In adults and children with sepsis, fluid bolus therapy is recommended as the initial treatment for acute circulatory failure in international treatment guidelines (1), yet the only randomized evidence comparing fluid bolus therapy with no fluid bolus therapy demonstrates increased mortality (2, 3). In addition, large-volume fluid bolus therapy and a cumulative positive net fluid balance are associated with worsening renal function, acute respiratory distress syndrome, prolonged ICU and hospital length of stay, and mortality, when corrected for disease severity at the time of presentation (4). Clarifying who may benefit and who may be harmed by fluid bolus therapy in the initial treatment of sepsis is therefore a current research imperative.
The physiologic rationale for administering fluid bolus therapy in sepsis is to increase cardiac index (CI), with the intention of increasing end-organ perfusion and oxygen delivery (5–13). In order for fluid administration to have its intended effect on CI, fluid administered into venous capacitance vessels must increase mean circulatory filling pressure more than right atrial pressure, providing a pressure gradient for increased venous blood flow to the heart (14). In addition, both ventricles must be operating on the ascending portion of the Frank-Starling curve (15). An increase in CI of greater than 10% following fluid bolus therapy is considered “fluid responsiveness” (16). Reproducibly, in multiple patient groups and settings, only 50% of adult patients with acute circulatory failure are fluid responsive (17). In those who are not fluid responsive, fluid bolus therapy that does not contribute to increased CI results in elevated central venous pressure, resulting in impaired end-organ perfusion (mean arterial blood pressure – central venous pressure), and interstitial edema and may be the mechanism underlying some of the harms observed following this therapy (16). Fluid responsiveness, therefore, has been postulated as a means of identifying patients with acute circulatory failure who may benefit from fluid bolus therapy, and the absence of fluid responsiveness as a means of identifying those who may be harmed (17).
The effect of fluid bolus therapy on CI in children with sepsis has not been described. The primary aim of this study was to measure changes in CI, both in terms of magnitude and duration of effect, in children with sepsis and acute circulatory failure, who were administered fluid bolus therapy. We hypothesized that fluid bolus therapy would result in an increase in CI at 5 and 60 minutes. Secondary outcomes included the prevalence of fluid responsiveness at 5 and 60 minutes (defined as an increase in CI of > 10% compared with baseline) (16), the change in CI using 10 mL/kg compared with 20 mL/kg, and the effect of cumulative fluid bolus administration on change in CI.
MATERIALS AND METHODS
The study was a prospective observational cohort study undertaken in the emergency department (ED) of The Royal Children’s Hospital, Melbourne, VIC, Australia; a tertiary level dedicated pediatric hospital with an annual ED census of greater than 90,000 children. Study methodology was as previously described (18). The study was approved by the hospital institutional review board (The Royal Children’s Hospital Human Research and Ethics Committee, approval number 33169A), registered with the Australian and New Zealand Clinical Trials Registry (ACTRN 12614000824662) and reported according to the STrengthening the Reporting of OBservational studies in Epidemiology statement. Recruitment was performed by the principal investigator (PI) who was notified by clinical staff of potential participants and was not acting in the role of attending clinician during participant recruitment. The PI obtained written informed consent/assent from parents and/or study participants prior to enrollment. Deferred/delayed consent was not deemed acceptable by the hospital ethics committee. In time critical situations, verbal assent was obtained for the initial ultrasound studies, and written informed consent was obtained between the 5- and 60-minute ultrasound studies. No parents and/or study participants provided verbal assent and subsequently refused/were unable to provide written informed consent. All clinical data were collected by the PI, who was not involved in patient care or treatment decisions.
Participant Inclusion and Exclusion Criteria
Participant inclusion criteria were suspected sepsis according to international consensus criteria (19) and treating clinician decision to administer fluid bolus therapy. Fluid bolus therapy was defined as the rapid IV or intraosseous administration of isotonic crystalloid solution using manual push-pull or pressure bag methods. Exclusion criteria were uncorrected structural cardiac disease, noncurative goals of therapy, and where the child’s family were non-English speaking.
Study procedures were vital sign measurement and transthoracic echocardiography immediately prior to, 5 minutes after, and 60 minutes after fluid bolus therapy. Using a parasternal long axis view in 2D mode, left ventricular outflow tract (LVOT) diameter was recorded. At each study time point, an apical five-chamber view was obtained, a 3 mm pulsed wave Doppler gate positioned 1 cm proximal to the aortic valve, and velocity-time integral (VTI) recorded over three to five respiratory cycles (20). Recorded images were deidentified, randomized, and interpreted by a Pediatric Cardiologist blinded to the patient identity and status pre/post fluid bolus. Mean VTI over one respiratory cycle was used to calculate CI in order to account for variation in VTI due to cardiorespiratory interactions (21). The PI performed all sonographic recordings and has the qualification of Post Graduate Certificate in Clinical Ultrasound (The University of Melbourne, Australia).
Calculations are based on the American Society of Echocardiography guidelines (22). Stroke volume (SV) = VTI (stroke distance) × LVOT area. Cardiac output (CO) = SV × heart rate (HR) (corrected for temperature (10 beats/min for every degree celsius above 38) (23). CI = CO/body surface area.
Sample Size Estimation
A precision-based estimate was used to ensure the variation between groups at each time point was due to the effect of the study intervention (FBT) and not due to imprecision of the measurement tool (echocardiogram). Using the following assumptions, a median increase in CI of 20% following fluid bolus therapy with SD of 10% and precision of echocardiogram of ±5%, a sample size of 50 was required.
Nonparametric data were reported as median and interquartile range (IQR). Repeated measurements within the same patient were analyzed using Wilcoxon signed-ranks test. CI and change in CI at 60 minutes were compared with baseline (prior to fluid bolus therapy) values. Analysis of covariance using linear regression (covariate = baseline CI, dependent variables = CI at 5 and 60 min, independent variables = participant age, baseline mean arterial blood pressure, baseline CI, fluid bolus volume, and prior volume of bolus fluid) was performed. Post hoc sensitivity analysis was performed excluding participants who received a repeat fluid bolus between 5 and 60 minutes. A p value of less than 0.05 was considered significant. Statistical analysis was performed using Stata 14 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). The corresponding author had full access to all of the data in the study and was responsible for data integrity.
Between August 2013 and February 2017, 44 participants were assessed for eligibility and 41 enrolled. The primary barrier to enrollment was the availability of the PI on-site and not in the role of attending clinician at the time of participant presentation. These extraordinary circumstances resulted in a prolonged enrollment period relative to sample size. Enrollment, allocation, follow-up, and analysis data are presented in Figure 1. Demographic and clinical data were recorded for all included participants. The fluid content used for resuscitation was 0.9% sodium chloride in all cases. Fluid bolus therapy was administered IV in all cases. All participants were in sinus rhythm at the time of study measurements.
Using international consensus thresholds for age (19), vital sign abnormalities prior to fluid bolus therapy were as follows: tachycardia in 37 of 50 (74%), tachypnea in 44 of 50 (88%), capillary refill time greater than or equal to 3 seconds in 33 of 50 (66%), hypotension in nine of 50 (18%), and Glasgow Coma Scale (GCS) score less than 9 in six of 50 (12%; abnormal baseline GCS in 3/50 [6%], status epilepticus in 2/50 [4%], and septic encephalopathy in 1/50 [2%]). Participant demographic data are presented in Supplemental Table 1 (Supplemental Digital Content 1, http://links.lww.com/PCC/A640). The median participant age was 1.5 years (IQR, 0.5–3.9 yr), 63% were male, and 34% had a comorbidity (most commonly malignancy). Bacteremia was identified in 13 of 41 (32%). The most common bacterial pathogen identified was Staphylococcus aureus in four participants (11%), methicillin sensitive in all cases. Four participants were receiving heated, humidified, high-flow nasal cannula oxygen therapy throughout the study period; none experienced escalation of respiratory support during study investigations. No participants were receiving inotropic support at the time study observations.
Primary Outcome Measurements
Primary outcome data are presented in Table 1. Median CI values immediately before fluid bolus administration, 5 minutes after fluid bolus administration, and 60 minutes after fluid bolus administration are shown in Figure 2. Initial (baseline) median HR was 168 (IQR, 145–190), 5 minutes after fluid bolus therapy was 160 (IQR, 130–172), and 60 minutes after fluid bolus therapy was 154 (IQR, 134–168). Initial median stroke distance was 13.2 cm (IQR, 12.1–15.3 cm), 5 minutes after fluid bolus therapy was 15.4 cm (IQR, 15.1–19.5 cm), and 60 minutes after fluid bolus therapy was 14.1 cm (IQR, 12.2–15.7 cm).
Thirty-one of 49 (63%) fluid boluses resulted in an increase in CI of greater than 10% 5 minutes after administration, and these participants were considered initial fluid responders (Fig. 3). This was sustained at 60 minutes in four of 31 (13% of initial fluid responders).
Secondary Outcome Measurements
The median changes in CI following a bolus volume of 10 and 20 mL/kg, and the median changes in CI relative to prior volume of fluid bolus therapy administered, are presented in Table 1.
On linear regression analysis, the participant age, baseline mean arterial blood pressure, volume of fluid bolus, and prior volume of fluid bolus therapy were not significantly associated with CI at 5 or 60 minutes after fluid bolus therapy.
Nine participants received a repeat fluid bolus between 5 and 60 minutes. On sensitivity analysis, CI and change in CI over the study period were not significantly different after exclusion of these participants from analysis (Supplementary Table 2, Supplemental Digital Content 2, http://links.lww.com/PCC/A641).
The main finding of this study was that fluid bolus therapy resulted in a transient increase in CI in the majority of cases. Fluid responsiveness was variable and, when present, not sustained. Fluid bolus volume and the prior volume of fluid bolus therapy were not correlated with the change in CI at 5 or 60 minutes.
The finding that median CI in our study population initially increased after fluid bolus administration is in keeping with the current physiologic understanding and rationale for fluid bolus administration (14). Return of CI to near baseline within 60 minutes of fluid bolus administration was an unexpected finding, although with no control group, we cannot rule out the possibility that an even greater reduction in CI would have been observed in participants who did not receive bolus fluid administration due to natural progression of disease. Preclinical studies support the observation of short-term improvement in CI, returning to baseline shortly after the cessation of fluid administration in conditions characterized by systemic inflammation (24–28). Human studies have had similar findings. Nunes et al (29) observed the effect of 500 mL of crystalloid on CI in critically unwell mechanically ventilated adults using thermodilution, all of whom had systemic inflammation (sepsis in 70%, major surgery in 25%, and multitrauma in 5%). They found an overall mean increase of 18% immediately after fluid bolus therapy (p = 0.05), which fell to 3% above baseline after 60 minutes. Caltabeloti et al (30) assessed changes in CI in mechanically ventilated adult ICU patients with septic shock using thermodilution after administering 1,000 mL of 0.9% saline and observed an overall mean increase of 14.7% immediately after fluid bolus therapy (p < 0.001), which fell to 3% above baseline after 40 minutes (p < 0.001). Both of these adult studies support our observation that increases in CI after fluid bolus therapy are transient in patients with systemic inflammation. This may result from rapid shifts of administered fluid out of the intravascular compartment (31). Experimental and clinical studies have demonstrated that the majority of fluid bolus therapy administered in sepsis redistributes out of the intravascular compartment within 20 minutes of administration (32–34). The rapid redistribution of fluid bolus therapy seems to be replicated in other conditions characterized by systemic inflammation (35), whereas in healthy volunteers occurs over a much slower time period (36, 37).
Subgroup analysis of participants receiving FBT volume of 10 rather than 20 mL/kg was limited by small sample size. The finding that fluid bolus volume was not correlated with the change in CI observed at 5 and 60 minutes after fluid bolus therapy was, however, consistent with preclinical data (38, 39). Preclinical studies are difficult to extrapolate to humans due to their use of alternative routes of fluid administration (subcutaneous), fluid volumes (35–100 mL/kg); timing of administration (immediately after the induction of sepsis), and differences in supportive care (variable antibiotic use, no organ support therapy). Human studies comparing the effect of different fluid volumes on CI are limited but suggest that small-volume fluid resuscitation in adults (< 500 mL) may be insufficient to result in a detectable change in CI (40).
Subgroup analysis of participants receiving multiple fluid boluses was limited by small sample size. The lack of correlation between the prior volume of fluid bolus therapy and the observed change in CI at 5 and 60 minutes was, however, a novel finding. To the best of our knowledge, no preclinical or human studies report the change in CI following fluid bolus therapy based on prior volume of administered fluid.
The study population was a convenience sample and may have systematically excluded some patient groups. We found, however, a similar range of ages, initial and final diagnoses, and rate of positive bacteriological diagnoses to previous sepsis audits performed in our unit using the same inclusion criteria (41). For stroke volume measurements, we assumed that the aortic annulus did not change in diameter following fluid bolus therapy. This assumption may be incorrect; however, we felt that changes in diameter would be minimal, and repeat measurements would introduce another potential source of variation. Multiple measurements in some participants receiving multiple fluid boluses may have introduced a source of sampling bias, although confounding did not appear to be significant on sensitivity analysis. At the time of participant enrollment, patients had an initial clinical diagnosis of sepsis, and some had an alternate final (discharge) diagnosis. The response to fluid bolus therapy in these patients may have been different to that in patients with sepsis. Last, the study observations only occurred in the first hour after fluid bolus administration, with unclear implications after this time, including the implications for patient-centered outcomes.
Fluid bolus therapy resulted in a transient increase in CI in children with sepsis and acute circulatory failure. Fluid responsiveness was not sustained in the majority of cases. The efficacy of other methods of acute circulatory support for achieving a sustained increase in CI warrant further exploration, as does the comparison between methods on patient-centered outcomes.
We thank the resuscitation staff in the Emergency Department of The Royal Children’s Hospital for their enthusiasm and help recruiting patients for this study. We also thank the families of enrolled children for allowing study procedures to be performed during a stressful time of their hospitalization. Last, we thank the children who acted as study participants for their involvement; improving their care was the primary motivator for this study.
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