The main findings of our study are, first, the proportion of NR, ER, and LR were comparable between gelatin and NS groups; second, FC induced the most frequency of CImax at T2 and T1 in gelatin and NS groups, respectively, and the positive FR status sustained until T4 in gelatin group, while until T1 in NS group; third, 14 patients identified as NR at T0 became LR at T1 or later, and both ER and LR achieved CImax at T2 after FC in gelatin group, whereas at T1 in NS group.
Our results showed gelatin exhibited a longer duration of positive response status than NS after FC. This might be due to the difference in hemodynamic effects between crystalloid and colloid. That is, colloid can maintain a longer-term hemodynamic effect when compared with crystalloid in equal scenario11,23. In a recent randomized trial, Gondos and colleagues examined the kinetics of volume loading with crystalloid and colloid infusions in 200 critically ill patients, and they found that 6% hydroxyethyl starch still produced a change in CI (23%) at 120 min after infusion, while this effect dissipated in lactated Ringer’s solution11.
On the other hand, positive response status over time to FC may also be affected by patient populations and details in performing FC (i.e., a CO monitoring technique, duration or volume of infusion)20,21. In their pharmacodynamic analysis in FC (250 ml crystalloid, injected in 5 min), Aya et al. found the maximal CO increase was observed 1 min after the end of FC, and the fluid bolus effect disappeared in 10 min21. However, in the FCREV study (500 ml crystalloid infusion, 10 min), 30% (43/143) patients exhibited positive responses to infusion 20 min after FC20.
Interestingly, 22% (14/63) of patients showed an initial negative response immediately after FC subsequently converted to LR. We called these patients “late responders to FC.” Such a phenomenon was observed in septic shock patients20 or post-cardiac surgery patients15–19 in some previously published studies. These patients are likely to be overlooked when FR is only evaluated immediately at the end of the infusion. Thus, this finding supports our hypothesis that timing assessment of FR could affect the proportion of patients responding to FC. However, our conclusion is in contrast with a recently published meta-analysis that focused on FC8. In this study, the authors grouped the 86 included studies into three categories based on assessment time (immediately, between 1 and 10 min, or >10 min after FC) and found FR timing assessment did not affect the proportion of responders. Of note, the pooled results of types of fluids (crystalloid or colloid), FR criteria (10% or 15%), techniques (PICCO, PAC, or ultrasound), and setting (ICU and operating room) might contribute to the significant heterogeneity among the included studies, Thus leading to their negative results8.
Another important finding is the different distribution of CImax between gelatin and NS after FC may provide meaningful clues to aid in the timing of assessment. When NS is used, FR should be performed from the end of FC to 10 min that after. Conversely, if the FR assessment was performed too later, some patients might have already changed their FR status from R to NR at that time point. Thus, these patients are susceptible to be identified as NR. In a randomized trial comparing hemodynamics in septic shock patients who received either hypotonic or hypertonic fluid24, the authors found only 30% (3/12) and 33% (4/12) responders in the two groups at 30 min after FC. Similarly, Nunes and colleagues identified all the responders at the end of FC. This may because they evaluated FR at the end of FC and 30 min thereafter10. As to gelatin, it is better to extend the assessment time to 30 min after FC, especially for patients who show negative responses immediately after infusion. Of note, the CI course over time was significantly different among LR, ER, and NR (P<0.001) as well as baseline CI (4.6±1.0, 3.5±1.0, 3.1±1.0 L/min/m2, respectively). Thus, we assume that CI values at baseline might help identify NR, and LR fluid responders immediately at the end of infusion and further research is warranted in the future.
The current study explored the effects of crystalloid and colloid on the time course of FR in septic shock and suggested reasonable ranges of FR assessment time. However, some details in our study design worth discussion. First, we used gelatin and NS in our study. Reasons for this included that NS is the most commonly used crystalloid7, safety considerations of hydroxyethyl starch25, and the availability of gelatin in our unit. However, it should be cautious about extrapolating our conclusion to other types of fluids since previous studies have demonstrated that various fluids (i.e., lactated Ringer’s solution, gelatin,hydroxyethyl starch, or album) exhibited different hemodynamic effects over time after volume loading11. Second, the volume of fluid used was 500 ml, the current “mainstream volume” selection for FC26. However, whether our results could also be applied for other fixed fluid volumes (i.e., 250 ml) or fluid volume adjusted for body-weight remains unclear. This would require further investigation. Third, the process of FC was completed in about 6 min, which is faster than most other FC studies8,10. Theoretically, the shorter infusion duration, the larger proportion volume of fluid will remain in the intravascular compartment at the end of infusion, and a higher positive FR rate may be obtained. This was also confirmed by the meta-analysis result, which demonstrated that the proportion response to an FC given in ≥30 min was lower than that in <15 min (P=0.045)8. Thus, this might indirectly add evidence for the reliability of negative FR in LR patients immediately after FC in the current study. Finally, we explored the time course of FR in 120 min after fluid infusion, a relatively longer period compared to the previous studies10,20,21. Apart from the purpose of a complete recording of hemodynamic effects on FR, the main consideration for this is the tolerability of volume-limited (infusion <100 mL/h) during 120 min in the enrolled patients. Overall, no adverse events were observed during the study period, which may be related to the initial fluid resuscitation performed in these patients before enrollment.
Our study had several limitations. The first and main limitation is the incapability to fully explain our results from the pathophysiology mechanism due to the pure observation nature of the current study, especially for LR patients. Nevertheless, our data may, at the very least, encourage clinicians to reevaluate their practice in deciding timing assessment of response to FC in septic shock patients. Second, FR was evaluated at only 7 predefined time points referred to most previous studies8,10,11,27. However, our results suggest that more assessment time points may be essential in the early stage after FC, especially in crystalloid group patients with relatively short periods of hemodynamic effect. Finally, only septic shock patients having received initial fluid resuscitation were included according to the current protocol. However, the fully initial fluid resuscitation has not been strictly defined and lacked individuation. A previous study reported FC (5 ml/kg crystalloid solution infusion over 15 min) induced a significant increase in CO and sustained for 120 min in severe hypovolemic sepsis patients without initial fluid resuscitation. Whether our results could apply to such a patient population is unclear.