Introduction

On the basis of present evidence, macrohaemodynamics and microcirculation need to be considered as two potentially dissociated compartments that need to be taken into account for therapeutic approaches in shock. A resuscitation protocol guided by global haemodynamic parameters may improve cardiac output and mean arterial pressure but is not necessarily associated with a restored microcirculation as demonstrated in several experimental and clinical studies in septic, cardiogenic or haemorrhagic shock . Haemodynamic coherence between macro- and microcirculation results in corresponding changes in global haemodynamics and microcirculation, e.g. an increase of microvascular flow index (MFI) by increasing cardiac output. Under these circumstances, resuscitation of macrocirculation results in improved tissue perfusion and oxygenation, the ultimate purpose of resuscitation. However, haemodynamic coherence is often suspended in shock states and in patients undergoing high-risk surgery. This loss of haemodynamic coherence contributes to the development of organ failure and eventually results in increased mortality rates .

The importance of microcirculatory changes and haemodynamic coherence or incoherence has been repeatedly demonstrated in different patient collectives. In critically ill patients, tissue oxygenation during early goal-directed therapy was independent from global haemodynamics and was consistently lower in patients with worse organ failure . In general, there is an abnormal microcirculation in 17% of critically ill patients. Although this impairment is not associated with mortality per se , in patients with tachycardia, an abnormal MFI is independently associated with increased hospital mortality rates . Microcirculatory alterations are more severe in non-survivors and strongly predict the outcome . In a prospective data collection of 252 patients with severe sepsis, sublingual microcirculatory parameters were altered despite preserved global haemodynamic parameters . Notably, in a prospective observational trial, an improved sublingual microcirculation in septic shock patients was associated with reduced organ failure without substantial differences in global haemodynamics. The authors concluded that microcirculation may be a better target than global haemodynamic variables to improve organ failure in sepsis . In accordance with these results, a lactate-guided therapy significantly reduced hospital mortality in a prospective clinical trial in critically ill patients. The lactate group received more fluids and vasodilators. However, there were no significant differences in lactate levels between the intervention and control groups .

Following traumatic haemorrhagic shock, several days are required for the microcirculation to recover despite early restoration of the macrocirculation. The length of microcirculatory recovery time correlated with the occurrence of organ dysfunction . The long-term outcome of patients with cardiogenic shock has also been linked to the restoration of microcirculation . Even after major abdominal surgery, an impaired microcirculation is associated with post-operative complications independent of systemic haemodynamics .

Formerly, surrogate variables of microcirculation such as serum lactate, capillary refill time, skin temperature and peripheral perfusion index were used. Presently, microcirculation can be directly monitored (e.g. by microvideoscopy techniques or tissue saturation monitoring) at the bedside to evaluate or even guide therapy. Thus, the effects of different therapeutic strategies on microcirculation can be immediately assessed, and this will allow clinicians to identify patients who may benefit from compounds with vasodilating properties for recruiting the microcirculation . The present review will briefly explain the theoretical rationale for the use of vasodilators and inodilators in this context. Thereafter, current experimental and clinical evidence for the individual compounds will be critically discussed.

Vasodilators vs standard therapy

Independent of the nature of shock, volume resuscitation and vasopressors are recommended as initial treatment strategies in patients with acute circulatory failure . However, a positive fluid balance and high doses of vasopressors are independent risk factors for mortality . What is the explanation for this obvious contradiction? At first glance, it appears logical that the sicker the patient, the more haemodynamic support is necessary and the higher will be the risk of adverse outcome. Another aspect is that according to current guidelines, fluid and vasopressor therapy are primarily guided by the variables of macrocirculation. Thus, despite macrohaemodynamic stabilization, microcirculation may be impaired because of excessive vasoconstriction caused by high doses of vasopressors, tissue oedema and venous congestion induced by high fluid volumes .

There is no doubt that a sufficient macrocirculation is a pre-requisite for adequate organ perfusion. However, after the initial stabilization, microcirculation may be impaired by increased post-capillary pressure, which may be related to fluid overload with venous congestion or tissue oedema associated with vascular leakage. Both may be associated with a decrease in capillary perfusion and/or density. Conventional resuscitation strategies such as fluids and vasopressors cannot improve microcirculation in this setting. Venous vasodilators, however, may dilate the post-capillary venules, thereby increasing capillary flow and decreasing trans-capillary pressure gradient and thus extravasation. Moreover, monitoring microcirculatory changes in vasodilatory shock revealed that contrary to the vasodilated vessels of the macrocirculation, microcirculatory vessels are constricted . In addition, it is well known that organ perfusion is regulated by local resistance vessels rather than by macrocirculation. Accordingly, administrating vasodilators may improve organ function by ‘opening’ the microcirculation as demonstrated in several clinical studies ( Table 1 ). In 50 patients with severe sepsis, topical application of acetylcholine restored the microcirculation to a level that was similar to that of the healthy volunteers . However, a randomized controlled pilot study by van der Poort et al. demonstrated that an early strategy to resuscitate microcirculation by administration of vasodilators or inodilators (nitroglycerin and enoximone) in 90 patients with severe sepsis or septic shock did not result in a faster reduction in organ failure than standard therapy. In fact, the microcirculation resuscitation group required more fluids . In addition, treating every septic patient with nitroglycerin to improve microcirculatory blood flow was not successful . These studies demonstrate that it is necessary to carefully identify patients who might benefit from vasodilators and achieve a well-balanced titration of vasodilators based on close microcirculatory and haemodynamic monitoring (similar to the use of vasopressors) to avoid impairing the macrocirculation. This implies that first, an impairment of microcirculation needs to be detected prior to a therapy that aims at improving the microcirculation, and second, the effects of the respective treatment (e.g. nitroglycerin) need to be closely monitored to allow adaption or cessation of the treatment, if necessary.

A combined use of vasopressors to maintain an adequate mean arterial pressure and vasodilators to restore microcirculation may be useful in some patients with shock and loss of haemodynamic coherence. The international paediatric sepsis guidelines recommend the use of vasodilators or inodilators in septic shock with low cardiac output and elevated systemic vascular resistance. However, it is explicitly emphasized that fluid resuscitation and restored haemodynamics are required prior to the administration of vasodilators .

Vasodilators vs standard therapy

Independent of the nature of shock, volume resuscitation and vasopressors are recommended as initial treatment strategies in patients with acute circulatory failure . However, a positive fluid balance and high doses of vasopressors are independent risk factors for mortality . What is the explanation for this obvious contradiction? At first glance, it appears logical that the sicker the patient, the more haemodynamic support is necessary and the higher will be the risk of adverse outcome. Another aspect is that according to current guidelines, fluid and vasopressor therapy are primarily guided by the variables of macrocirculation. Thus, despite macrohaemodynamic stabilization, microcirculation may be impaired because of excessive vasoconstriction caused by high doses of vasopressors, tissue oedema and venous congestion induced by high fluid volumes .

There is no doubt that a sufficient macrocirculation is a pre-requisite for adequate organ perfusion. However, after the initial stabilization, microcirculation may be impaired by increased post-capillary pressure, which may be related to fluid overload with venous congestion or tissue oedema associated with vascular leakage. Both may be associated with a decrease in capillary perfusion and/or density. Conventional resuscitation strategies such as fluids and vasopressors cannot improve microcirculation in this setting. Venous vasodilators, however, may dilate the post-capillary venules, thereby increasing capillary flow and decreasing trans-capillary pressure gradient and thus extravasation. Moreover, monitoring microcirculatory changes in vasodilatory shock revealed that contrary to the vasodilated vessels of the macrocirculation, microcirculatory vessels are constricted . In addition, it is well known that organ perfusion is regulated by local resistance vessels rather than by macrocirculation. Accordingly, administrating vasodilators may improve organ function by ‘opening’ the microcirculation as demonstrated in several clinical studies ( Table 1 ). In 50 patients with severe sepsis, topical application of acetylcholine restored the microcirculation to a level that was similar to that of the healthy volunteers . However, a randomized controlled pilot study by van der Poort et al. demonstrated that an early strategy to resuscitate microcirculation by administration of vasodilators or inodilators (nitroglycerin and enoximone) in 90 patients with severe sepsis or septic shock did not result in a faster reduction in organ failure than standard therapy. In fact, the microcirculation resuscitation group required more fluids . In addition, treating every septic patient with nitroglycerin to improve microcirculatory blood flow was not successful . These studies demonstrate that it is necessary to carefully identify patients who might benefit from vasodilators and achieve a well-balanced titration of vasodilators based on close microcirculatory and haemodynamic monitoring (similar to the use of vasopressors) to avoid impairing the macrocirculation. This implies that first, an impairment of microcirculation needs to be detected prior to a therapy that aims at improving the microcirculation, and second, the effects of the respective treatment (e.g. nitroglycerin) need to be closely monitored to allow adaption or cessation of the treatment, if necessary.

Table 1

Important clinical trials investigating the effect of vasodilators on haemodynamic coherence.

Author		Design	Participants	n	Drug	Dosage	Results
Lima		Interventional, single centre	Circulatory shock	15	Nitroglycerin	Started at 2 mg/h, doubled stepwise every 15 min up to 16 mg/h	Peripheral perfusion↑, tissue oxygenation saturation↑, MAP↓, CI=
Boerma		RCT, single centre	Severe sepsis	70	Nitroglycerin (compared with placebo)	loading dose of 2 mg, 2 mg/h infusion	Microvascular flow=, global haemodynamics=
den Uil		Interventional	Cardiogenic shock or end-stage chronic heart failure	17	Nitroglycerin	0.5 mg/h, doubled stepwise up to 8 mg/h	Tissue perfusion↑, MAP↓, CI=, lactate=
Spronk		Interventional, single centre	Septic shock	8	Nitroglycerin	Loading dose of 0.5 mg, 2 mg/h infusion	Microvascular flow↑
Backer		Interventional, cross-over	Sepsis, stable haemodynamic and normal blood lactate level	17	Prostacyclin (compared with dobutamine)	20-min infusion of 5 ng/kg/min	CO↑, MAP↓, oxygen uptake=, oxygen extraction↓
Levy		Interventional, single centre	Septic shock, MAP > 75 mmHg and CI > 3.5 L/min/m 2	20	Dobutamine	5 μg/kg/min	MAP=, CI=, oxygen delivery/consumption=, arterial lactate↓, gastric mucosal perfusion↑
Backer		Interventional, single centre	Septic shock	22	Dobutamine	5 μg/kg/min	Lactate↓ sublingual capillary perfusion↑, CI=, MAP=
Enrico		Interventional, single centre	Septic shock	23	Dobutamine	2.5–10 μg/kg/min	CI↑, MAP=, sublingual microcirculation=or ↑
Hernandez		RCT	Septic shock, CI ≥ 2.5 L/min/m 2 and hyperlactatemia	20	Dobutamine (compared with placebo)	5 μg/kg/min	CI↑, sublingual microcirculation=, lactate=, tissue oxygen saturation=
Morelli		RCT, single centre	Septic shock	20	Levosimendan (compared with dobutamine)	0.2 μg/kg/min	Sublingual microcirculation↑, global haemodynamics=
Morelli		Interventional, multicentre	Septic shock with left ventricular dysfunction	28	Levosimendan	0.2 μg/kg/min	CI↑, lactate↓, gastric mucosal flow↑

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

Hemodynamic coherence: Its meaning in perioperative and intensive care medicine Haemodynamic coherence — The relevance of fluid therapy Haemodynamic coherence in haemorrhagic shock Haemodynamic coherence in perioperative setting Effect of non-adrenergic vasopressors on macro- and microvascular coupling in distributive shock The response of the microcirculation to mechanical support of the heart in critical illness

Stay updated, free articles. Join our Telegram channel

Join