Mini-fluid Challenge of 100 ml of Crystalloid Predicts Fluid Responsiveness in the Operating Room

RATIONAL fluid administration is the cornerstone of perioperative hemodynamic optimization.^1–3  Hypovolemia increases the risk of organ hypoperfusion, sepsis, and multiorgan failure, whereas a large amount of fluid may induce pulmonary and peripheral edema and increase cardiac demands.^4,5  Broadly, there are two strategies that can be used in the operating room. The first is based on the prediction of fluid responsiveness. For more than 15 yr, dynamic variables based on heart–lung interactions have been proposed.⁶  Among these indices, respiratory variations in pulse pressure (PPV) and respiratory variations in stroke volume are the most popular. They are very effective in predicting the effects of volume expansion but under very strict conditions.⁷  The main limitation is the use of low tidal volume.⁸  It is well known nowadays that a protective ventilation strategy is associated with a decrease in postoperative pulmonary complications.^9,10  When tidal volume is less than 7 ml/kg of ideal body weight, high PPV values remain accurate to predict fluid responsiveness, but low values are not informative.¹¹  The second strategy is based on titration and monitoring of the effects of volume expansion. Several randomized control trials suggest that stroke volume maximization with fluid challenge decreases both the postoperative length of hospital stay and morbidity.^2,3  The main algorithm used is based on the administration of 250 ml of crystalloid or colloid for more than 10 min. Volume expansion is continued until the volume of ejection does not increase and another volume expansion is performed if the stroke volume decreases. This protocol is recommended by the National Institute for Clinical Excellence and by the French Society of Anesthesiologists.^12,13  Although this algorithm is associated with good outcome, this method may result in repeated ineffective fluid boluses. During lengthy surgery, the repetition of ineffective fluid challenge should be avoided. Indeed, perioperative fluid overload and positive fluid balance are associated with poor outcome.^4,5  One way to limit unnecessary fluid infusion is the mini-fluid challenge.

Muller et al.¹⁴  demonstrated in their intensive care unit (ICU) that the increase in stroke volume induced by rapid infusion of 100 ml colloid (mini-fluid challenge) is able to predict stroke volume increase induced by 500 ml. In other words, the plateauing of stroke volume after 100 ml might preclude the need for additional volume expansion and thus avoid administering the remaining 400 ml. More recently, Mallat et al.¹⁵  showed that the decrease in PPV or stroke volume variations after a mini-fluid of colloid predicted fluid responsiveness.

We hypothesized that changes in stroke volume index induced by rapid infusion of a small quantity of crystalloid could predict the effects of a larger amount of fluid in patients ventilated mechanically in the operating room. Therefore, the present study sought to evaluate the degree to which changes in stroke volume index (ΔSVI) induced by the rapid infusion of 50 and 100 ml crystalloid could predict the effects of administering 250 ml crystalloid.

This study obtained the approval of the institutional review board (Comité de Protection des Personnes Sud-Ouest et Outre Mer III, Bordeaux, France, No. DC2015/117), and oral informed consent was obtained from all of the patients (the institutional review board waived the need for written informed consent because the studied strategy did not change the current strategy of fluid administration). The inclusion of patients lasted for 1 yr, from July 2014 to July 2015. Inclusion criteria were as follows: patients older than 18 yr scheduled for neurosurgery, equipped with radial arterial catheter and cardiac output monitor, surgery in supine position, and the absence of arrhythmia. Volume expansion (250 ml saline 0.9%) was performed at the discretion of the attending physician.

Patients were monitored with noninvasive blood pressure, oxygen saturation measured by pulse oximetry, and electrocardiogram. Total IV anesthesia was used by target-controlled infusion of remifentanil and propofol. Patients were mechanically ventilated using a volume-control mode with a tidal volume of 6 to 8 ml/kg of ideal body weight, respiratory rate was adjusted to maintain normocapnia, positive expiratory pressure was set between 3 and 6 cm H₂O, inspired oxygen fraction was adjusted to maintain pulse oximetry above 95%, and inspiratory/expiratory ratio was 0.5.

A radial arterial catheter was linked to a bedside monitor on one side and to a specific transducer (ProAQT; Pulsion Medical System, Germany) for stroke volume index monitoring on the other side. The initial value of cardiac output was estimated with a proprietary algorithm performing an autocalibration. Cardiac output was then determined by pulse contour analysis. PPV was continuously displayed on the Pulsioflex (Pulsion Medical System, Germany) monitor.

The design of the study is shown in figure 1. Hemodynamic measurements included heart rate; systolic, diastolic, mean, and pulse arterial pressure; stroke volume index; and PPV. Volume expansion consisted of an infusion of 250 ml saline 0.9% over 10 min. Sets of measurements were performed before volume expansion, 1 min after the infusion of 50 ml given over 1 min, 1 min after the infusion of another 50 ml (total = 100 ml) given over 1 min, and 1 min after the infusion of the remaining 150 ml (total = 250 ml) given over 5 min.

In view of previous results (PPV area under the receiver operating characteristics curves of 0.51 in nonselected conditions),¹⁶  sample size estimation showed that at least 42 patients were necessary to highlight a difference of 0.25 between ΔSVI 100 and PPV areas under the receiver operating characteristics curves (two-tailed type I error at 5%, power equal to 80%, and ratio of sample sizes in negative/positive groups at 1/4).^17,18  Positive fluid challenge was defined as an increase in stroke volume index of 10% or higher from baseline after an infusion of 250 ml.

Results were expressed as mean ± SD if data were normally distributed or median (25 to 75% interquartile range) if not. Hemodynamic parameters were compared at baseline between positive and negative fluid challenges using the Mann–Whitney U test. The effects of volume expansion on hemodynamic parameters were studied using the Friedman nonparametric repeated measures comparisons, and post hoc analyses were performed using the Wilcoxon test with Bonferroni adjustment. To take into account the fact that several fluid challenges were performed in the same patient, random-effects models were performed to study between- and within-patient variability, as well as generalized linear mixed models (logit link function to dichotomous endpoint). The same statistical approach was used for repeated measures in the receiver operating characteristic curve and the gray zone.^19,20  Receiver operating characteristic curves were generated for PPV, ΔSVI 50, and ΔSVI 100 by varying the discriminating threshold of each parameter, and areas under the receiver operating characteristics curves (95% CIs) were calculated and compared as proposed by DeLong et al.¹⁷  The best cutoff value was chosen so as to maximize the Youden index (sensitivity + specificity – 1). A P value less than 0.05 was considered to be statistically significant. Receiver operating characteristics curve methodology does not take into account the existence of an overlap between positive and negative fluid challenges. The gray zone methodology avoids the binary response proposed by the receiver operating characteristics curves and proposes a low cutoff value that excludes positive fluid challenge in 90% of patients, whereas a high cutoff value predicts positive fluid challenge in 90% of cases.^21–23 

Estimation of the gray zone was based on two major steps. First, receiver operating characteristics curves were created by using a bootstrap methodology, which creates multiple samples (1,000) by randomly drawing instances, with replacement, from the original study population. So, this first step was useful to determine 95% CI of the best thresholds of the bootstrap population (1,000).²⁴  The second step was performed to define a threshold related to a sensitivity of 90% and another threshold related to a specificity of 90% using the 1,000 population. Finally, the larger gray zone obtained using these two steps was retained.

Statistical analysis was performed using Medcalc (software 11.6; Mariakerke, Belgium), R Development Core Team (http://www.R-project.org, version R 3.4.0, accessed January 2017), and NCSS 8 (NCSS, LLC, USA).

Eighty-eight volume expansions (positive fluid challenge = 28, negative fluid challenge = 60) were performed in 44 nonconsecutive patients. The main characteristics of the patients are reported in table 1, and their hemodynamic variables are shown in table 2.

Hemodynamic variables in positive fluid challenge and negative fluid challenge at different steps of volume expansion are shown in table 2. The evolution of stroke volume index in positive and negative fluid challenges at different steps of volume expansion are shown in figure 2.

The intraclass correlation coefficient, estimated from random-effects generalized linear models used to predict the effect of volume expansion, was approximately 0 (intraclass correlation coefficient = 0.02), thereby describing a low patient effect and little impact on results.^19,20,25  The ability of ΔSVI 50, ΔSVI 100, and PPV to predict the effect of volume expansion is shown in table 3 and figure 3. Areas under the receiver operating characteristics comparison demonstrated the superiority of ΔSVI 100 over ΔSVI 50 (P < 0.005) and over PPV (P < 0.0001) and the superiority of ΔSVI 50 over PPV (P = 0.01).

If volume expansion was stopped when ΔSVI 100 was not above 4% (low value of the gray zone), it would have avoided 150 ml inefficient fluid challenge in 44 (73%) of 60 with negative fluid challenge.

This study demonstrates that, in neurosurgical patients ventilated with low tidal volume in the operating room, (1) the performance of ΔSVI 100 is better than that of ΔSVI 50 and PPV to predict the effect of volume expansion; (2) the probability of a positive response to volume expansion is greater than 90% when ΔSVI 100 is greater than 7%; (3) the probability of a negative response to volume expansion is greater than 90% when ΔSVI 100 is less than 4%; and (4) 19% of patients are in the gray zone (ΔSVI 100 between 4 and 7%).

The main interest of mini-fluid is to limit unnecessary fluid infusion. Interestingly, our study suggested that volume expansion would be stopped after 100 ml in 73% of negative fluid challenges. Results of ΔSVI 50 are disappointing because best threshold value (2%) and lower value of the gray zone (0%) are very small and thus not clinically relevant. Furthermore, almost half of the patients (47%) are in the gray zone.

Recently, MacDonald et al.²⁶  published a substudy of the OPTIMISE Trial. This article reported 556 fluid challenges in 100 patients. Only 159 fluid challenges (28.6%) were associated with increased stroke volume. Our results are close to theirs (32% of positive fluid challenges). The mini-fluid approach in the operating room makes sense because several fluid challenges are performed per patient. Avoiding 150 ml per patient has little impact on fluid balance, but, as demonstrated by this recent study,²⁶  several fluid challenges are performed per patient during surgery. In this way, the mini-fluid approach may impact fluid balance and significantly avoid unnecessary fluid administration.

Three studies evaluated the performance of mini-fluid challenge in critically ill patients. Muller et al.¹⁴  investigated 39 critically ill ventilated patients with acute circulatory failure. They showed that an increase of 10% or higher in aortic blood flow (measured using echocardiography) after rapid infusion (1 min) of a mini-fluid challenge (100 ml hydroxyethyl starch) could predict the effects of a 500-ml infusion. Wu et al.²⁷  demonstrated in 55 critically ill patients that the increase in aortic blood flow (measured using echocardiography) after an ultra-rapid (10-s) micro-fluid challenge (50 ml crystalloid) was able to predict the effects of 500 ml. More recently, Mallat et al.¹⁵  studied 49 critically ill patients and showed that the increase in stroke volume (measured using pulse contour) after a rapid infusion of 100 ml colloid accurately predicted fluid responsiveness but with a large gray zone.

Our study differs on many points with the abovementioned studies. First, it was performed in the operating room and not in an ICU, so the goals, therapeutics, and monitoring were different. Second, fluid challenge was not performed in acute circulatory failure patients but was given to maximize cardiac output and to bring the patient’s heart to the beginning of the flat portion of the Frank–Starling curve. Third, volume expansions were performed with a smaller quantity of fluid (250 ml) than in ICU studies (recommendations are different between ICU and operating room),^13,28  and only crystalloids were used. Finally, the response to fluid challenge was defined as an increase in stroke volume greater than 10% from baseline.

Dynamic indices are known to predict fluid responsiveness accurately in precise conditions.²⁹  The main limitation in the operating room is the use of low tidal volume.⁸  On one hand, several studies demonstrated that, when compared with a standard strategy (using tidal volume of 10 to 12 ml/kg of ideal body weight), a protective ventilation strategy (using tidal volume of 6 to 8 ml/kg of ideal body weight) is associated with a decrease in pulmonary postoperative complications, so the interest of these indices is limited.^9,10  Our study confirms the low ability of PPV in these conditions and the large gray zone.^21,30  On the other hand, no published study demonstrated the superiority of tidal volume of 6 to 8 ml/kg of ideal body weight compared with 8 to 10 ml/kg. Thus, the use of dynamic parameters (which are easier to use and less expensive than cardiac output monitoring) may still be interesting in the future.

Colloids, and particularly hydroxyethyl starch solutions, are extensively used during goal-directed fluid optimization strategies in surgical patients.^2,3  However, several randomized control trials undertaken in ICUs suggest that hydroxyethyl starch may compromise renal function and outcome.^31,32  On the other hand, the administration of a large quantity of saline 0.9% may induce hyperchloremic metabolic acidosis and acute kidney injury.^33,34  Several studies suggest that colloid and crystalloid are not interchangeable in terms of volume expansion and that greater fluid volumes are necessary with crystalloids than with colloids.^35–37  We exclusively used crystalloid in the present study and found that the increase in SVI after a bolus of 50 ml saline seemed able to predict positive fluid challenge but that the cutoff (2%) did not seem clinically relevant. We therefore hypothesize that the increase in SVI induced by a bolus of 50 ml colloid would be greater and clinically relevant so other studies investigating this issue are needed.

This study has some limitations. First, cardiac output was monitored by using pulse contour analysis without external calibration. This technology may be wanting in the event of vasoplegia and/or large changes in systemic vascular resistance, but it accurately estimates changes in cardiac output induced by volume expansion.^38–40  We did not calculate the reproducibility and the least-significant change of the SVI measurement determined by Pulsioflex monitor. However, using the same pulse pressure analysis algorithm, Monnet et al.⁴¹  demonstrated that a 5% cardiac index increase during an occlusion test predicted fluid responsiveness. This result suggests that this algorithm is able to detect 5% changes in cardiac index and thus in stroke volume. Second, patients with cardiac dysfunction and/or arrhythmia were not included, so the findings cannot be extrapolated. Finally, the patients were in the supine position and were scheduled for neurosurgery, so extrapolation to patients positioned otherwise and in other types of surgery is not possible.

The rapid administration of 100 ml crystalloid can predict the effects of administering 250 ml crystalloid in mechanically ventilated patients undergoing neurosurgery. This strategy would permit a limitation of fluid administration during three quarters of negative fluid challenges.

Support was provided solely from institutional and/or departmental sources.

Dr. Biais received honoraria from Edwards Lifesciences, Irvine, California, and Pulsion Medical System, Munich, Germany, for lectures. The other authors declare no competing interests.