Passive leg raising test versus rapid fluid challenge in critically ill medical patients

Fluid resuscitation is a frequent measure used to restore hemodynamic stability [23]. The passive leg raising (PLR) test is a simple and dynamic method and is one of the recommended tests to assess fluid responsiveness in critically ill patients [7]. Jabot et al. reported that a significant increase in cardiac output (CO) during PLR is observed when an average of 312 ml of blood is mobilized from the lower extremities [10]. However, published studies on PLR in comparison to exogenous fluid challenge used different amounts of fluid and/or different infusion times, which may compromise a general comparison of the results [19, 22, 28, 31]. The effect of a fluid challenge on hemodynamics dissipates within 10 min [2]. Therefore, the infusion time can affect fluid response [29].

A positive cardiac preload response to PLR or fluid challenge has been defined as an increase in CO of at least 10 or 15% [6, 18], with an increase in CO of at least 10% considered to be the best cutoff [18]. However, continuous CO monitoring may not be possible or feasible in every case. Septic shock is the most common type of shock [30] and international guidelines recommend a mean arterial pressure (MAP) target during hemodynamic resuscitation [7]. Therefore, MAP still plays a role as a monitoring tool despite its limitations. In a study on mechanically ventilated patients using PLR, responders showed a mean increase in MAP from 69 to 78 mm Hg, which is an increase by approximately 13% [19]. Another study using a fluid infusion in patients with acute circulatory failure reported a 13% increase in MAP as the best cutoff to detect a significant increase in CO with a positive predictive value of 82% [17].

Based on the above observations, the authors aimed to prospectively compare the hemodynamic effects of PLR and a rapid fluid challenge (RFC) in critically ill medical patients with signs of hemodynamic compromise using continuous CO and MAP measurements. Since the effect of PLR is immediate, it was hypothesized that a fluid bolus of 300 ml administered within 5 min in adults may allow a physiologically acceptable comparison with PLR. The major study objective was to assess the agreement between PLR and RFC regarding changes in CO and MAP.

This was a prospective study on critically ill medical patients with hemodynamic instability admitted to the medical intensive care unit (ICU) of a university hospital between September 2019 and September 2021. The study protocol was approved by the local ethics commission and conducted according to good clinical practice. The study conformed to the provisions of the Declaration of Helsinki (as revised in 2013).

Patients were included in the study after written informed consent. If a patient was not able to give consent and a legal guardian not yet available, study inclusion was achieved after a physician not belonging to the ICU team confirmed the urgency and validity of the study. Informed consent was then obtained once the patient or the legal guardian were able to do so. If a patient could not be included in the study, hemodynamic resuscitation was conducted according to the protocol of the unit that allows physicians to either apply PLR or an exogenous fluid challenge based on their preferences.

The inclusion criteria were hemodynamic instability defined as a MAP <65 mm Hg or the need for vasopressor support to maintain a MAP >65 mm Hg and/or blood lactate >2 mmol/l plus the decision by the intensivist that testing for fluid responsiveness was justified. The exclusion criteria were hemorrhagic shock, irreversible brain damage, pregnancy and lactation as well as age <18 years (Fig. 1).

Continuous invasive arterial blood pressure measurement was established on every patient. Leveling and zeroing the transducer were carried out as described in the literature [26]. Continuous CO measurements were conducted with the PiCCO System (Pulsion Medical Systems, Feldkirchen, Germany) whenever this could be established without delay. CO is reported as cardiac index in l/min/m².

A positive preload response to PLR and RFC was defined as an increase in CO of ≥ 10%. An increase in MAP of ≥ 13% was used to define a positive preload response. Where continuous CO measurements could not be established, only changes in MAP were used to evaluate preload response.

Baseline hemodynamic variables were documented immediately before the test. For patients on mechanical ventilation, ventilator settings and sedation dose were left unchanged during the test. Patients on controlled ventilation mode were managed with low tidal volume ventilation, which is the standard procedure of the unit. PLR was conducted according to published recommendations [21]. After the effect of PLR on CO and MAP had subsided, baseline hemodynamic variables were again recorded prior to RFC with the patient in the semi-recumbent position. Regardless of the results of the PLR, RFC was carried out with 300 ml of Ringer acetate solution as a bolus within 5 min. Hemodynamic variables were then recorded immediately after the fluid bolus. The changes in CO and MAP following PLR and RFC are given in percent of the baseline data recorded immediately before PLR and RFC, respectively.

The following variables were also recorded: age, gender, body weight (in kg), major reason for ICU admission, acute physiology and chronic health evaluation (APACHE) ΙΙ score, sequential organ failure assessment (SOFA) score, the need for mechanical ventilation and sedatives, the Richmond agitation sedation scale (RASS), and vasopressor dose for those on such a support.

A total of 1220 patients were screened for eligibility and 124 included in the study. The patient recruitment flow diagram is shown in Fig. 1. Most of the patients presented with sepsis (Table 1). The baseline clinical and laboratory data are shown in Table 2. Less than a third of the patients were on controlled mode of mechanical ventilation.

Continuous CO recording could be established in 42 patients (33.9%). The changes in CO and MAP for responders and non-responders for both PLR and RFC are shown in Table 3. Based on the CO cutoff, 40.5% of the patients were PLR responders, while 46.3% were RFC responders. Comparing the response with PLR to that with RFC, 28.0% of the PLR non-responders became RFC responders, while 29.4% of the PLR responders were RFC non-responders (p = 0.011). Compared to RFC, the false positive and false negative rates with PLR were 21.7 and 36.8%, respectively, with positive and negative predictive values of 70.6 and 72.0%, respectively.

The ROC analysis showed that a CO increase by ≥ 10.2% with PLR was the best cutoff to detect fluid responsiveness with an area under the curve (AUC) of 0.73 ± 0.08 (95% confidence interval 0.58–0.89), with a sensitivity of 63.2% and specificity of 78.3%.

The ROC analysis showed that an MAP increase by ≥ 12.5% with RFC was the best cutoff to detect fluid responsiveness with an AUC of 0.65 ± 0.08 (95% confidence interval 0.48–0.82), with a sensitivity of 68.4% and specificity of 69.6%.

This prospective study showed a moderate agreement between the PLR test and an RFC in hemodynamically unstable medical patients. The reasons for discrepancies with regard to published results may be multifactorial. First, the amount of fluid administered to test fluid responsiveness in the literature was heterogeneous, ranging from 250 to 1000 ml [14, 29]. The authors administered 300 ml based on the findings of Jabot et al. [10]. A recent study reported that a fluid bolus of 4 ml/kg body weight would reliably detect responders and non-responders [1]. Another recent study also reported that 250 ml fluid with a threshold of 9.6% increase in stroke volume showed the highest accuracy in detecting fluid responsiveness in patients with shock [3]. Second, the duration of fluid infusion also varies in the literature. Previous studies reported infusion times of up to 30 min [14, 29], while this was only 5 min in the current study.

The results of the ROC analysis in this study are in agreement with previous publications for both PLR compared to exogenous fluid challenge [18] as well as for an increase in MAP compared to that in cardiac output [17].

Pain or discomfort should be avoided during PLR [21]. Nevertheless, critically ill patients may be restless, which may contribute to false positive results with PLR or make PLR impossible. Changes in heart rate as a sign of sympathetic activity during PLR may not be reliable enough [5]. In the current study, only 30% of the patients were on controlled ventilation mode and just over half of the patients were sedated, with a variable agitation and sedation state.

PLR may also be false negative, one possible reason being intra-abdominal hypertension (IAH), with an intra-abdominal pressure >15 mm Hg considered a limitation [13]. IAH also reduces the amplitude of the PLR-induced changes in cardiac output in fluid-responsive patients [4]. No clinical sign of such a marked IAH was observed in this study. However, intra-abdominal pressure was not measured to confirm this assumption. It is not fully clear why certain patients with IAH are fluid responsive, while others are not, although the PLR test even led to a decrease in intra-abdominal pressure [4]. Another possible cause of a false negative PLR test could be marked intravascular hypovolemia, so that the blood volume to be shifted from the lower extremities following PLR might have been insufficient. However, this possibility has not been systematically investigated. Furthermore, most of the patients were on a vasopressor infusion, which may have a dose-dependent influence on cardiac preload that may affect preload response to PLR [16]. The ventilator settings among the patients on mechanical ventilation in the current study could not have had a negative influence on the PLR test [20].

PLR can help avoid unnecessary fluid administration. However, holding back fluid resuscitation on the basis of a possibly false negative PLR may also be unfavorable. Fluid challenge is only a tool to test for cardiac preload response. The unresolved issue is the fluid dose to be administered following a positive preload challenge. This uncertainty may be a source of fluid overload that is associated with poor outcome [15].

The appropriate means to rapidly assess preload response is a challenge in daily patient care. Continuous CO monitoring is the standard method to detect fluid responsiveness. However, this may not be possible or easily established or feasible. The cost of such monitoring techniques should also be taken into consideration. Other dynamic techniques have their own limitations [20], and they may also not be easily available everywhere. Additionally, the shortage of qualified staff mastering these techniques should be considered. Nevertheless, lack of a CO measurement technique would be an unlikely argument to withhold testing for fluid responsiveness. A recent Danish survey showed that blood pressure is still the most frequently used trigger to evaluate fluid response in emergency departments [11]. International guidelines still recommend MAP as a target variable for hemodynamic resuscitation [7], with due consideration of its limitations [18, 20].

An increase in cardiac output does not necessarily translate into improvement of the microcirculation. Correct identification of the patients who may benefit from resuscitation in terms of microcirculatory improvement is still a challenge [24]. Clinical signs such as cold and pale extremities, capillary refill time or skin mottling may be useful to identify patients with systemic hypoperfusion. Normalization of the capillary refill time during hemodynamic resuscitation of patients with septic shock has been investigated [9]. However, inter-observer variations and patient heterogeneity may be relevant limitations for its use as a monitoring tool [27]. A recent study on healthy volunteers has also demonstrated variations depending on how capillary refill time is investigated [12]. The time span between fluid challenge and the detection of such microcirculatory changes may also be variable [8]. Furthermore, fluid responsiveness is time-dependent, with the hemodynamic effect lost within a short time in a proportion of patients [25]. Further studies are still required to identify objective, timely, reproducible and widely available parameters of tissue perfusion to monitor the effect of fluid resuscitation.

This study has certain limitations. First, it is monocentric and included only critically ill medical patients. However, the findings may contribute to our understanding of the routine management of the patient with acute circulatory dysfunction. Second, patients could not be included in the study during the night shifts due to staff shortage. It is not clear how far this could have been a challenge in similar studies, since this issue was not systematically addressed. However, the authors believe that this should not have significantly affected the conclusion, since every patient was her or his own control. Third, continuous cardiac output measurements could not be performed in every patient. However, the authors believe that their observations show the real world acute patient care, in which cardiac output monitoring may not be immediately available or feasible for various reasons. Such techniques are usually reserved for the severely ill patients in need of complex and protracted hemodynamic management. Fourth, intra-abdominal pressure was not measured unless this was justified based on clinical judgement. However, it is unlikely that patients with an IAH of > 15 mm Hg would be overlooked during a proper clinical examination.

The present study showed moderate agreement between the passive leg raising test and a rapid fluid challenge with 300 ml fluid bolus assessed using both continuous cardiac output and mean arterial pressure measurements in critically ill medical patients, which should be considered when testing preload responsiveness.