The noninvasive cardiac output monitor and passive leg-raising maneuver has been shown to be reasonably accurate in predicting fluid responsiveness in critically ill patients. We examine whether using a noninvasive protocol would result in more rapid lactate clearance after 3 hours in patients with severe sepsis and septic shock in the emergency department.
Methods
In this open-label randomized controlled trial, 122 adult patients with sepsis and serum lactate concentration of greater than or equal to 3.0 mmol/L were randomized to receive usual care or intravenous fluid bolus administration guided by measurements of change of stroke volume index, using the noninvasive cardiac output monitor after passive leg-raising maneuver. The primary outcome was lactate clearance of more than 20% at 3 hours. Secondary outcomes included mortality, length of hospital and ICU stay, and total hospital cost. Analysis was intention to treat.
Results
Similar proportions of patients in the randomized intervention group (70.5%; N=61) versus control group (73.8%; N=61) achieved the primary outcome, with a relative risk of 0.96 (95% confidence interval [CI] 0.77 to 1.19). Secondary outcomes were similar in both groups (P>.05 for all comparisons). Hospital mortality occurred in 6 patients (9.8%) each in the intervention and control groups on or before 28 days (relative risk=1.00; 95% CI 0.34 to 2.93). Among a subgroup of patients with underlying fluid overload states, those in the intervention group tended to receive clinically significantly more intravenous fluids at 3 hours (difference=975 mL; 95% CI –450 to 1,725 mL) and attained better lactate clearance (difference=19.7%; 95% CI –34.6% to 60.2%) compared with the control group, with shorter hospital lengths of stay (difference=–4.5 days; 95% CI –9.5 to 2.5 days).
Conclusion
Protocol-based fluid resuscitation of patients with severe sepsis and septic shock with the noninvasive cardiac output monitor and passive leg-raising maneuver did not result in better outcomes compared with usual care. Future studies to demonstrate the use of the noninvasive protocol-based care in patients with preexisting fluid overload states may be warranted.
Introduction
The global incidence and mortality from severe sepsis and septic shock remain high.1, 2, 3 The Surviving Sepsis Campaign4 is an initiative to improve mortality from sepsis, incorporating some principles from the landmark article on early goal-directed therapy.5 Various resuscitation bundles have since been formulated and practiced to treat severe sepsis.6 However, the exact targets of early, quantitative resuscitation of severe sepsis and septic shock of the landmark study have been challenged, particularly by 3 recent large multicenter trials.7, 8, 9 The generalizability of early goal-directed therapy is also questioned.10 The necessity of central venous pressure monitoring to assess fluid status and blood transfusion also lacks evidence.11, 12, 13 Drawbacks include the invasive nature and complications of central catheter insertion, and the significant amount of physician and nursing time required to set up the equipment in the emergency department (ED).14
Editor’s Capsule Summary
What is already known on this topic
Structured quantitative resuscitation has been associated with improved outcomes in patients with severe sepsis and septic shock. However, structured noninvasive measurements as goals of resuscitation have not been studied extensively.
What question this study addressed
Whether a noninvasive measurement of change stroke volume using a noninvasive cardiac output monitor and passive leg raise would lead to more rapid clearance of lactate compared with usual care.
What this study adds to our knowledge
Noninvasive cardiac output monitoring led to no improvement in lactate clearance compared with usual care; however, clinically important differences in amount of fluid administered and lactate clearance percentage were observed in patients with underlying volume overload.
How this is relevant to clinical practice
This study informs clinical practice that clinician judgment and usual care in guiding resuscitation is equivalent to quantitative noninvasive physiologic measurements. Future studies of resuscitation should focus on difficult clinical scenarios such as volume overload.
Lactate levels in the blood have been shown to be a key indicator of global organ hypoperfusion and shock.15 It has also been well documented to be a good marker for the severity and outcome of sepsis; likewise, for the success of resuscitation.16, 17 In addition, if there is a failure of lactate clearance in the process of resuscitation, a much worse outcome ensues.18 Studies have shown that the speed with which lactate is cleared is an independent prognostic factor for improved mortality.19, 20, 21 As such, targeting lactate clearance as a surrogate outcome in clinical studies is a valid endpoint.
Improving cardiac output and end-organ perfusion by increasing preload through the administration of fluid boluses remains a cornerstone for resuscitation of patients with sepsis. However, ascertaining the volume status and fluid responsiveness of critically ill patients remains a challenge for physicians practicing in the ED, especially in patients with impaired cardiac function. There are few data to show the incidence of preload responsiveness in patients presenting to the ED. Excessive fluid administration could have deleterious effects on the individual, such as interstitial edema and organ dysfunction.22 Hence, there is a need for noninvasive and uncomplicated alternatives to advanced hemodynamic assessment in the ED.23
The noninvasive cardiac output monitor (Cheetah Medical, Tel Aviv, Israel) is capable of providing continuous dynamic measurement of hemodynamic parameters by using bioreactance technology (Appendix E1, available online at www.annemergmed.com). Clinical validation studies have shown that the noninvasive cardiac output monitor has acceptable accuracy.24, 25 Noninvasive monitoring of hemodynamic parameters can be coupled with the passive leg-raising maneuver, which results in mobilization of fluid from the venous capacitance system of the lower extremities to the core, resulting in an effective volume challenge of 250 to 300 mL (Appendix E2, available online at www.annemergmed.com). The ability of passive leg raising to assess fluid responsiveness has been well demonstrated.26, 27, 28, 29, 30
To our knowledge, no randomized trials have reported a resuscitation protocol that examines the use of a noninvasive hemodynamic monitoring device such as the noninvasive cardiac output monitor in sepsis resuscitation particularly relating to the outcome of such a strategy. The use of noninvasive hemodynamic protocols may allow treating physicians in the ED to be able to quickly attain hemodynamic optimization and resultant faster lactate clearance, which could translate into better outcomes for patients.18, 19
Our goal in this study was to determine whether the use of noninvasive hemodynamic optimization combined with passive leg-raising maneuver resulted in early clearance of lactate in patients with severe sepsis and septic shock in the ED.
Section snippets
Study Design and Setting
This was a randomized, open-label, single-center study enrolling patients with severe sepsis or septic shock from the ED of National University Hospital, a tertiary university-affiliated hospital in Singapore. The study period was during 22 months, from February 2012 to November 2013. Patients or their legally acceptable representatives provided written informed consent, and all protocols were approved by the Domain Specific Review Board, National Healthcare Group, Singapore (DSRB 2011/00286).
Selection of Participants
Characteristics of Study Subjects
A total of 122 patients were enrolled from the ED of National University Hospital, Singapore. Patients were randomized to either control (N=61) or intervention group (N=61) (Figure 1). All patients who were assigned to the intervention group adhered strictly to the protocol (Figure 2), apart from 3 patients (4.9%) assigned to the intervention group who switched to the control group at the decision of treating physicians. All efficacy analyses, however, were performed on an intention-to-treat
Limitations
There are several limitations to our study. First, the target sample size of 140 patients was not achieved because of manpower constraints that prohibited continual recruitment beyond 122 patients. Although the study did not achieve the calculated target sample size, the 95% CI (0.77 to 1.19) of the RR obtained for the primary outcome is relatively narrow, depicting adequate precision and power of the study.34 We also analyzed the results of the primary endpoint under the most extreme scenario.
Discussion
In this open-label randomized controlled study, we report similar outcomes between the intervention group comprising a noninvasive fluid resuscitation protocol using the noninvasive cardiac output monitor and passive leg-raising maneuver compared with the control group of usual care according to best practice. This conclusion is in line with those of 3 large multicenter trials that have been published recently concluding that usual care did not perform worse than early goal-directed therapy or
The monitoring and regulation of cardiovascular function are increasingly based on dynamic indices. The aim of the present review is to scrutinize the history, physiological foundation, development, statistical apparatus and clinical impact on morbidity and mortality of one of the maneuvers leading to a dynamic index of fluid responsiveness, viz. the passive leg raising.
Tracing the development of PLR from the early 80-ies revealed contrasting and irreconcilable perceptions of physiological mechanism in PLR and an increasing consensus on the formalities in analyzing results of validation studies in terms of ROC analysis, gray zones and Bayesian statistics resulting in the demonstration of good ability of PLR to predict volume responsiveness in an experimental setting. The impact on decreased morbidity and mortality, however, is absent in clinical trials involving PLR vs normal care.
The passive leg raising manoeuvre is lacking in a consistent physiological modelling of the cardiovascular system, the purpose of the manoeuvre is ill-defined, the execution and timing are unclear and monitoring in the longer term leaves much to be desired. This serves to corroborate that the manoeuvre so far hasn’t demonstrated a significant benefit in terms of survival in a clinical context. A call for an alternative approach is presented.
For example, when assessing whether a patient will augment their cardiac output in an ICU population, a number of studies have suggested that approximately only 50% of patients will respond to an intravenous fluid bolus.2,3 This rate goes up to about 80% when examining an ED population for the same hemodynamic response, suggesting these 2 patient populations exist at different points on their respective Starling curves.4 There is also a broader question unaddressed by the current trial.
Despite the availability of extensive literature on the concept of fluid responsiveness and assessment techniques, the use of fluid responsive tests has not become standard of care because the techniques can be time-consuming, operator-dependent, and are not universally applicable. Furthermore, several small randomized controlled studies in septic patients comparing fluid responsiveness-guided resuscitation to standard techniques found no significant difference in major outcomes.80–84 Owing to lack of standardization and strong evidence for improved outcomes, no consensus exists on how frequently to assess fluid responsiveness; certainly doing so too infrequently can lead to inadequate resuscitation, and testing too frequently may lead to volume overload if IV fluids are being administered as part of the test.
Accurate assessment of intravascular volume status in critically ill patients remains a very challenging task. Recent data have shown adverse outcomes in critically ill patients with either inadequate or overaggressive fluid therapy. Understanding the tools and techniques available for accurate volume assessment is imperative. This article discusses the concept of fluid responsiveness and reviews methods for assessing fluid responsiveness in critically ill patients.
Patients with any of the following were excluded from the study: (1) Child-Turcotte-Pugh class B and C chronic liver disease, (2) scleral icterus at presentation, (3) on metformin therapy, (4) received beta-adrenergic agonist nebulization 4 h prior to blood sampling, (5) refusal of consent and (6) do-not-resuscitate status. Using data from a previous randomized controlled trial on patients with sepsis from the same center [16], we estimated the prevalence of chronic beta-blocker therapy to be 25%. Based on previous related studies by Contenti et al. [12] and Fuchs et al. [17], we estimated a mean serum venous lactate difference of 1.5 mmol/L. For this study to achieve 80% power and alpha of 5%, assuming a mean difference of 1.5 mmol/L and a standard deviation of 3.0 mmol/L, a total sample size of at least 172 patients (with and without beta-blocker therapy) was required.
In the assessment and management of septic patients in the emergency department (ED), serum lactate is often measured to stratify severity to guide decision making. Increased adrenergic drive has been postulated as a contributory factor for hyperlactatemia in sepsis. We aim to prospectively evaluate the effect of chronic beta-blocker use on serum lactate levels in sepsis at initial presentation to the ED.
We conducted a prospective observational study at the ED of a tertiary care academic medical center in Singapore. One hundred and ninety-five ED patients who fulfilled all of the following: (1) age 45 years and above, (2) tympanic temperature ≥ 37.8 °C or clinically suspected to have an infection, and (3) quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) score ≥ 1 were included in the study. Serum venous lactate was sampled within two hours from presentation to the ED. The primary outcome measure was the difference in initial serum venous lactate concentration at presentation to the ED in patients on chronic beta-blockers versus patients without.
Seventy patients (35.9%) were on long-term beta-blocker therapy. The primary outcome of mean initial serum venous lactate concentration was similar between patients prescribed chronic beta-blocker therapy and patients without (1.78 mmol/L versus 1.70 mmol/L, p = .540). Chronic beta-blocker therapy also did not significantly affect mean initial serum venous lactate concentration across all subgroups of sepsis risk stratification.
Long-term beta-blocker therapy did not significantly affect initial serum venous lactate concentration in ED patients with suspected sepsis.
We showed that antibiotics were the most commonly administered medications at the emergency department. Kuan et al. reported a similar finding for patients with sepsis at the emergency department [26]. Our study revealed a significant difference between the two groups with regard to the qSOFA score, although a logistic regression analysis failed to identify qSOFA scores as an independent predictor of mortality.
Sepsis is a potentially fatal condition with high treatment costs, and is especially common among the elderly population. The emergency management of septic patients has gained importance.
Herein, we investigated the effect of admission lactate levels and the platelet-lymphocyte ratio (PLR) on the 30-day mortality among patients older than 65 years who were diagnosed with sepsis and septic shock according to the qSOFA criteria at our hospital's emergency department.
This observational study was conducted retrospectively. We obtained information regarding patients' demographic characteristics, comorbid conditions, hemodynamic parameters at admission, initial treatment needs at the emergency department.
131 patients received a diagnosis of sepsis and septic shock at our emergency department in two years. Among these, 45% (n = 59) of the patients died within 30 days of admission. Forty (30.5%) patients required mechanical ventilation. There was a significant difference between the survival and non-survival groups with regard to systolic and diastolic blood pressures (p = 0.013 and 0.045, respectively). There were significant differences between the two groups with respect to the Glasgow Coma Scale score (p < 0.001) and BUN levels (p < 0.001). The mortality status according to qSOFA scores was revealed a significant difference between the two groups (p < 0.001).
Our results showed that the patients who died within 30 days of admission and those who did not had comparable PLR and lactate levels (p = 0.821 and 0.120, respectively). We opine that serial lactate measurements would be more useful than a single admission lactate measurement for the prediction of mortality.
Please see page 368 for the Editor’s Capsule Summary of this article.
Supervising editor: Alan E. Jones, MD
Author contributions: WSK, II, BSHL, YBC, and MM conceived the study, designed the trial, and obtained research funding. WSK, SJ, and QL supervised the conduct of the trial and data collection and managed the data, including quality control. QL and YBC provided statistical advice on study design and analyzed the data. WSK, QL, and MM drafted the article, and all authors contributed substantially to its revision. WSK takes responsibility for the paper as a whole.
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist and provided the following details: This work was supported by the National University Health System Clinician Research Grant (FY2011) and the National Medical Research Council New Investigator Grant (NIG11may049) to Dr. Kuan. Dr. Kuan reports receiving grant support from the National Medical Research Council Transition Award. Dr. Lu’s institution (Singapore Clinical Research Institute) received funding from the National University Health System Clinician Research Grant (FY2011) in statistical analysis and preparation of the article.
