Does Point-of-Care Ultrasound Affect Fluid Resuscitation Volume in Patients with Septic Shock: A Retrospective Review

Background Fixed, large volume resuscitation with intravenous fluids (IVFs) in septic shock can cause inadvertent hypervolemia, increased medical interventions, and death when unguided by point-of-care ultrasound (POCUS). The primary study objective was to evaluate whether total IVF volume differs for emergency department (ED) septic shock patients receiving POCUS versus no POCUS. Methods We conducted a retrospective observational cohort study from 7/1/2018 to 8/31/2021 of atraumatic adult ED patients with septic shock. We agreed upon a priori variables and defined septic shock as lactate ≥4 and hypotension (SBP <90 or MAP <65). A sample size of 300 patients would provide 85% power to detect an IVF difference of 500 milliliters between POCUS and non-POCUS cohorts. Data are reported as frequencies, median (IQR), and associations from bivariate logistic models. Results 304 patients met criteria and 26% (78/304) underwent POCUS. Cardiac POCUS demonstrated reduced ejection fraction in 15.4% of patients. Lung ultrasound showed normal findings in 53% of patients. The POCUS vs. non-POCUS cohorts had statistically significant differences for the following variables: higher median lactate (6.7 [IQR 5.2–8.7] vs. 5.6], p = 0.003), lower systolic blood pressure (77.5 [IQR 61–86] vs. 85.0, p < 0.001), more vasopressor use (51% vs. 34%, p = 0.006), and more positive pressure ventilation (38% vs. 24%, p = 0.017). However, there were no statistically significant differences between POCUS and non-POCUS cohorts in total IVF volume ml/kg (33.02 vs. 32.1, p = 0.47), new oxygen requirement (68% vs. 59%, p = 0.16), ED death (3% vs. 4%, p = 0.15), or hospital death (31% vs. 27%, p = 0.48). There were similar distributions of lactate, total fluids, and vasopressors in patients with CHF and severe renal failure. Conclusions Among ED patients with septic shock, POCUS was more likely to be used in sicker patients. Patients who had POCUS were given similar volume of crystalloids although these patients were more critically ill. There were no differences in new oxygen requirement or mortality in the POCUS group compared to the non-POCUS group.


Introduction
Patients diagnosed with septic shock in the emergency department (ED) carry a high risk for morbidity and mortality.A dysregulated host response to infection that results in new or worsening organ dysfunction is sepsis by defnition [1,2] and carries mortality rates that can reach 20% or higher in the inpatient setting [1,3].Risk-adjusted mortality continues to vary greatly between regions and hospitals despite many national and systemic initiatives, indicating there may be opportunities to optimize and improve care [1].Early recognition with appropriate hemodynamic management and source control is regarded as imperative in the management of sepsis [1.4].Te 2021 Surviving Sepsis Campaign guidelines recommend early, fxed, large volume (30 ml/kg) intravenous fuids (IVFs) administration in cases of suspected severe sepsis or septic shock within the frst 3 hours of clinical presentation [4,5].However, while ample fuid resuscitation is a crucial part of early goal-directed therapy, adoption of a fxed volume regimen across all patients risks over-resuscitation and fuid overload, especially in patients with congestive heart failure (CHF) and end-stage renal failure (ESRD) [6][7][8].Adverse efects of over-resuscitation include hypervolemia and increased oxygen requirement, potentially resulting in further medical interventions or even death [9].Tese risks call for efective monitoring and assessment of volume with hemodynamic status changes, which is difcult based on clinical and laboratory evaluation alone [10][11][12].
Point-of-care ultrasound (POCUS) including echocardiography and lung ultrasound has been used to assess volume and guide hemodynamic management with IVF administration [13][14][15].Volume overload can present as increased extravascular lung water, which can be accurately detected via POCUS prior to clinical symptoms [16][17][18].A number of studies have shown a correlation between increased extravascular lung water and mortality in the critically ill [19,20].As such, POCUS of the lung has been suggested as an additional tool that can rapidly and accurately identify early increased extravascular lung water (pulmonary edema) that develops when patients are overresuscitated, providing a signal in the risk-beneft consideration for further volume expansion [21,22].
Te primary study objective was to evaluate whether the total IVF volume given difers for septic shock patients receiving POCUS versus no POCUS in the ED.Secondary objectives included 'evaluation of new oxygen requirements, overall mortality, and outcomes in a subgroup of patients with CHF and severe renal failure.

Methods
Tis study was performed according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observational studies (Supplemental File 1) [23].Te Institutional Review Board reviewed and approved the study.

Setting and Subjects.
We conducted a retrospective cohort study of patients who presented to the ED between 7/1/2018 and 8/31/2021 according to standards of chart review in case selection, abstractor training, monitoring and blinding, and interrater agreement to improve accuracy and minimize inconsistencies [24,25].Te setting was a large (∼1200 hospital beds) urban academic, residency-afliated, tertiary care medical center.Patients were included in our analysis if they were 18 years old or older, with a diagnosis of sepsis.Sepsis was defned using the Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT) [26,27], an internationally maintained hierarchical terminology system.Te label was set to 1 if the parent concept for sepsis, SNOMED-CT identifer (SCTID � 91302008), or any of its descendants was found in the problem list.To increase the likelihood that patients were critically ill and being treated for severe sepsis or septic shock, we restricted inclusion to patients who had both Centers for Medicare and Medicaid Services (CMSs) Severe Sepsis/Septic Shock (SEP-1) fuid requirement criteria of 30 cc/kg fuid bolus within 3 hours of presentation: a lactate ≥4 and hypotension (SBP <90 or MAP <65) [28,29].POCUS was performed at the discretion of the bedside clinical team and was included in the analysis if a POCUS report was available in the medical chart.In this study, POCUS is performed by the emergency medicine (EM) team, which can include EM residents, ultrasound fellows, and or EM faculty.Furthermore, if POCUS is performed by other trainees during their clinical role in the ED, each ultrasound image is reviewed with an EM faculty who are all profcient in basic cardiac and lung POCUS.In addition, advanced EM ultrasound faculty provides weekly ultrasound image quality assurance for each ultrasound study performed in the ED.Using standardized abstracted forms, trained chart abstractors reviewed electronic medical records for comorbidities (CHF, hypertension, diabetes, chronic obstructive pulmonary disease, severe renal failure defned as renal failure greater than stage 3 chronic kidney disease, and coronary artery disease); disposition and mortality; ED vital signs; total IV fuids received; vasopressor initiation; new oxygen requirement; and reported POCUS results.

Data Collection.
Chart abstractors were trained using a standardized abstractor form to guide data collection and minimize bias including explicit criteria for case selection or exclusion.Te performance of the chart abstractors was monitored by the lead study investigator (EA).Variables were defned a priori to minimize ambiguity, and clarifcations and inconsistencies were discussed until consensus was reached among team members (EA, CH, and DT).Tenpercent random samples of abstracted data were reviewed for agreement and reliability.

2.3.
Outcomes.Te primary outcome was total IVF volume delivered to ED septic shock patients who had POCUS versus no POCUS.Secondary objectives included new oxygen requirements, overall mortality, and if these variables change in the subgroup of patients with CHF and severe renal failure.

Statistical Analyses. Continuous variables were expressed as medians with interquartile ranges (IQRs).
Categorical variables were expressed as proportions and frequencies.A power analysis suggested that a minimum sample size of 300 patients would be required to detect an IVF diference of 500 milliliters between POCUS and non-POCUS cohorts, with a signifcance level of 5% to achieve power of 80%.Te analysis also needed a 4 : 1 non-POCUS to POCUS ratio based on observed practice patterns in our ED.Te Fisher exact test was used to compare diferences between proportions.Bivariate comparisons were performed using chi-square or t-tests.A 2-tailed signifcance level of 0.05 was regarded statistically signifcant.All data were stored on a spreadsheet (Excel 2011; Microsoft Corporation, Redmond, WA), and analyses were performed with a commercially available statistical package (SPSS version 24; IBM Corporation, Armonk, NY).

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Patient Characteristics.
We identifed a total of 374 charts for review and 304 were included in the fnal analysis (Figure 1).Tere was 90% agreement in the random sample between the abstractors.Tis study's patient characteristics are presented in Table 1.Patients were predominantly male (56%), with a median age of 65 years.History of CHF and/or severe renal disease was present in 42% of the POCUS group and 29% of the non-POCUS group.Similar distributions of lactate, total fuids, and vasopressors were found in CHF and severe renal disease subsets (Table 3).
Table 4 shows statistically signifcant predictors of POCUS in ED by univariable logistic regression, including the lactate level, systolic blood pressure (SBP), diastolic blood pressure (DBP), positive pressure ventilation, and vasopressors in ED with odds ratios of 1.1, 0.98, 0.98, 1.9, and 2.01, respectively.Furthermore, we performed stepwise logistic regression with all the covariates (except outcomes) to evaluate independent efects of the variables.Te criteria used were a p value of 0.1 required for entry into the model and a p value <0.05 to stay.In Table 5, only lactate (OR 1.09, 95%CI 1.01-1.17)and SBP (OR 0.98, 95%CI 0.97-0.99)were consistently and strongly associated with POCUS use (data not shown).

Discussion
Our study demonstrates that septic shock patients with increased severity of critically illness were more likely to get POCUS during their ED resuscitation.However, both POCUS and non-POCUS groups received the same total fuid volume, and there was no diference between groups with regards to new oxygen requirement or mortality, even in subgroups with CHF and severe renal disease.Tis confrms that although POCUS utilization may be embraced, without clear protocols of care, the efect of POCUS on important patient-centric outcomes may not be immediately perceived and healthcare workers may be reluctant to depart from Surviving Sepsis Campaign recommendations.
First, our data confrm the selection bias that those patients receiving POCUS evaluations were physiologically more critically ill (higher lactate, lower blood pressure, more mechanical ventilation requirement, and vasopressor use in the ED).As has been demonstrated in prior randomized controlled and observational trials that lack clear POCUSbased protocols for care, it would be expected that those with baseline characteristics suggestive of more severe illness will receive more interventions, including fuids and POCUS [30][31][32].Wang et al. used POCUS fndings in a protocolized fashion in postresuscitated critically ill patients and found improved fuid balance and reduced ICU length of stay [33].Unfortunately, in our study, the timing of these interventions in relation to POCUS was unknown (e.g., whether vasopressors were started before or after POCUS), and the retrospective nature of the study renders it difcult to draw further conclusions of how POCUS guided clinical management.
Second, our data showed that the total amount of fuids administered between the POCUS and non-POCUS groups in the acute resuscitation phase was the same even though sicker patients were more likely to receive POCUS.While there appears to be a lack of studies that specifcally quantify volume resuscitation in the setting of POCUS use, there exists some literature with mixed fndings on this topic.In a proof-of-concept study by Le   Emergency Medicine International sepsis who received POCUS to assess volume status received less than the recommended 30 ml/kg of crystalloid over 3 hours [34], indicating the potential for POCUS use to decrease fuid administration.A randomized controlled trial showed signifcantly decreased fuid administration in the POCUS group with septic shock as follows: 36 ml/kg in the POCUS group compared to 48 ml/kg in the non-POCUS group [14].Similar to another systematic review, decreased IVFs in POCUS recipients did yield to signifcant diferences in 28-day mortality, duration of mechanical ventilation, or length of ICU stay between the two groups [35].
Te efects of POCUS on the volume status and fuids given do not often appear to be quantifed explicitly in the literature [36,37], but the connection is often implied through clinical intuition.Conceptually, studies that have shown improved clinical outcomes in septic patients who 4 Emergency Medicine International received POCUS theorize the benefts to be largely related to lessened fuid overload [9], a proxy for fuid administration.While not numerous, other studies addressing the efect of POCUS have tended to demonstrate decreased amounts of fuid given to septic patients who received POCUS evaluations, diferent from our fndings.As our POCUS cohort selected for patients with greater disease burden, it is possible that patients with more severe physiological derangements will receive more cumulative fuid and confound the true efects of POCUS examination.Te reasons are unknown but may be due to prolonged resuscitation or clinical inertia to intervene more intensely [38,39].Unfortunately, the timeline of fuid administration is not known, making it difcult to identify whether POCUS fndings altered fuids given or clinical decision making.
Furthermore, work controlling for variables of illness severity in the form of randomized controlled trials should be developed to clarify the utility and efect of POCUS in fuid management.Finally, our data suggest no diference in mortality or oxygen requirements between the POCUS and non-POCUS cohorts.Te efects of POCUS on patient mortality seem to be unclear, with some studies suggesting diagnostic improvement with POCUS while others have failed to identify a signifcant mortality beneft.Literature suggests that sonographic fndings of fuid overload such as B-lines were predictive of hypoxemia and respiratory failure [16,18,40].We were unable to fully consider this in our population because lung ultrasound was not performed on all patients in the POCUS group, which may afect the impact of lung       [35], yet found no statistically signifcant diference in the length of intubation, length of ICU stay, or 28-day mortality like other articles [14,41,42].Te exact relationship among POCUS, mortality, and oxygen requirement may be especially difcult to tease out in our study, as the timing and impact on medical decision making of POCUS is unknown.We found similar results in our subgroup analysis of CHF and patients with severe kidney disease.Literature suggests these patient populations are perceived as being "at risk" for fuid overload and as a result are underresuscitated during sepsis [43].Our fndings support this, as on average patients with CHF and severe renal disease received less IVF in both the POCUS and non-POCUS cohorts.Several retrospective studies suggest that while overall mortality is high, outcomes including intubation and mortality are not signifcantly diferent in these patient populations when given similar volumes of fuid (>30 mL/kg) [44][45][46].Tis may be due to the altered hemodynamics in septic shock or the overall high mortality of the disease.Te literature directly analyzing the impact of POCUS on these specifc patient populations in the setting of severe sepsis is sparse and also requires further investigation.

Limitations.
Our study has several limitations.First, the sample size, although powered, is limited to a single academic institution.Our results must be confrmed in a larger, multicenter cohort.Second, only patients with a documented POCUS report were included.Te POCUS images were not reviewed by consensus/experts and we assume that the POCUS fndings are accurate as reported.In addition, we do not know when along the ED timeline any labs, measurements, or POCUS was performed, which diminishes our ability to draw conclusions regarding the efect (if any) that physiological measurements (e.g., blood pressure) and/or POCUS fndings had in ED provider decision making.Tird, we do not know whether the clinicians were aware of patients' history of severe renal disease or CHF prior to initiation of fuids and if that knowledge impacted fuid management decisions.Fourth, we selected patients with the most severe forms of sepsis, as defned by the high lactate and hypotension, which may produce bias in the total fuid volume administered.Lastly, our institution has no recognized guidelines for protocolizing POCUS fndings in the resuscitation of septic patients.Since the study design was retrospective and noninterventional, we intended to evaluate association only and not a causal relationship.Whether POCUS and history of CHF or severe renal disease afects total amount of fuid administered during septic shock needs further investigation.

Conclusion
Among ED patients with septic shock, POCUS was more likely to be used in patients with higher lactate, lower blood pressure, and vasopressor use and in those requiring mechanical ventilation.Tere were no diferences in total IVF received, new oxygen requirement, or mortality in the POCUS group compared to the non-POCUS group.Tere is an urgent need for studies that incorporate POCUS fndings with specifc resuscitation protocols or guidelines to evaluate the impact of POCUS-informed management in septic shock patients.
CHF, congestive heart failure; HTN, hypertension; COPD, chronic obstructive pulmonary disease; CAD, coronary artery disease; SBP, systolic blood pressure; DBP, diastolic blood pressure; ED, emergency department; SpO 2 , oxygen saturation.Continuous variables are reported as the mean (standard deviation) and median (interquartile range).1pvalue calculated by the Wilcoxon test. 2 p value calculated by the chi-square test. 3p value calculated by Fisher's exact test.* p value calculated by the T-test.

Table 2 :
Clinical outcomes occurring during index hospitalization.,intravenousfuid;ED,emergency department; ICU, intensive care unit.Continuous variables are reported as the mean (standard deviation) and median (interquartile range). 1 p value calculated by the Wilcoxon test.2pvaluecalculated by the chi-square test.3pvalue calculated by Fisher's exact test. IVF

Table 3 :
Subgroup analysis.IVF, intravenous fuid; ED, emergency department; ICU, intensive care unit.Continuous variables are reported as the mean (standard deviation) and median (interquartile range). 1 p value calculated by the Wilcoxon test. 2 p value calculated by the chi-square test.
* p value calculated by the T-test.

Table 4 :
Logistic regression for predictors of POCUS in the emergency department.

Table 5 :
Adjusted backward logistic regression for predictors of POCUS in the emergency department (only fnal model covariates shown).