Changes in circulating blood volume generated by a fluid challenge can also be assessed by mean systemic filling pressure (Pmsf) . It is defined as the pressure in the cardiovascular system when the heart is stopped and there is no fluid motion. The Pmsf depends on the ‘stressed volume’, which is the blood that stretches the blood vessels and causes intravascular pressure, and the compliance of the cardiovascular system. After a fluid challenge, an increase in blood volume is related to an increase in Pmsf.
Because it has been estimated that only 50% of critically ill patients respond to fluid challenge , clinicians are interested in knowing whether the patient will increase SV as a consequence of fluid challenge before fluid administration, especially in the case of patients with a limited cardiac reserve or increased lung capillary permeability. For this purpose, several dynamic parameters and tests have been developed.
In mechanically ventilated patients, the cyclical variation in intrathoracic pressure produces hemodynamic effects useful to determine whether the patient's heart is working on the steep or the flat portion of the Frank–Starling curve. During positive pressure ventilation, the increase in intrathoracic pressure that occurs during inspiration reduces the preload of the right ventricle (RV). At the same time, RV afterload increases in relation to the inspiratory increase in trans-pulmonary pressure. All together, these modifications are responsible for a decrease in RV SV. After two to three heart beats, the reduction of RV ejection leads to a reduction of left ventricle (LV) filling. Thus, LV preload reduction may induce a decrease in LV SV, with a minimum value during the expiratory phase. The magnitude of the respiratory changes in SV depends on the volume status and on the preload dependence of both ventricles. In the case of hypovolemia, these cyclic increase and reduction of SV are more pronounced.
Nowadays, several hemodynamic monitors are able to calculate SV continuously, providing dynamic parameters such as stroke volume variation (SVV) and pulse pressure variation (PPV).
Recently, a ‘grey zone approach’ has been introduced, based on the overlap of PPV values between responders and nonresponders when a single cut-off of 13% is used [21,22▪]. The grey zone approach proposes a low cut-off value that excludes fluid responsiveness in 90% of patients (favouring negative predictive value), whereas a high cut-off value predicts fluid responsiveness in 90% of cases (favouring positive predictive value). Between these two cut-off values, no decision can actually be taken. Biais et al. [22▪] reported that PPV cannot reliably guide fluid loading for values between 4 and 17%, which occurred in 62% of patients enrolled from nine French ICUs.
All these dynamic parameters have several limitations. First, the patients need to be mechanically ventilated without spontaneous breathing efforts, and tidal volume should be enough to promote adequate preload variations. More than 8 ml/kg is usually required for adequate interpretation of dynamic parameters , and this condition precludes their use during protective lung ventilation such as in patients with acute respiratory distress syndrome (ARDS) . Second, a ratio between heart rate and respiratory rate less than 3.6 is required . Third, conditions under which one of the two ventricles is preload independent, such as RV failure  or elevated LV filling pressures , preclude the usefulness of dynamic parameters. Finally, arrhythmias are the last exclusion criterion for the use of dynamic variables. Two recent studies have shown that the percentage of patients admitted to the ICU suitable to be assessed using PPV was between 1.3 and 2% [28▪,29]. In these situations, clinicians cannot use dynamic variables based on heart–lung interaction and need other parameters able to predict fluid responsiveness.
As previously stated, the increase in intrathoracic pressure during mechanical ventilation reduces venous return and consequently SV. Thus, a short end-expiratory occlusion (EEO) may prevent the cyclic impediment in left cardiac preload and may act like a fluid challenge. This could serve as a functional test for fluid responsiveness. Because its duration encompasses several cardiac cycles, the prediction of fluid responsiveness could be independent of cardiac arrhythmias. The test could also be used in patients with a spontaneous breathing activity. Nevertheless, as the EEO test consists of interrupting mechanical ventilation at end expiration, its hemodynamic effects, and thus its reliability in predicting fluid responsiveness, could depend upon the positive end-expiratory pressure. Monnet et al.  performed a 15-s EEO test in 34 patients with shock, and fluid responsiveness was predicted by an increase in cardiac index more than 5% during the EEO with a sensitivity and a specificity of 91 and 100%, respectively. Good results were obtained also in patients affected by ARDS with low-respiratory compliance, a condition that precludes the use of PPV and SVV [31,32].
Echocardiography is a noninvasive technique widely used in intensive care medicine to assess the cardiac function of critically ill patients. Static echocardiographic parameters of cardiac preload, such as volumes and estimated filling pressures, exhibit the same limitations as those reported for invasive cardiac filling pressures. Dynamic evaluation of echocardiographic variables during respiratory cycle has, however, assumed a major role in predicting fluid responsiveness . Clinical data suggest that respiratory variation of inferior vena cava (IVC) diameter can be used to predict the preload-dependence status in mechanically ventilated patients [34,35]. Barbier et al.  calculated the distensibility index for the IVC (dIVC) using transthoracic echocardiography and showed that a threshold of 18% was able to discriminate responders and nonresponders with 90% sensitivity and 90% specificity. A strong correlation (r = 0.9) was observed between dIVC at baseline and the cardiac index increase following blood volume expansion. Transesophageal echocardiography has also been used to evaluate collapsibility of superior vena cava with similar results [36,37].
Using pulsed Doppler in the LV outflow track, echocardiography is able to measure LV SV by multiplying the area under the curve of the aortic flow [velocity time integral (VTI)] by the cross-sectional area of the aortic annulus. Because the cross-sectional area of the aortic annulus remains constant during the respiratory cycle, changes in VTI directly reflect changes in LV SV. Therefore, VTI variations have been used as a surrogate of SVV to predict fluid responsiveness [38,39].
Passive leg raising (PLR) is a manoeuvre that transiently and reversibly increases venous return by shifting venous blood from the legs to the intrathoracic compartment. If the ventricles are preload dependent, PLR may result in an increase in SV. Therefore PLR can be considered a brief and completely reversible ‘self-volume challenge’ [40,41▪▪], avoiding the risk of fluid overload. The effect of PLR is time limited, and SV reaches the maximum value approximately 1 min after starting the manoeuvre, returning to the baseline after the procedure . A further advantage of this test is that it remains reliable when parameters based on heart–lung interaction cannot be used. Monnet et al. evaluated PLR in 71 mechanically ventilated patients, 31 of them presenting spontaneous breathing activity and/or arrhythmias. They showed that an increase in aortic blood flow of at least 10% by PLR predicted a volume expansion-induced increase in aortic blood flow of at least 15% with a sensitivity of 97% and specificity of 94% and AUC ROC of 0.96 ± 0.02. Moreover, it has been demonstrated that PLR works better than PPV in patients with low-respiratory system compliance (≤30 ml/cmH2O), with AUC ROC of 0.94 ± 0.05 and 0.69 ± 0.10, respectively . This offers an opportunity to test fluid responsiveness also in patients with ARDS, in whom fluid overload is deleterious and a restrictive fluid strategy might be preferred. A meta-analysis performed by Cavallaro and co-workers confirmed PLR accuracy to predict fluid responsiveness in patients with arrhythmias and spontaneous breathing . PLR is based on recruitment of both splanchnic and leg blood. Because intra-abdominal hypertension reduces venous return, compressing the inferior vena cava, this condition could impair the ability of this manoeuvre to detect fluid responsiveness. In patients with intra-abdominal hypertension, PLR has been associated with a 48% false negative rate, and an intra-abdominal pressure cut-off value of 16 mmHg discriminated between responders and nonresponders to PLR with a sensitivity of 100% (95% CI: 78–100%) and specificity of 86% (95% CI: 61.6–98.1%) . Finally, PLR cannot be performed in patients with traumatic brain injury because of the risk of increasing intracranial pressure.
During resuscitation of patients in shock, an increase in blood flow is not the only target for clinicians, but a rise in perfusion pressure is also expected. An increase in blood pressure does not automatically follow the increase of SV, since the pressure–volume relation depends on arterial tone . Assessment of dynamic arterial elastance (Eadyn) has been recently proposed to predict the arterial pressure response after volume loading in preload-dependent patients [46,47,48▪]. Arterial elastance is defined as the ratio of changes in pressure to changes in volume. Although PPV and SVV cannot be accurately interpreted as measures of volume responsiveness in patients with atrial fibrillation and spontaneous breathing, their ratio always defines Eadyn, as the impact of irregular variations in intrathoracic pressure should influence both components to the same degree. Monge García et al.  showed that a baseline Eadyn value greater than 0.89 predicted a mean arterial pressure increase after fluid administration with a sensitivity of 94% (95% CI: 70–100%) and a specificity of 100% (95% CI: 66.4–100%), in patients under mechanical ventilation. Recently, Cecconi et al.[48▪] confirmed this result also in spontaneously breathing patients. Although fluid administration remains the first recommended therapy to treat shocked patients, low arterial blood pressure could be related not only to inadequate blood flow but also to a loss of arterial tone. In this regard, the assessment of Eadyn could help to discriminate those preload-dependent patients in whom arterial blood pressure will improve only with fluids or by using vasopressors. Hypothetically, if a hypotensive patient is not a pressure-responder (low Eadyn), vasopressors should be initiated to improve mean arterial pressure, even if the patient is preload dependent. If the patient is a pressure-responder (high Eadyn), vasopressor therapy should be delayed and intravascular volume administration alone should increase arterial blood pressure.
Considering microvascular response to fluid challenge, different organs may present different behaviours. Edul et al. showed that an increase in red blood cell velocity in sublingual microcirculation after fluid challenge was not accompanied by the same response as the intestinal microcirculation. Thus, therapeutic approaches aimed at improving systemic haemodynamics may also affect microcirculation in different ways.
When clinicians identify an impaired tissue perfusion, they must understand whether their patient will benefit from a fluid infusion or whether other strategies of cardiovascular resuscitation are needed (e.g., inotropic or vasoactive drugs). Echocardiography is a fundamental tool for evaluating patients with cardiovascular impairment, as it is able to give information about preload, afterload and contractility. In addition, several continuous CO monitor systems are now available to evaluate the patients’ response to therapy. The decision to give fluids may be difficult in the critical care setting. Clinicians can use many parameters and can perform several tests to assess fluid responsiveness. It is important that a clinician knows the limits of each of them to avoid incorrect interpretation. Probably, different parameters or tests should be considered together to increase their single accuracy to predict the changes of CO after fluid infusion. Finally, we must not forget that the oxygen delivery to tissue can increase only if therapeutic interventions are able to reach the microcirculation. Even if microvascular evaluation is not currently part of routine clinical practice, technologies for the monitoring of the microcirculation are progressing quickly, so that in future a point-of-care tool could be available.
Papers of particular interest, published within the annual period of review, have been highlighted as:
1. Zhang L, Chen Z, Diao Y, et al. Associations of fluid overload with mortality and kidney recovery in patients with acute kidney injury: a systematic review and meta-analysis. J Crit Care 2015; 30:860.
2▪. Sirvent J-M, Ferri C, Baro A, et al. Fluid balance in sepsis and septic shock as a determining factor of mortality. Am J Emerg Med 2015; 33:186–189.
This study showed that the accumulated positive fluid balance in the first 48, 72 and 96 h was associated with higher mortality in critically ill patients with severe sepsis and septic shock.
3▪. Lee J, de Louw E, Niemi M, et al. Association between fluid balance and survival in critically ill patients. J Intern Med 2015; 277:468–477.
This study showed that positive fluid balance at the time of discharge from the ICU was associated with increased risk of death, particularly in patients with underlying heart or kidney disease.
4. Kelm DJ, Perrin JT, Cartin-Ceba R, et al. Fluid overload in patients with severe sepsis and septic shock treated with early goal-directed therapy is associated with increased acute need for fluid-related medical interventions and hospital death. Shock 2015; 43:68–73.
5. Donati A, Carsetti A, Damiani E, et al. Fluid responsiveness
in critically ill patients. Indian J Crit Care Med 2015; 19:375–376.
6. Cecconi M, Parsons AK, Rhodes A. What is a fluid challenge? Curr Opin Crit Care 2011; 17:290–295.
7▪▪. Cecconi M, De Backer D, Antonelli M, et al. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 2014; 40:1795–1815.
The current guidelines for the haemodynamic management of patients with circulatory shock.
8. Osman D, Ridel C, Ray P, et al. Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challenge. Crit Care Med 2007; 35:64–68.
9. Wiesenack C, Fiegl C, Keyser A, et al. Continuously assessed right ventricular end-diastolic volume as a marker of cardiac preload and fluid responsiveness
in mechanically ventilated cardiac surgical patients. Crit Care 2005; 9:R226–R233.
10. Endo T, Kushimoto S, Yamanouchi S, et al. Limitations of global end-diastolic volume index as a parameter of cardiac preload in the early phase of severe sepsis: a subgroup analysis of a multicenter, prospective observational study. J Intens Care 2013; 1:11.
11. Patterson SW, Starling EH. On the mechanical factors which determine the output of the ventricles. J Physiol 1914; 48:357–379.
12. Magder S. Bench-to-bedside review: an approach to hemodynamic monitoring–Guyton at the bedside. Crit Care 2012; 16:236.
13. Cecconi M, Aya HD, Geisen M, et al. Changes in the mean systemic filling pressure during a fluid challenge in postsurgical intensive care patients. Intens Care Med 2013; 39:1299–1305.
14. Guinot P-G, Bernard E, Defrancq F, et al. Mini-fluid challenge predicts fluid responsiveness
during spontaneous breathing under spinal anaesthesia. Eur J Anaesthesiol 2014; [Epub ahead of print].
15. Muller L, Toumi M, Bousquet P-J, et al. An increase in aortic blood flow after an infusion of 100 ml colloid over 1 min can predict fluid responsiveness
. Anesthesiology 2011; 115:541–547.
16. Michard F, Teboul J-L. Predicting fluid responsiveness
in ICU patients: a critical analysis of the evidence. Chest 2002; 121:2000–2008.
17. Jardin F, Farcot JC, Gueret P, et al. Cyclic changes in arterial pulse during respiratory support. Circulation 1983; 68:266–274.
18. Michard F, Boussat S, Chemla D, et al. Relation between respiratory changes in arterial pulse pressure and fluid responsiveness
in septic patients with acute circulatory failure. Am J Respir Crit Care Med 2000; 162:134–138.
19. Marik PE, Cavallazzi R, Vasu T, Hirani A. Dynamic changes in arterial waveform derived variables and fluid responsiveness
in mechanically ventilated patients: a systematic review of the literature. Crit Care Med 2009; 37:2642–2647.
20▪. Yang X, Du B. Does pulse pressure variation predict fluid responsiveness
in critically ill patients? A systematic review and meta-analysis. Crit Care 2014; 18:1–13.
This meta-analysis showed that pulse pressure variation is an accurate predictor of fluid responsivenes in mechanically ventilated critically ill patients.
21. Cannesson M, Le Manach Y, Hofer CK, et al. Assessing the diagnostic accuracy of pulse pressure variations for the prediction of fluid responsiveness
: a ‘gray zone’ approach. Anesthesiology 2011; 115:231–241.
22▪. Biais M, Ehrmann S, Mari A, et al. Clinical relevance of pulse pressure variations for predicting fluid responsiveness
in mechanically ventilated intensive care unit patients: the grey zone approach. Crit Care 2014; 18:1–11.
This study showed that a pulse pressure variation value between 4 and 17% was not able to predict fluid responsiveness. The authors proposed two cut-off levels to discriminate the ‘grey zone’.
23. De Backer D, Heenen S, Piagnerelli M, et al. Pulse pressure variations to predict fluid responsiveness
: influence of tidal volume. Intensive Care Med 2005; 31:517–523.
24. Lakhal K, Ehrmann S, Benzekri-Lefèvre D, et al. Respiratory pulse pressure variation fails to predict fluid responsiveness
in acute respiratory distress syndrome. Crit Care 2011; 15:R85.
25. De Backer D, Taccone FS, Holsten R, et al. Influence of respiratory rate on stroke volume
variation in mechanically ventilated patients. Anesthesiology 2009; 110:1092–1097.
26. Wyler von Ballmoos M, Takala J, Roeck M, et al. Pulse-pressure variation and hemodynamic response in patients with elevated pulmonary artery pressure: a clinical study. Crit Care 2010; 14:R111.
27. Shim J-K, Song J-W, Song Y, et al. Pulse pressure variation is not a valid predictor of fluid responsiveness
in patients with elevated left ventricular filling pressure. J Crit Care 2014; 29:987–991.
28▪. Mahjoub Y, Lejeune V, Muller L, et al. Evaluation of pulse pressure variation validity criteria in critically ill patients: a prospective observational multicentre point-prevalence study. Br J Anaesth 2014; 112:681–685.
This study showed that only 2% of critically ill patients met the criteria for the use of pulse pressure variation.
29. Fischer M-O, Mahjoub Y, Boisselier C, et al. Arterial pulse pressure variation suitability in critical care: a French national survey. Anaesth Crit Care Pain Med 2015; 34:23–28.
30. Monnet X, Osman D, Ridel C, et al. Predicting volume responsiveness by using the end-expiratory occlusion in mechanically ventilated intensive care unit patients. Crit Care Med 2009; 37:951–956.
31. Monnet X, Bleibtreu A, Ferré A, et al. Passive leg-raising and end-expiratory occlusion tests perform better than pulse pressure variation in patients with low respiratory system compliance. Crit Care Med 2012; 40:152–157.
32. Silva S, Jozwiak M, Teboul J-L, et al. End-expiratory occlusion test predicts preload responsiveness independently of positive end-expiratory pressure during acute respiratory distress syndrome. Crit Care Med 2013; 41:1692–1701.
33. Charron C, Caille V, Jardin F, Vieillard-Baron A. Echocardiographic measurement of fluid responsiveness
. Curr Opin Crit Care 2006; 12:249–254.
34. Barbier C, Loubières Y, Schmit C, et al. Respiratory changes in inferior vena cava diameter are helpful in predicting fluid responsiveness
in ventilated septic patients. Intensive Care Med 2004; 30:1740–1746.
35. Feissel M, Michard F, Faller JP, Teboul JL. The respiratory variation in inferior vena cava diameter as a guide to fluid therapy. Intensive Care Med 2004; 30:1834–1837.
36. Vieillard-Baron A, Augarde R, Prin S, et al. Influence of superior vena caval zone condition on cyclic changes in right ventricular outflow during respiratory support. Anesthesiology 2001; 95:1083–1088.
37. Vieillard-Baron A, Chergui K, Rabiller A, et al. Superior vena caval collapsibility as a gauge of volume status in ventilated septic patients. Intensive Care Med 2004; 30:1734–1739.
38. Slama M, Masson H, Teboul J-L, et al. Respiratory variations of aortic VTI: a new index of hypovolemia and fluid responsiveness
. Am J Physiol Heart Circ Physiol 2002; 283:H1729–H1733.
39. Monnet X, Rienzo M, Osman D, et al. Esophageal Doppler monitoring predicts fluid responsiveness
in critically ill ventilated patients. Intensive Care Med 2005; 31:1195–1201.
40. Monnet X, Richard C, Teboul JL. Passive leg raising. Intensive Care Med Annu Updat 2007; 2007:542–548.
41▪▪. Monnet X, Teboul J-L. Passive leg raising: five rules, not a drop of fluid!. Crit Care 2015; 19:1–3.
This article stated the fundamental rules to correctly perform a passive leg raising test in critically ill patients.
42. Monnet X, Rienzo M, Osman D, et al. Passive leg raising predicts fluid responsiveness
in the critically ill. Crit Care Med 2006; 34:1402–1407.
43. Cavallaro F, Sandroni C, Marano C, et al. Diagnostic accuracy of passive leg raising for prediction of fluid responsiveness
in adults: systematic review and meta-analysis of clinical studies. Intensive Care Med 2010; 36:1475–1483.
44. Mahjoub Y, Touzeau J, Airapetian N, et al. The passive leg-raising maneuver cannot accurately predict fluid responsiveness
in patients with intra-abdominal hypertension. Crit Care Med 2010; 38:1824–1829.
45. Monge García MI, Guijo González P, Gracia Romero M, et al. Effects of fluid administration on arterial load in septic shock patients. Intensive Care Med 2015; 41:1247–1255.
46. Monge García MI, Gil Cano A, Gracia Romero M. Dynamic arterial elastance to predict arterial pressure response to volume loading in preload-dependent patients. Crit Care 2011; 15:R15.
47. Monge García MI, Romero MG, Cano AG, et al. Dynamic arterial elastance as a predictor of arterial pressure response to fluid administration: a validation study. Crit Care 2014; 18:1–11.
48▪. Cecconi M, Monge García MI, Gracia Romero M, et al. The use of pulse pressure variation and stroke volume
variation in spontaneously breathing patients to assess dynamic arterial elastance and to predict arterial pressure response to fluid administration. Anesth Analg 2015; 120:76–84.
This study showed that only patients with a high value of dynamic arterial elastance have increased arterial blood pressure after a fluid challenge.
49. Ince C. The microcirculation
is the motor of sepsis. Crit Care 2005; 9 (Suppl 4):S13–S19.
50. De Backer D, Creteur J, Dubois M-J, et al. The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. Crit Care Med 2006; 34:403–408.
51. Dubin A, Pozo MO, Casabella CA, et al. Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study. Crit Care 2009; 13:R92.
52. Jhanji S, Stirling S, Patel N, et al. The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock. Crit Care Med 2009; 37:1961–1966.
53. De Backer D, Donadello K, Taccone FS, et al. Microcirculatory alterations: potential mechanisms and implications for therapy. Ann Intensive Care 2011; 1:27.
54. De Backer D, Ortiz JA, Salgado D. Coupling microcirculation
to systemic hemodynamics. Curr Opin Crit Care 2010; 16:250–254.
55. Donati A, Domizi R, Damiani E, et al. From macrohemodynamic to the microcirculation
. Crit Care Res Pract 2013; 2013:892710.
56. Donati A, Tibboel D, Ince C. Towards integrative physiological monitoring of the critically ill: from cardiovascular to microcirculatory and cellular function monitoring at the bedside. Crit Care 2013; 17 (Suppl 1):S5.
57. Pranskunas A, Koopmans M, Koetsier PM, et al. Microcirculatory blood flow as a tool to select ICU patients eligible for fluid therapy. Intensive Care Med 2013; 39:612–619.
58. Edul V, Ince C, Navarro N, et al. Dissociation between sublingual and gut microcirculation
in the response to a fluid challenge in postoperative patients with abdominal sepsis. Ann Intensive Care 2014; 4:39.