Intravenous fluid administration is one of the most important interventions in the resuscitation of critically ill patients. Titration of fluid resuscitation to optimally fill the intravascular compartment without causing tissue edema from excessive administration holds the key to important clinical outcomes. Injudicious fluid administration without appropriate evaluation of fluid responsiveness has been clearly shown to worsen clinical outcomes, including a longer duration of mechanical ventilation, ICU stay, and mortality.1,2 The practice of repeated fluid challenges using blood pressure or urine output as the sole target is fraught with the risk of creating tissue edema with adverse consequences. It is important to note that an increase in the cardiac output occurs only in approximately 50% of critically ill patients after a fluid bolus.3
Basic physiology: the Frank-Starling curve
The relationship between cardiac preload and stroke volume is depicted by the Frank-Starling curve. If the patient lies along the ascending limb of the Frank-Starling curve, fluid administration would result in myocardial distension, an increase in the preload, and a consequent rise in the stroke volume. If the patient lies in the plateau phase of the curve, fluid administration does not lead to an increase in the stroke volume (Fig. 1). Thus, it is important to distinguish between fluid “responders” and “non-responders” based on their position along the Frank-Starling curve. Phasic changes in preload that occur with respiratory excursions, resulting from a change in intrathoracic pressures may be utilized to evaluate fluid responsiveness. If the myocardial function is impaired, the curve becomes flatter, with a blunted response to fluid administration.
Techniques to assess fluid responsiveness
Passive leg raising
This technique utilizes the increase in preload that occurs with raising both lower limbs passively. Approximately 300 ml of fluid is mobilized from the lower part of the body to augment the cardiac preload during this maneuver. An increase in the stroke volume associated with passive leg raising indicates fluid responsiveness.
The passive leg raising maneuver is commenced with the patient in the propped-up position, with the trunk at an angle of 45 degrees. The baseline cardiac output is measured using the preferred technique. This is followed by returning the trunk to the flat position and raising the legs by adjusting the bed position appropriately. Cardiac output measurement is repeated in this position. The final step is to reposition the patient in the original semi-recumbent position with the reassessment of cardiac output to confirm return to baseline level. A rise in cardiac output of more than 10 ± 2 % to passive leg raising was noted to be the best cut-off in a meta-analysis.4 The passive leg raising test is valid with low tidal volume ventilation, spontaneous or controlled ventilation, in the presence of atrial fibrillation, and in patients with poor lung compliance.4 It may not be reliable in patients with intra-abdominal hypertension.5
Pulse pressure and stroke volume variation
The pulse pressure variation helps identify the location of the patient along the Frank-Starling curve. If a patient lies on the ascending portion of the curve, preload changes associated with phasic changes of the respiratory cycle results in a wide pulse pressure variation (Fig. 2). Conversely, on the plateau phase of the curve, the pulse pressure variation becomes narrower.
In practice, the highest (PP max) and the lowest (PP min) values of pulse pressure during a respiratory cycle are noted. The mean of these two values is also obtained (PP mean). The pulse pressure variation (PPV) is obtained by the formula:
PPV = (PPmax – PPmin / PPmean) x 100
A pulse pressure variation of 13% or more has been shown to indicate fluid responsiveness.6 Myatra et al. performed a “tidal volume challenge” among 20 patients. From a baseline of 6 ml/kg, the tidal volume was increased to 8 ml/kg for a one-minute duration in patients with circulatory failure. An absolute change in pulse pressure variation of 3.5% before and after an increase of tidal volume predicted fluid responsiveness.8
Stroke volume variation is also based on the reduction in preload and stroke volume that occurs during the inspiratory phase of positive pressure ventilation. If the stroke volume varies significantly between the inspiratory and expiratory phases, it suggests that the patient lies along the preload-dependent part of the Frank-Starling curve. Conventionally, a stroke volume variation of 13% has been used as the threshold level to indicate fluid responsiveness.7 Using the tidal volume challenge technique described above, an absolute change in the stroke volume variation by more than 2.5% was shown to indicate fluid responsiveness.8
Pulse pressure variation and stroke volume variation are considered applicable in mechanically ventilated patients with a tidal volume ≥ 8 ml/kg and no spontaneous respiratory efforts. However, a recent meta-analysis suggests that these parameters may be reliable even at tidal volumes ≤ 8 ml/kg.9 Both measurements may be unreliable in patients with lung compliance of less than 30 ml/cm H2O and in the presence of intra-abdominal hypertension.10
End-expiratory occlusion test
The end-expiratory occlusion test is performed by interruption of ventilation at the end of expiration for a duration of 15 seconds, followed by evaluation of the change in cardiac output or surrogate parameters before and after occlusion. This test is based on the principle that in volume-responsive subjects, the cardiac output increases significantly during the expiratory phase of mechanical ventilation.
The test is performed by a baseline measurement of cardiac output or a surrogate parameter. A 15-second expiratory hold is carried out, with repeat measurement during the last 5 seconds of the expiratory hold. A final measurement is carried out 30 seconds after the expiratory hold maneuver to assess the return of values to the baseline. An increase in cardiac output of 5% or more following end-expiratory occlusion has been shown to indicate fluid responsiveness.8,11 However, another study revealed that the end-expiratory occlusion test was unreliable in predicting volume-responsiveness during laparotomy for colorectal, pancreatic, or major gynecological surgery.12
Respiratory variation of the inferior vena caval diameter
The diameter of the inferior vena cava (IVC) is usually evaluated by transthoracic echocardiography. The IVC is viewed from the subxiphoid position in the long axis. The cursor is positioned close to the entry to the right atrium or 1–2 cm downstream to the junction between the hepatic vein and the IVC. The degree of change in the IVC diameter is calculated on the M-mode view. A variation in IVC diameter of 12–18% with fully controlled ventilation and more than 50% in spontaneously breathing patients is suggestive of fluid responsiveness.13
Although easy to perform by the bedside, the phasic variation in the inferior vena caval diameter (Δ IVC) with respiration has been inconsistent in predicting fluid responsiveness. Ventilation with low tidal volumes, poor lung compliance, and the presence of intra-abdominal hypertension may contribute to relative inaccuracy. In particular, Δ IVC may be a poor indicator of fluid-responsiveness in patients with isolated left ventricular dysfunction.
Variation in the end-tidal carbon dioxide level
An increase in the cardiac output leads to a rise in the pulmonary blood flow, improved perfusion of the alveoli, and a rise in the end-tidal carbon dioxide (ETCO2), provided alveolar ventilation and carbon dioxide production are constant. Thus, in patients who are maintained at a constant level of mechanical ventilation, ETCO2 rise may be used as a simple, non-invasive measure of fluid responsiveness. Fluid responsiveness assessed by an increase in ETCO2 following passive leg raising has been evaluated. An increase by 2 mm Hg16 or 5% from the baseline level17 has been proposed to indicate fluid responsiveness. ETCO2 may be superior to other non-invasive surrogates of cardiac output assessment, including pulse pressure variation.18
The mini-fluid challenge
The conventional fluid challenge of 250–500 ml over approximately 30 min may result in a large volume overload, especially with repeated, injudicious administration. To circumvent this complication, a much smaller fluid volume of 100 ml over a one minute-period has been proposed.19 A 6% increase in the cardiac output induced by a mini-fluid challenge has been shown to be superior to pulse pressure variation in the prediction of fluid responsiveness among patients undergoing neurosurgical procedures.20 A meta-analysis of seven studies revealed a sensitivity of 0.82 (95%CI 0.76-0.88) and a specificity of 0.83 (95%CI 0.77-0.89) for the mini-fluid challenge in identifying fluid responsiveness.21 It is important to note that continuous, real-time measurements are required during the mini-fluid challenge as the increase in cardiac output is relatively low.
- Fluid resuscitation is a crucial intervention in the early phase of circulatory shock. Judicious fluid administration based on the assessment of fluid-responsiveness is critical, especially in the later phase of resuscitation
- Injudicious fluid administration based solely on blood pressure or urine output may result in inadvertent hypervolemia and impact clinical outcomes adversely
- The passive leg raise maneuver is an effective method to assess fluid responsiveness; it is valid in spontaneous or controlled ventilation, with low tidal volumes, in the presence of atrial fibrillation, and in patients with poor lung compliance
- Pulse pressure and stroke volume variation may be useful primarily in patients who receive mechanical ventilatory support with a tidal volume of ≥ 8 ml/kg, with no spontaneous respiratory effort.
- ETCO2 rise following a passive leg raise maneuver is yet another non-invasive method that indicates fluid-responsiveness
- If a volume challenge is necessary, it is probably safer and equally effective to use a “mini” volume of 100 ml over 1 min instead of a larger volume
- It is of paramount importance not to be swayed by a single parameter while assessing fluid responsiveness; decisions must be based on the holistic clinical picture
1. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564-2575. doi:10.1056/NEJMoa062200
2. Van Mourik N, Metske HA, Hofstra JJ, et al. Cumulative fluid balance predicts mortality and increases time on mechanical ventilation in ARDS patients: An observational cohort study. PLoS One. 2019;14(10):e0224563. doi:10.1371/journal.pone.0224563
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7. Lee Y-H, Jang H-W, Park C-H, et al. Changes in plasma volume before and after major abdominal surgery following stroke volume variation-guided fluid therapy: a randomized controlled trial. Minerva Anestesiol. 2020;86(5):507-517. doi:10.23736/S0375-9393.19.13952-1
8. Myatra SN, Prabu NR, Divatia JV, Monnet X, Kulkarni AP, Teboul J-L. The Changes in Pulse Pressure Variation or Stroke Volume Variation After a “Tidal Volume Challenge” Reliably Predict Fluid Responsiveness During Low Tidal Volume Ventilation*: Critical Care Medicine. 2017;45(3):415-421. doi:10.1097/CCM.0000000000002183
9. Alvarado Sánchez JI, Caicedo Ruiz JD, Diaztagle Fernández JJ, Amaya Zuñiga WF, Ospina-Tascón GA, Cruz Martínez LE. Predictors of fluid responsiveness in critically ill patients mechanically ventilated at low tidal volumes: systematic review and meta-analysis. Ann Intensive Care. 2021;11(1):28. doi:10.1186/s13613-021-00817-5
10. Shi R, Monnet X, Teboul J-L. Parameters of fluid responsiveness. 2020;26(3):8.
11. Messina A, Montagnini C, Cammarota G, et al. Tidal volume challenge to predict fluid responsiveness in the operating room: An observational study. Eur J Anaesthesiol. 2019;36(8):583-591. doi:10.1097/EJA.0000000000000998
12. Weil G, Motamed C, Monnet X, Eghiaian A, Le Maho A-L. End-Expiratory Occlusion Test to Predict Fluid Responsiveness Is Not Suitable for Laparotomic Surgery. Anesthesia & Analgesia. 2020;130(1):151-158. doi:10.1213/ANE.0000000000004205
13. Feissel M, Michard F, Faller J-P, Teboul J-L. The respiratory variation in inferior vena cava diameter as a guide to fluid therapy. Intensive Care Med. 2004;30(9):1834-1837. doi:10.1007/s00134-004-2233-5
14. Vignon P, Repessé X, Bégot E, et al. Comparison of Echocardiographic Indices Used to Predict Fluid Responsiveness in Ventilated Patients. Am J Respir Crit Care Med. 2017;195(8):1022-1032. doi:10.1164/rccm.201604-0844OC
15. Zhang H, Zhang Q, Chen X, Wang X, Liu D, Chinese Critical Ultrasound Study Group (CCUSG). Respiratory variations of inferior vena cava fail to predict fluid responsiveness in mechanically ventilated patients with isolated left ventricular dysfunction. Ann Intensive Care. 2019;9(1):113. doi:10.1186/s13613-019-0589-5
16. Toupin F, Clairoux A, Deschamps A, et al. Assessment of fluid responsiveness with end-tidal carbon dioxide using a simplified passive leg raising maneuver: a prospective observational study. Can J Anesth/J Can Anesth. 2016;63(9):1033-1041. doi:10.1007/s12630-016-0677-z
17. Monnet X, Bataille A, Magalhaes E, et al. End-tidal carbon dioxide is better than arterial pressure for predicting volume responsiveness by the passive leg raising test. Intensive Care Med. 2013;39(1):93-100. doi:10.1007/s00134-012-2693-y
18. Lakhal K, Nay MA, Kamel T, et al. Change in end-tidal carbon dioxide outperforms other surrogates for change in cardiac output during fluid challenge. Br J Anaesth. 2017;118(3):355-362. doi:10.1093/bja/aew478
19. Muller L, Toumi M, Bousquet P-J, et al. An increase in aortic blood flow after an infusion of 100 ml colloid over 1 minute can predict fluid responsiveness: the mini-fluid challenge study. Anesthesiology. 2011;115(3):541-547. doi:10.1097/ALN.0b013e318229a500
20. Biais M, de Courson H, Lanchon R, et al. Mini-fluid Challenge of 100 ml of Crystalloid Predicts Fluid Responsiveness in the Operating Room. Anesthesiology. 2017;127(3):450-456. doi:10.1097/ALN.0000000000001753
21. Messina A, Dell’Anna A, Baggiani M, et al. Functional hemodynamic tests: a systematic review and a metanalysis on the reliability of the end-expiratory occlusion test and of the mini-fluid challenge in predicting fluid responsiveness. Crit Care. 2019;23(1):264. doi:10.1186/s13054-019-2545-z