and many attempts to apply therapeutic strategies to humans that have been successful in animals have been in vain. It is therefore understood how the use of two drugs that can replace NE or be used alongside it to obtain sufficient pressure value levels can be regarded with interest. They are the two drugs that appear in the title of this chapter: vasopressin and terlipressin. This must not, however, be interpreted as alternative treatment to NE in serious cases of hypotension in septic patients. NE remains the drug of choice that is to be used as first-line treatment in these patients, and even the amine used as an alternative for many years, dopamine, is losing its consensus recently. In fact, the most recent study [8] has shown that, apart from hemodynamic effects, dopamine has more cardiovascular adverse events than NE. In particular there is a greater incidence of arrhythmias and atrial fibrillation, which undoubtedly make the management of these patients even more difficult, by enhancing hemodynamic imbalance. The particular utility of NE is reaffirmed by studies that have been published in recent years [9, 10]. These studies have shown that in patients with preload dependency (demonstrated by positive tests upon raising the lower limbs), NE improves venous return by increasing global end-diastolic volume (GEDV), cardiac output, and CVP. NE, probably by increase mean systemic pressure (mean circulatory filling pressure, MCFP), which is the most important factor in venous return, improves cardiac filling and therefore output. This shows that in patients with preload dependency, cardiac filling can be improved not only with fluid administration but also with early use of NE. These observations confirm what has already been said for hemorrhagic shock, namely, that NE is able to reduce PPV in patients with artificial ventilation [11]. The important clinical implication that arises from these observations is that NE has the same effects as fluid infusion and that there can therefore be savings with infusions, which, as we all know, are a double-edged sword: on the one hand, they are helpful if used early to counter the imbalance between the dilated circulatory bed and the circulating mass, but on the other hand, they promote interstitial edema, which is one of the greatest problems for septic patients. Confirmation of this possible therapeutic strategy is found in the study by Sennoun [12], which, by using an animal model of endotoxic shock and combing fluid reanimation alone with fluid reanimation accompanied by early use of NE, has demonstrated the possibility of reducing fluids without systemic, regional, or tissue damage with NE. Another advantage of NE is in its effects on the heart. By increasing MAP and diastolic arterial pressure (DAP), it improves both the perfusion pressures of the left ventricle (DAP) and right ventricle (MAP). In particular, DAP is considerably reduced in septic shock, and therefore maintaining it with NE is a clear advantage and makes it possible to prevent ischemic events and contractility disorders that are anything but rare in septic patients, especially if they also suffer from coronary stenosis [13]. If, therefore, we take into account the fact that NE also has beta-adrenergic activity, a positive effect on myocardial contractility can also be expected. Considering the positive effect that NE has on preloading, coronary perfusion, and myocardial contractility, a constant increasing effect on cardiac output can also be deduced. In reality this effect is not highly expected, and along with studies that show an increase in cardiac output with NE [14], there are others that do not show it [15]. This apparent discrepancy may depend on the difference between the patients studied. Based on the above, it can be presumed that patients with preload dependency in particular are those who benefit most from NE, at least in terms of cardiac output, whereas those with high levels of filling with infusions are likely to respond less. This observation is right for the effects of NE on regional fluids and microcirculation. According to Monnet and Teboul [13], it is necessary to distinguish between patients with very serious hypotension (e.g., MAP 45–55 mmHg) and high cardiac output and those with moderate hypotension. In the former, MAP recovery with NE can improve renal function, even without any effects on output [16, 17], and it has been shown that it can improve microcirculation examined with near–infrared spectroscopy (NIRS) [14]. In patients with moderate hypotension (e.g., MAP 65–75 mmHg), Derundt et al. demonstrated that by increasing MAP to 85–90 mmHg from 65 to 75 with NE can lead to an improvement in microcirculation if the patient has not yet experienced an improvement in the microcirculation with generous early infusions of fluids. This has been demonstrated in the study by Thooft et al. [18], which, by increasing MAP from 65 to 85 mmHg, showed an increase in cardiac output and SVO₂ as well a reduction in lactate and an improvement in microcirculation. In concluding this chapter, we must therefore stress that NE is an extremely valid support in the treatment of hypotension in patients with sepsis; and that, considering the resistance found in this type of pathology, the dosage is variable from patient to patient and is regulated according to the pressure response that reasonably stabilizes around a MAP of 85–90 mmHg; and finally that early use of this drug can enable savings of useful infusions to reduce the trend for interstitial edema. The above, however, should not create the illusion that increasing MAP above 80 mmHg with NE leads to a positive result. Unfortunately, as repeated many times, each septic patient is a separate case, and even in the literature, there are negative opinions on the real possibility of gaining and advantage by increasing MAP to above 65 mmHg. Is this another case of the “pendulum effect”?