In a sensitivity analysis, we also examined the value of VCCI and AoVV in predicting hemodynamic response to VE if variation were calculated from the minimum and maximum values over a 20-s period. In this case, AoVV had an AUC of 0.86 (0.65–1.00), and VCCI had an AUC of 0.84 (0.63–1.0).
This is the first study to demonstrate that SVV can predict hemodynamic response to VE in patients with septic shock who are not receiving mechanical ventilation and the second study to demonstrate that VCCI can predict VE in the same population (34). Prior studies in this area have largely been confined to the mechanically ventilated patient receiving fully controlled ventilation (14, 16, 17, 20, 22, 23). Before this study and the study by Muller and colleagues (34), the only dynamic parameter that reliably predicted hemodynamic response to VE in the nonintubated septic patient is the passive leg-raise maneuver (35). However, the passive leg-raise maneuver requires manipulation of patient position, as well as a device to measure changes in cardiac output or stroke volume. Furthermore, the passive leg raise may be inaccurate in the setting of abdominal compartment syndrome (36). The parameters in this study require no cooperation from or movement of the patient and can be easily obtained in less than 1 min by a trained clinician, and they do not require measurement of cardiac output after the VE.
Dynamic fluctuations in intrathoracic pressure will occur not only in the passive mechanical breath but also in the spontaneously breathing patient (37). A measurable delta in intrathoracic pressure, whether positive or negative, may allow the clinician to infer the patient’s position on the Frank-Starling curve. In the patient receiving passive mechanical ventilation, the change in intrathoracic pressure is positive deflection, whereas in the patient free from mechanical ventilation, the change is a negative deflection. In a patient receiving a mechanically assisted breath, the net effect of intrathoracic pressure change may be difficult to assess (38).
We suspect that reported poor prediction of dynamic parameters in the spontaneously breathing, mechanically ventilated patient may be due to two factors. First, spontaneous breathing in assisted mechanical ventilation may have more complex hemodynamic effects than either unassisted breathing or controlled ventilation (38–40). Kimura and colleagues (41) demonstrated that the inferior vena cava collapsibility may be affected by the amount of diaphragmatic excursion versus the amount of chest excursion. Second, the tidal volumes and intrathoracic pressures are inconsistent in the spontaneously breathing patient. One of the few positive studies in which dynamic parameters predicted hemodynamic response to VE in non–mechanically breathing subjects did so in healthy volunteers (30). That study required the subjects to synchronize their breathing to a metronome set at 6 breaths/min to decrease breath-to-breath variability. Our study made no attempts to pace the breathing of the patient.
This study is the second study to demonstrate that VCCI is predictive in the spontaneously breathing patient. Muller and colleagues (34) examined VCCI in a group of spontaneously breathing patients with acute circulatory failure, 24 of whom were in septic shock. In their nonblinded study, they demonstrated that a VCCI of 40% or greater was likely to predict hemodynamic response to VE, whereas a VCCI of less than 40% was not very useful. Taken together with our study, it appears that either very large or very small values of VCCI may have some utility in predicting response to VE, although VCCI may have a wide range where it is clinically indeterminate in the spontaneously breathing patient.
In our study, the echocardiographically derived AoVV was poorly predictive, whereas the SVV, derived from arterial pulse contour, had excellent predictive value. In most cases, the peak aortic blood velocity should be proportional with the stroke volume, although it does not correlate with stroke volume as well as the velocity-time integration. One possible explanation for the discrepancy between AoVV and SVV is that the FloTrac uses an algorithm that calculates SVV from all data points, continuously averaged over a period of time (20 s), whereas our AoVV was calculated from the largest single variation over a 20-s period. Calculation of the AoVV from the largest and smallest values over a 20-s period yielded a greater AUC (0.86; 0.64–1.0). Another possible explanation for the difference between AoVV and SVV is that the AoVV is dependent on the ultrasound probe angle and therefore may be prone to artifact from cardiac movement or from operator technique. If either the heart or the ultrasound probe moved during recording, it would alter the measurement of aortic blood velocity. We attempted to mitigate the possibility of cardiac translation during respiration by always measuring cardiac output at end expiration. However, respiration-induced cardiac translation cannot be eliminated from the AoVV, as it is measured throughout respiration.
We chose the largest single respiratory variation during a 20-s observation (to capture the largest signal) because it may be difficult for a clinician at beside to average several consecutive measurements in real time. This methodology is similar to previous studies in mechanically ventilated patients, which measured changes over the course of a single breath, or an average over several consecutive respiratory cycles (17, 19, 20, 22). However, in these previous studies, there was minimal breath-to-breath variation, and thus no preference was given to one respiratory cycle over another.
The thresholds of the studied parameters are somewhat larger than similar values reported in mechanically ventilated patients receiving chemical paralysis. Vieillard-Baron and colleagues (19) assessed superior vena cava collapsibility using transesophageal echocardiography in septic shock, finding that a threshold of 36% had good sensitivity and specificity. Barbier and colleagues (22) assessed inferior vena cava distensibility in mechanically ventilated patient in septic shock, with a threshold of 18%. Feissel and colleagues (17) calculated an AoVV of 12% in mechanically ventilated septic patients, whereas Skulec and colleagues (30) calculated a threshold value for AoVV of 14% in spontaneously breathing, healthy volunteers. Stroke volume variation obtained from FloTrac device has been validated in mechanically ventilated patients recovering from cardiac surgery (13, 15), but at the time of this writing, it has not yet been validated in patients with septic shock (31). The useful threshold for SVV in mechanically ventilated postoperative patients is 10% (15). We posit two possible explanations for why the optimal thresholds for VCCI and AoVV in this study were larger than those calculated in previous studies: First, we used the largest single respiratory variation observed over a 20-s period rather than an average breath-to-breath calculation. Second, there may be greater efficiency in the work of breathing in patients free from mechanical ventilation compared with patients receiving passive mechanical ventilation. This increased efficiency may result in decreased delta to the intrathoracic pressure for a comparable tidal volume and therefore may require a larger signal to achieve comparable effect.
This study enrolled patients after their initial emergency department resuscitation. Every enrolled patient had received 2 to 5 L of intravenous fluid before enrollment. Therefore, this study is relevant to the intensivist managing early septic shock after the initial emergency department resuscitation. In our study, 64% (8/14) of VEs, all of which were administered for clinical indications, failed to improve hemodynamics. This number is within range of other similar studies (28%–70%) (10, 22, 42). These studies, combined with the known harms of excess VE, serve as a reminder to the intensivist that continued administration of fluid may not be indicated in the early ICU resuscitation of septic patients (3–5).
This is a pilot study and therefore is limited by its small size. However, the sample size is not much smaller than similar studies in the field. Feissel and colleagues (17) demonstrated AoVV to be predictive in 19 mechanically ventilated patients, and Barbier and colleagues (22) demonstrated inferior vena cava distention was predictive in 23 mechanically ventilated patients. All echocardiographic measurements were obtained by a single physician, which eliminates interobserver variability but does not allow for assessment of reproducibility. The study assessed only a single 10-mL/kg VE and cannot inform on the value of larger or smaller VEs. Clinical parameters, such as increase in urine output or improved survival, were not studied. Strengths of this study include its prospective nature and its measurement of cardiac index by echocardiography, which is more relevant to current clinical practice and avoids the risks of assessing cardiac index with a pulmonary artery catheter (26). This study also more closely replicates the clinical setting, as the intensivist typically treats patients in septic shock who have already received initial emergency department resuscitation.
Further work in this area, in addition to external validation, should explore composite measurements of these parameters and others to create a robust model to predict a patient’s likelihood to respond to fluid administration.
The authors thank Ben Briggs for screening patients, Naresh Kumar for consenting patients, and Amanda Borba for administrative support.
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