Critical Care Ultrasound Oriented Shock Treatment in Intensive Care Unit: A Randomized Controlled Trial

Objective: To determine whether our established Pathophysiology and etiology treatment for shock based on critical ultrasonography (PESCUS) workow is superior to standard care in the setting of Intensive Care Unit (ICU). Materials and Methods: This is a prospective randomized controlled study. Critically ill adult shock patients were assigned to critical care ultrasound oriented treatment (CUOT) group who received treatment designed for different phases of shock guided by PESCUS workow or standard care (SC) group who received standard care without treatment guided by PESCUS workow. Results: Of the 147 enrolled patients, 77 were assigned to the CUOT group and 70 to the SC group. There were no signicant difference between the two groups at baseline. The ICU mortality in CUOT group was signicantly lower (29.9% vs. 45.7%, P=0.047). The CUOT group received signicantly less uid than SC group in the stabilization and de-escalation phases. The median duration of stabilization and de-escalation phase of shock in CUOT group was 35.0 [IQR 19.3-59.8] hours compared with 60.0[IQR 24.0-78.0] hours in SC group, p=0.024). Conclusions: Our study suggests utilization of PESCUS workow can potentially improve ICU outcome in shock patient and avoid unnecessary uid overload during shock recovery phase. Trial registration: Critical Care Ultrasound Oriented Shock Treatment in Registered, Retrospectively registered .


Introduction
Shock is a common condition in critical care, affecting about one third of patients in the intensive care unit (ICU) (1,2) and resulting from four potential but not necessarily exclusive pathophysiological mechanisms: hypovolemia, cardiogenic factors, obstruction, or distributive factors. The treatment of shock requires accurately monitoring the above pathophysiological changes (2,3).
Critical care ultrasound (CCUS) has been used widely in critically ill to monitor organ function, diagnose etiology or guide procedures (4)(5)(6)(7)(8)(9). Usage of transthoracic ultrasound has been reported to improve ICU survival (10). Supported by echocardiography and lung ultrasound, CCUS was used in monitoring hemodynamics (11)(12)(13). Even more important, CCUS is an e cient and reliable way when incorporated into protocolized examinations to visualize the pathophysiological changes and to rule in or out the etiologies, which then can further guide a more appropriate and accurate treatment strategy (13,14,15). Now many protocols focused on the diagnosis and to guide treatment were established for shock patients (16)(17)(18). These protocols were proved to be helpful in early diagnosis, to differentiate the type of shock (19,20), and to guide further shock treatment (21)(22)(23)(24). However, despite the encouraging situation, there was no well-designed randomized control study to prove that by adhering to protocolized CCUS application in shock patients can actually improve patient outcomes. We conducted this randomized controlled trial in ICU to evaluate whether our established Pathophysiology and etiology treatment for shock based on critical ultrasono -graphy (PESCUS) work ow can improve shock patients' outcomes.

Methods And Materials
Study design This was a prospective, randomized, controlled study which enrolled shock patients in medical intensive care unit (MICU), neurology intensive care unit (NICU) and surgical intensive care unit (SICU) in West China Hospital from March 2017 to October 2017.
Patients were randomly assigned into the study group (CUOT group) and the control group (SC group).
The patients assigned to the study group received shock treatment guided by PESCUS work ow(described in detail in the following part of method section), and patients in the control group received standard ICU care without the use of PESCUS work ow. The physicians (medical team) who participated in the study were those certi ed for critical care medicine and had over 5 years' experience in critical care practice. Besides, they were also certi ed for bedside CCUS practice. The members of the CCUS team who assigned to perform the ultrasound examination according to the protocol were certi ed by the Chinese Critical Ultrasound Study Group (CCUSG) and had at least one-year practice experience. The measurements were recorded using the CX50 diagnostic ultrasound system (Philips, CX50, Bothell, WA, USA) and M-Turbo ultrasound system (FUJIFILM Sonosite, Bothell, WA, USA).
The protocol of the study was approved by the human ethics committees at Sichuan University (No. 2017 (35)) and was carried out in accordance with the Declaration of Helsinki (2000) of the World Medical Association.

Patients
Patients admitted in MICU, SICU and NICU during the study period were screened for entry into this trial.
The study inclusion criteria are: (1) systolic blood pressure (SBP) < 90mmHg or mean blood pressure < 65mmHg or SBP decrease >40mmHg; (2) the onset of shock was less than 6 hours before ICU admission; (3) positive with at least one of the conditions below: Lactate level >2mmol/L; Capillary Re ll Time >4.5s; Urine output per hour<0.5ml/kg; Clammy skin, limbs cold, unconsciousness. The patient who met all three above mentioned criteria was eligible for entry into the study. Patients were excluded from the study if they were: (1) age of <18 years; (2) pregnant; (3) refused to participate the study.
The patients were followed once enrolled and the data were recorded till death or end of ICU stay by dedicated investigators. Primary and secondary outcomes were analyzed after the trial was completed.
The study team discussed the trial's risks, bene ts and other aspects with the patients and, if required, the participants' legal representatives, before the trial began. The study team gave the potential participant ample time and opportunity to ask questions about the trial and discuss it with relatives and family members. Informed written consent was obtained from a legal representative of the family under the circumstance that the patient was unconsciousness or sedated upon the enrollment. They were informed they have the right to withdraw consent at any time without penalty, repercussions or reason. In condition that the patient in salvage phase, the verbal consent was obtained immediately, and the informed written consent was signed after the rescue by the patient or the patient's legal representative.

Interventions
Once enrolled, patients in the study group were immediately screened by PESCUS work ow. The results of the CCUS exams were double checked by two different quali ed CCUS team members and reported to the leading physician of the medical team right after the examination. Then, the PESCUS work ow based treatment in different shock phases were enforced by the medical team under the lead of the responsible physician. The protocol compliance was monitored consistently by a dedicated study coordinator, who also was responsible to provide timed prompts.
Patients in the control group received standard ICU care which including standard but not protocolized ultrasound exam if it was decided to be necessary by the team attending.

Pathophysiology and etiology treatment for shock based on critical ultrasonography(PESCUS) work ow
The PESCUS work ow was created by the Critical Care Medicine Department at West China Hospital based on the guidelines recommended shock diagnosis and treatment strategy (2,25,26) and the 3-year cumulative CCUS experience of the team. The protocol was not only an examination protocol to facilitate diagnosis but also to guide the treatment plan based on the established work ow (Figure 1).
If a patient was in shock salvage phase upon enrollment, a cardiorespiratory focused assessment performed by CCUS team will be initiated rst (27), which included ve standard views of heart (12) and ten views of lung. This bedside assessment was nished within 5 minutes and the results were then applied immediately to the patient to initiate "Pivotal treatment" or "Rapidly launching target treatment", or both. The "Pivotal treatment" focused on nding whether there were ultrasonic signs of massive pulmonary embolism, cardiac tamponade and pneumothorax that could be the culprit to the life threatening shock, and the bedside interventions were then applied immediately to "salvage" the conditions such as guided thrombolysis, needle aspiration, and tube drainage. As those interventions were the key to save shock patients in such conditions, they were de ned as "Pivotal treatment". The "Rapidly launching target treatment" was then launched after "Pivotal treatment" or in the case patient did not require "Pivotal treatment" to shorten duration of salvage phase of shock, which included uid challenge, inotrope and vasoactive drugs to treat the severe hypovolemia, pump failure and vasoparalysis, respectively.
For patients in optimization phase upon enrollment, hemodynamic detailed assessment with CCUS was performed. The examination which were performed within 20 minutes and the results were interpreted to guide treatment plan. The ECHO included the assessment of IVC, the right heart, the diastolic and systolic function of LV, the cardiac output, the left atrium pressure, and the deduced systemic resistance; the lung ultrasound included the eight-area exam focused on the lung water. The detailed ultrasonic assessment has two aims: the rst is to diagnose the type of shock to guide etiological treatment, which has been shown leading to a better outcome in previous publications (28,29), such as searching and treating massive hemorrhage in hypovolemic shock; screening infection sources for drainage or surgery in patients who have distributive shock pattern; and nding the regional wall motion abnormalities which may indicate acute coronary syndrome in patients undergoing cardiogenic shock. The second aim is to initiate goal directed titration therapy, which is through searching the abnormally pathophysiological changes of circulation to provide precise treatments (2,13,15,30) to improve the tissue perfusion. The treatments, such as uid resuscitation and vasopressin administration, were titrated to an improvement of more than 10% lactate clearance every two hours (31,32). The medical team repeated the examination every four hours thereafter and adjusted the treatments accordingly until the end of the optimization phase, which is indicated by no increasing of the vasopressors, the lactate level reached less than 2.0 mmol/L or Capillary re ll time <2s, and hour urine volume>0.5 ml/kg.h. (25,33,34).
The patients in de-escalation phase were performed with volume focused ultrasonic assessment which mainly focused on the IVC, the left atrium pressure and the lung water to evaluate whether there was uid overload (35)(36)(37). If there were signs of uid overload, diuresis was administrated without compromise the hemodynamics.
Details regarding the PESCUS work ow are provided in the Methods section in the Supplementary Appendix (S1).

Data collection
Data were collected at baseline in both groups including age, sex, APACHE II, SOFA, diagnosis at admission, mean blood pressure, use of vasoactive agents, urine output per hour, lactate level, tidal volume and PEEP and PaO 2 /FiO 2 . Reports of CCUS exam, hemodynamics, uid and drugs usage in both groups were recorded. The ICU mortality was our primary outcome. We also recorded the volume of uid balance, source control, length of shock, duration of ventilation, length of ICU and hospitalization as secondary outcomes.

Statistical Analysis
All analyses were conducted according to the intention-to-treat principle. The results were illustrated as continuous variables as means ±SD or medians and interquartile ranges depending on the normality of data. Categorical data were presented as proportions or percentages. Student's t-test or the Wilcoxon rank-sum test was used to analyze differences between groups as needed. Fisher's exact test was used to analyze categorical variables including the primary outcome. The Kaplan-Meier method was used to demonstrate patient risk of death from the start of the trial to the 28 th day of treatment. The SPSS for mac (version 22.0; IBM Corp., Armonk, NY) was used for data statistical analysis. P < 0.05 was considered as statistically signi cant.

Results
A total of 296 patients were screened, of whom 146 were excluded due to onset of shock > 6h, declined or unable to give consent. The remaining 150 patients were randomly assigned to CUOT group or SC group. After randomization, 2 patients failed to provide delayed consent in the CUOT group and 1 patient in the SC group lost follow up, eventually 147 patients completed the study (Fig. 2).
Demographic and clinical characteristics at baseline were similar in the two groups, as listed in Table 1. There were no signi cant differences between CUOT group and SC group in terms of APACHE II score, SOFA score, norepinephrine dose, mean blood pressure, lactate, urine output, PaO 2 /FiO 2 , mechanical ventilation and types of shock on admission. Only one patient suffered obstructive shock secondary to pulmonary embolism which was con rmed by computed tomographic pulmonary angiography (CTPA). The control group received standard non-protocolized ultrasound exam for 28 cases of cardiac structural examination, 32 cases of thrombosis screening, and 30 cases of hemodynamic examination.
Primary outcomes 23 out of 77 patients in the CUOT group died during ICU stay, while 32 out of 70 patients died in the SC group. The ICU mortality in CUOT group was lower than SC group (29.9% vs. 45.7%, p=0.047). The 28-day risk of death after ICU admission was also higher in the SC group (p=0.036) (Figure 3).

Secondary outcomes
There was no signi cant difference between CUOT group and SC group regarding the total uid intake and output, and shock duration during the salvage and optimization phase. However, the CUOT group received signi cantly less uid intake and output than the SC group in the stabilization and de-escalation  Table 2). Infection sources were successfully detected at bedside by PESCUS work ow in 3 patients in the CUOT group, who were subsequently transferred to the operation room and had the source removed without delaying in the optimization phase of shock.

Discussion
In this randomized trial conducted in a tertiary hospital in China, we showed that critical care ultrasound oriented shock treatment signi cantly reduced ICU mortality in shock patients. By utilization the PESCUS work ow, the source of infection is more likely to be detected at the early phase of septic shock, and less uid is needed to maintain hemodynamic stability. This is the rst randomized controlled study to show that protocolized CCUS utilization improves the mortality in shock patients. It is different from the other published randomized controlled trial on shock patients, such as ARISE, ProCESS, PROMISE, ALBIOS and SEPSISPAM (1,(38)(39)(40)(41)(42), Since those studies were mainly focused on septic shock patients, especially early phase of septic shock to investigate whether an appropriate goal or the type of uid used for resuscitation could improve the outcomes of shock. The negative results indicate to expect achieving a single target or administrating a special type of uid to reverse shock is unrealistic at current stage (43). Thus, a protocol to continuously guide and integrate individual therapy into different phases of shock is required to improve outcomes in all types of shock in the setting of ICU. This PESCUS work ow we presented in this study was designed to ful ll this need.
There are several advantages by utilizing PESCUS work ow in shock patient. First, PESCUS work ow is not a protocol that aiming to achieve certain goals, instead, it is a work ow to guide the best clinical practice and improve e ciency during all phases of shock. This protocol was designed to facilitate shock etiology treatment as well as the standard critical care supportive treatment simultaneously, and this combined etiology and support treatment strategy has been proved more effective in previous publications (29). Furthermore, by utilizing protocolized CCUS at bedside, the types of shock can be identi ed in minutes and the etiology treatment can be initiated and completed signi cantly quicker after shock onset. To a patient presented with distributive shock on US with accompanied clinical signs of infection, septic shock would be highly suspected and the source of infection potentially can be searched immediately by using the same equipment and personnel at the same time without any delay, as presented by PESCUS work ow (44). On the other hand, without protocolized bedside US, the control group may cost more time identifying the type of shock and then search the source of infection with other tools, such as CT, MRI that needs transferring or may miss the diagnosis with non-protocolized ultrasound examination. In our study, infection sources were successfully identi ed in 3 patients at bedside in the CUOT group, who were then sent to the operation room and had the source controlled in timely manner. This is the most important factor which have contributed to the observed survival bene t in this group.
Second, PESCUS work ow guides the individual treatment regarding the pathophysiological changes in different courses of shock. Depending on the phase of shock, the main treatment focus are different. In the situation of acute severe shock, salvage treatment is usually the only option left (2); detailed monitoring of the hemodynamics should be initiated right after salvage to optimize the treatment; when the circulation is stable, try to remove the overloaded uid and de-escalation should be always considered. The PESCUS work ow is designed to guide treatment at all phases of shock. By visualization of the heart and lung, CCUS makes it more e cient to search the cause of life threatening shock, as well as to facilitate the life-saving procedures. In the optimization phase the CCUS not only provides numbers but also pathophysiological changes in detail including the ventricular interaction which are essential to carry out optimized individual treatment.
Third, by following PESCUS work ow, we had demonstrated less uid administration during de-escalation and stabilization phases of shock. In many cases, the uid resuscitation is double-edged sword to patients; many studies had proved that uid overload lead to bad outcome (45)(46)(47). The volume focused ultrasonic assessment in de-escalation phase operated as one of the daily routine can potentially limit the uid intake without insult the circulation. The CUOT group in our study received signi cantly less uid in the stabilization and de-escalation phases, which could contribute to the signi cantly shorter shock duration.
Therefore, PESCUS work ow application in shock treatment can not only monitor the hemodynamics to guide therapy, but also help to diagnose the type of shock to decide the key measurements, guide the etiologies searching and improve the outcome. Furthermore, in our protocol, the treatments for different phase of shock are covered and integrated into a bundle, which makes the therapy to shock patients more informative and effective.
There are several drawbacks of our study. First, though the mortality rate we reported in control group is comparable to several literatures reported (48,49). The overall mortality rate reported in our study is higher than most of the other similar studies (49,50). The reason behind may be the patients we recruited were usually more severe with overall condition since we are the end point of referral center for whole west part of China. This might affect the representativeness of the study to generally healthier patient population. Second, the patients and physicians were not blinded in this study which can potentially cause bias. We had set up regulations to minimize CCUS team's participation into the patients' management, however, with more eyes on the study group than the control group, this could potentially increase the attention to the patient and contribute to better outcome. Third, as a single center research, although the differences highlighted seem clinically substantial, the data are actually fragile. We have planned to expand the sample size with a multicenter study design to con rm those results.

Conclusion
Our study suggests that CCUSOST is an effective and promising tool which can lead to more accurate and precise evaluation and treatment for the shock patients. The utilization of protocolized CCUS can potentially improve ICU outcome in shock patients.

Declarations
Ethics approval and consent to participate Our study was endorsed by the ethics committee of West China Hospital, Sichuan university, the committee's reference number is 2017 (No.35).All participants in the trial were agreed by the subjects or their family members and signed a consent form.

Consent for publication
Written informed consents were obtained from all the patients for publication of this review and accompanying images.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. WH wrote the manuscript and revised the manuscript. YQ organized and analyzed data, wrote the manuscript. DW and YK revised the manuscript. TZ, XZ, YL, CM, JY, HK and BL participated in trials and data collection. XW, YC and LZ participated in experimental design. All authors read and approved the nal manuscript.