Over the last decade, there has been an increased interest in the use of goal-directed therapy (GDT) in patients undergoing high-risk surgery, and various haemodynamic monitoring tools have been developed to guide perioperative care. Both the complexity of the patient and surgical procedure need to be considered when deciding whether GDT will be beneficial. Ensuring optimum tissue perfusion is paramount in the perioperative period and relies on the coherence between both macrovascular and microvascular circulations. Although global haemodynamic parameters may be optimised with the use of GDT, microvascular impairment can still persist. This review will provide an overview of both haemodynamic optimisation and microvascular assessment in the perioperative period.
Introduction
It is well established that surgical intervention leads to the rapid activation of the stress response in a living organism. This response results in an increase in adrenocorticotropic hormone along with an excess of cortisol release, insulin resistance and a rise in catecholamine levels . This metabolic alteration induced by the surgical stress response is responsible for both proteolysis and muscle breakdown . Immunomodulation also occurs because of the surgical insult, with an increase in leucocyte infiltration, raised levels of circulating dendritic cells and reduced natural killer cell toxicity and T-cell responses . In addition, the stress response is responsible for an increase in oxygen consumption. In the 1990s, Shoemaker et al. demonstrated that an oxygen debt starts to develop intraoperatively in high-risk surgical patients and that if these patients are unable to overcome this deficit during the first few hours post-operatively, the morbidity and mortality will increase . They also observed that the incidence of organ failure and mortality were reduced when the oxygen deficit was rapidly compensated by optimising haemodynamic variables using a protocol aimed to reach the same haemodynamic values recorded in patients who survived . These data clearly demonstrated that some patients required haemodynamic support to overcome the surgical stress. Therefore, over the last two decades, several protocols have been developed to optimise haemodynamic parameters with the aim of reducing tissue hypoperfusion and meeting the increased metabolic demands of the tissue as soon as possible. The effectiveness of this goal-directed therapy (GDT) is strictly time related, and a reduction in morbidity and mortality can be shown only when organ failure is not yet established . Thus, haemodynamic optimisation should be started intra-operatively to prevent organ hypoperfusion and continued for at least 6–8 h post-operatively to rapidly compensate the oxygen debt.
It is well known now that not all patients can overcome the oxygen debt, and therefore, these patients may benefit from haemodynamic modulation. The inability to repay the oxygen debt may be due to the following: first, the characteristics of the surgical procedure that are related to the significant derangement of homoeostatic milieu because of severe tissue damage and second, whether the patient has a limited physiological reserve and is able to sustain minor stress . Thus, the decision to perform GDT should take into consideration both surgical and patient factors. The risk of mortality related to the surgical procedure should also be considered, and patients undergoing a procedure with a probable mortality of >20% are considered as extremely high-risk patients . Regarding patient status, patients with an individual risk of death >5% are considered to be high risk . This risk can be assessed using several tests , scores or physical status classifications, e.g. the American Society of Anesthesiologists Physical Status . Evidence has shown that GDT can only improve the survival in high-risk surgical patients and reduce complications in the intermediate-risk population.
However, the adequacy of perfusion in each peripheral tissue cannot be derived only from macro-haemodynamic assessment. Each organ and each tissue within the organ regulates local blood flow according to local conditions , and several clinical studies have shown that microvascular alterations are not always associated with classic macro-haemodynamic parameters . Impaired microvascular perfusion is responsible for organ failure, although macro-haemodynamic and blood flow have been optimised by clinical interventions . Therefore, the clinician should adequately optimise haemodynamic parameters with microcirculation as the final target. All information obtained from a haemodynamic monitoring system should recognise any incoherence between macro- and micro-haemodynamics.
The haemodynamic puzzle
The main haemodynamic elements that clinicians must assess and optimise during perioperative period are preload, afterload and contractility. Their interaction determines blood flow and pressure.
The role of preload pressure parameters has been evaluated over the last few years, and the current approach is based on the assessment of fluid responsiveness. In the operating theatre, dynamic parameters such as stroke volume variation (SVV) and pulse pressure variation (PPV) could be more reliable and useful than in intensive care unit (ICU), where the pre-conditions for their accuracy are not always available (such as during spontaneous/assisted ventilation) . Alternatively, a fluid challenge is the simplest way to assess the ventricle preload-dependence status .
Afterload is an important determinant of cardiac output (CO) under the given conditions of contractility and preload. In clinical practice, the most common way to evaluate afterload is by calculating the systemic vascular resistance (SVR). However, we must consider that the arterial SVR value only represents opposition or resistance to a constant flow, which is fundamentally found at arteriolar level, where the compensating mechanisms that control vasomotor tone keep the perfusion pressure within a physiological range. Therefore, this parameter cannot provide a complete description of global arterial impedance because of the fluctuating nature of blood flow and arterial pressure . Arterial elastance (Ea) has been proposed as a more accurate parameter of estimating arterial tone. It is defined as the ratio of change in pressure to change in volume rather than resistance and takes into account the pulsating characteristic of flow. Dynamic Ea (Eadyn) can be simply calculated from the ratio of PPV to SVV. Assessment of Eadyn has been recently proposed to predict the arterial pressure response after volume loading in preload-dependent patients . Optimisation of afterload is important to maintain blood pressure within auto-regulation range values .
Echocardiography offers clinicians alternative parameters to assess the contractility function of the heart. The ejection fraction is the most commonly used parameter for evaluating contractility even if it is dependent on the afterload. However, echocardiography offers other parameters such as dP/dt (left ventricular contractility) that are less dependent on loading condition. The limits of echocardiography are the expertise required to perform it and the limited role of the trans-thoracic approach in theatre, where the only possible technique is the trans-oesophageal one. Presently, several monitoring systems based on pulse contour analysis can calculate dP/dt max by assessing the steep part of the arterial curve. Moreover, trans-pulmonary thermodilution allows the calculation of the cardiac function index and global ejection fraction. These parameters can enable an easy bedside detection of alteration in contractility that may require an extensive evaluation by echocardiography and could be used to monitor the efficacy of inotropic therapy .
Finally, peripheral perfusion should be carefully assessed to verify the adequacy of haemodynamic values. Mixed/central venous oxygen saturation, arterial lactate level and the difference between central venous and arterial PCO 2 (Pcv-aCO 2 ) can be measured to develop further interventions . Alteration of perfusion parameters without an impairment in the global haemodynamics may reflect a local hypoperfusion, altered microvascular flow with shunting or inability of cell to utilise oxygen. The last condition is characteristic of sepsis, where mitochondrial dysfunctions are associated with microvascular shunting.
The myriad of information generated from several haemodynamic monitoring tools must be integrated and correctly interpreted to provide an accurate overview of the cardiovascular status.
The haemodynamic puzzle
The main haemodynamic elements that clinicians must assess and optimise during perioperative period are preload, afterload and contractility. Their interaction determines blood flow and pressure.
The role of preload pressure parameters has been evaluated over the last few years, and the current approach is based on the assessment of fluid responsiveness. In the operating theatre, dynamic parameters such as stroke volume variation (SVV) and pulse pressure variation (PPV) could be more reliable and useful than in intensive care unit (ICU), where the pre-conditions for their accuracy are not always available (such as during spontaneous/assisted ventilation) . Alternatively, a fluid challenge is the simplest way to assess the ventricle preload-dependence status .
Afterload is an important determinant of cardiac output (CO) under the given conditions of contractility and preload. In clinical practice, the most common way to evaluate afterload is by calculating the systemic vascular resistance (SVR). However, we must consider that the arterial SVR value only represents opposition or resistance to a constant flow, which is fundamentally found at arteriolar level, where the compensating mechanisms that control vasomotor tone keep the perfusion pressure within a physiological range. Therefore, this parameter cannot provide a complete description of global arterial impedance because of the fluctuating nature of blood flow and arterial pressure . Arterial elastance (Ea) has been proposed as a more accurate parameter of estimating arterial tone. It is defined as the ratio of change in pressure to change in volume rather than resistance and takes into account the pulsating characteristic of flow. Dynamic Ea (Eadyn) can be simply calculated from the ratio of PPV to SVV. Assessment of Eadyn has been recently proposed to predict the arterial pressure response after volume loading in preload-dependent patients . Optimisation of afterload is important to maintain blood pressure within auto-regulation range values .
Echocardiography offers clinicians alternative parameters to assess the contractility function of the heart. The ejection fraction is the most commonly used parameter for evaluating contractility even if it is dependent on the afterload. However, echocardiography offers other parameters such as dP/dt (left ventricular contractility) that are less dependent on loading condition. The limits of echocardiography are the expertise required to perform it and the limited role of the trans-thoracic approach in theatre, where the only possible technique is the trans-oesophageal one. Presently, several monitoring systems based on pulse contour analysis can calculate dP/dt max by assessing the steep part of the arterial curve. Moreover, trans-pulmonary thermodilution allows the calculation of the cardiac function index and global ejection fraction. These parameters can enable an easy bedside detection of alteration in contractility that may require an extensive evaluation by echocardiography and could be used to monitor the efficacy of inotropic therapy .
Finally, peripheral perfusion should be carefully assessed to verify the adequacy of haemodynamic values. Mixed/central venous oxygen saturation, arterial lactate level and the difference between central venous and arterial PCO 2 (Pcv-aCO 2 ) can be measured to develop further interventions . Alteration of perfusion parameters without an impairment in the global haemodynamics may reflect a local hypoperfusion, altered microvascular flow with shunting or inability of cell to utilise oxygen. The last condition is characteristic of sepsis, where mitochondrial dysfunctions are associated with microvascular shunting.
The myriad of information generated from several haemodynamic monitoring tools must be integrated and correctly interpreted to provide an accurate overview of the cardiovascular status.
The right monitoring system for the right patient
Presently, clinicians can choose between several haemodynamic monitoring systems, ranging from less invasive to more complex and invasive tools . Clinicians should select the most appropriate device according to the complexity of the patient. Taking into consideration the surgical procedure and the morbidity of the patient, the use of an invasive haemodynamic system and application of a GDT protocol should only be considered in high-risk patients. Nevertheless, several GDT protocols are based on dynamic parameters of fluid responsiveness that can be easily assessed using mini-invasive systems based on pulse contour analysis.
To help the anaesthesiologist interpret the information from the haemodynamic monitor, a closed-loop technology has been recently proposed. An automated closed-loop system has been developed to control fluid administration in a GDT protocol for SV maximisation. This new approach of perioperative haemodynamic optimisation has been evaluated only in few studies, and further trials are required to verify its utility on outcome compared with current practice .
Several tools aim to assess microvascular function at different levels. Near-infrared spectroscopy (NIRS) is an indirect method to evaluate tissue perfusion and can measure tissue oxygen saturations (StO 2 ). The NIRS signal, applied to the thenar muscle, is limited to vessels that have a diameter of <1 mm (arterioles, capillaries and venules); however, as 75% of the blood in a skeletal muscle is venous, NIRS StO 2 measurements mostly represent local venous haemoglobin (Hb) O 2 saturation and the local balance between oxygen delivery (DO 2 ) delivery and oxygen consumption (V0 2 ) . A vaso-occlusive test can be performed to assess microvascular reactivity. In this test, arterial occlusion is caused by the transient inflation of a cuff placed around the arm. After StO 2 reaches approximately 40%, the ascending slope of the StO 2 value observed just after the release of the cuff reflects the quality of flow recovery. Abdelmalak et al. performed an observational study to evaluate the relationship between perioperative StO 2 and surgical outcomes in patients undergoing major non-cardiac surgery. StO 2 was measured at the thenar eminence during surgery and for 2 h post-operatively. The minimum StO 2 was inversely associated with 30-day mortality and serious in-hospital complications ( p = 0.02) . Moreover, Govinda et al. showed that the evaluation of StO 2 during the post-operative period after colorectal surgery could predict the development of post-operative surgical site infection (SSI). StO 2 in the upper arm was lower in patients who developed SSI than in those who did not develop SSI (52% ± 22% vs 66% ± 21%; p = 0.033). A cut off of 66% had a sensitivity of 71% and specificity of 60% for predicting SSI .
Direct visualisation of the microvascular bed at sublingual level can be easily performed using special cameras, but a fast and operator independent analysis cannot be yet performed . Orthogonal polarisation spectral and sidestream dark field are two video microscopic imaging techniques that can be used at the bedside to visualise microcirculation. However, the analysis of microvascular parameters is offline, time consuming and operator dependent . This represents the main limitation of using microvascular imaging in clinical practice as a ‘point-of-care’ tool. Only microcirculatory flow index has been evaluated in real time . Recently a third-generation handheld microscope based on incident dark-field imaging was introduced. This technique can provide higher quality images than SDF imaging, visualising approximately 20%–30% more capillaries than the SDF device . This camera is provided with an automatic analysis software that allows us to obtain results quickly. However, the ability of this new software to obtain microvascular parameters needs to be improved and validated . Thus, future technological developments look promising.
No microvascular monitor systems have been used in clinical practice to guide haemodynamic optimisation during the perioperative period in a specific GDT protocol.
Haemodynamic targets
Originally, Shoemaker et al. based their optimisation protocol on targeting supra-normal value for cardiac index, DO 2 and VO 2 . These goals were empirically derived from the mean values observed in patients who survived. The majority of perioperative optimisation protocols continue to use a DO 2 of >600 ml/min/m 2 as the principal goal to reach, whereas other are based on SV maximisation. Presently, these parameters can be easily monitored using several mini-invasive monitoring systems that are responsible for a wide range of GDT application. DO 2 is regionally regulated according to tissue metabolism, and an inadequate global DO 2 may be associated with impaired local tissue perfusion. Although a supra-normal DO 2 value will most likely result in a lower probability of tissue hypoperfusion, it should not be the only parameter to be examine d when we try to optimise tissue perfusion. An inadequate tissue DO 2 is responsible for an increase in oxygen extraction rate (O 2 ER), a decrease in SvO 2 or its surrogate ScvO 2 and, finally, an increase in lactate level. Pearse et al. monitored ScvO 2 for 8 h post-operatively and demonstrated that a cut-off value of 64.4% can discriminate patients at higher risk of developing complications. Other studies have confirmed these results, although with different cut-off values . Using the concept that O 2 ER reflects the balance between DO 2 and VO 2 , Donati et al. performed a multicentre randomised controlled trial to evaluate the effectiveness of a GDT protocol based on O 2 ER estimation (O 2 ERe), which is calculated as (SaO 2 − ScvO 2 )/SaO 2 (arterial oxygen saturation; SaO 2 ). The patients in the protocol group were optimised to maintain an O 2 ERe of <27% using fluids, dobutamine and/or packed red blood cells (RBCs). These patients developed a significantly lower incidence of organ failure post-operatively than the control group (9 vs 27; p < 0.001). Despite this evidence, doubts currently regarding the ability of ScvO 2 to guide haemodynamic optimisation during the perioperative period persist. First, the ScvO 2 is dependent on several conditions such as hypoxia, shivering, anaesthesia, haemorrhage and myocardial ischaemia. Second, it is reflected by the relationship between global DO 2 and VO 2 and may not be able to unmask regional hypoperfusion . To overcome this problem, Pcv-aCO 2 has been proposed as a better predictor of tissue hypoperfusion . Futier et al. showed that among patients with an intraoperative ScvO 2 of ≥71%, Pcv-aCO 2 was higher in those that developed post-operative complications (7.7 ± 2 vs 5 ± 2 mmHg, p < 0.001) . The cut-off to discriminate these two conditions was 5 mmHg. Moreover, Ospina-Tascon et al. recently demonstrated that a higher value of Pcv-aCO 2 was associated with a lower proportion of small perfused vessels, lower functional capillary density and a higher heterogeneity of microvascular blood flow in patients with septic shock. Pcv-aCO 2 significantly correlated with PPV ( p < 0.001), and changes in Pcv-aCO 2 between baseline value and 6 h after resuscitation were significantly related to changes in PPV (R 2 = 0.42, p < 0.001). Interestingly, absolute values and changes in Pcv-aCO 2 were not related to global haemodynamic variables.
Stens et al. recently evaluated the effect of two haemodynamic optimisation protocols on sublingual microcirculation during abdominal surgery. Thirty-one patients were randomised to PPV and cardiac index or mean arterial pressure (MAP)-guided protocol and microvascular parameters were recorded at 1, 2 and 3 h after anaesthesia induction. Although the administration of more fluids in PPV/CI group resulted in lower PPV values and higher cardiac index values, no differences were noted between the two groups in microvascular parameters.
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Effects of vasodilators on haemodynamic coherence
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