Study on the Application Value of Fluid Resuscitation Guided by Lung Ultrasound in Neonatal Septic Shock
Phase: NA
Conditions: Septic Shock
Sponsor: Guangdong Second Provincial General Hospital

 
 
Clinical research protocol 
 
 
 
Project name: Application of severe ultrasound in fluid 
resuscitation of neonatal septic shock 
leading unit：Guangdong Second Provincial General Hospital 
project leader：Zhenyu Liang 
Department: Pediatrics  
Research period: January 1,2022 to December 31,2023  
NCT No.: none. 
Version No.: V3.0  
Version Date: November 29, 2021

 
1
Abstract 
object name 
Lung ultrasound-guided fluid resuscitation in neonatal septic shock 
goal of study 
In this study, a prospective observational study was conducted to 
compare the effects of severe ultrasound-assisted fluid resuscitation and 
conventional fluid resuscitation on the prognosis of children with neonatal 
septic shock, so as to evaluate the application value of the two techniques in 
fluid resuscitation of neonatal septic shock. 
research design 
n this study, children with neonatal septic shock diagnosed in the neonatal 
intensive care unit of the Second People 's Hospital of Guangdong Province from 
January 1,2022 to December 31,2023 were included in the population. According 
to the different monitoring methods used in conventional / clinical shock 
treatment, 30 cases of fluid resuscitation assisted by severe ultrasound, 30 cases 
of fluid resuscitation assisted by NICOM and 30 cases of conventional fluid 
resuscitation were collected, a total of 90 cases.  
( 1 ) The demographic data, blood examination and microbiological examination 
data of the two groups at admission were collected.  
( 2 ) The fluid volume, blood lactic acid, blood pressure, vasoactive drugs ( such 
as dopamine and epinephrine / norepinephrine ), mechanical ventilation, renal 
replacement therapy and antibiotic use were collected before fluid resuscitation.  
( 3 ) The cumulative fluid infusion volume during fluid resuscitation ( 6 hours ), 
and the use of vasoactive drugs and mechanical ventilation for 6 hours were 
collected.  
( 4 ) NICU hospitalization time, cumulative hospitalization time and mortality 
were collected. 
Total number of 
cases studied 
90 cases (30 cases in each group) 
case selection 
Inclusion criteria: 
1 Born less than 28 days on admission; 2 Conform to the diagnostic 
criteria for neonatal septic shock in the ' 2020 International 
Guidelines for Saving Sepsis Campaign: Management of Septic Shock 
and Sepsis-related Organ Dysfunction in Children; 3 For children 

 
2
diagnosed with septic shock, fluid resuscitation should be 
performed according to the routine diagnosis and treatment. 4 The 
legal guardian has signed the informed consent. 
excluded criteria: 
1 combined with neurogenic shock, trauma and hemorrhagic shock; 
2 symptomatic patent ductus arteriosus; 3 combined with congenital 
heart disease; 4 give up treatment or death within 24 hours of 
admission; 5 The legal guardian refused to participate in the 
study; 6 Key information and information missing. 
Treatment plan 
This study was an observational study. Clinicians developed a 
diagnosis and treatment plan based on the treatment plan for 
neonatal sepsis in the sixth edition of " Practical Neonatology 
" and the " International Guidelines for the 2020 Saving Sepsis 
Campaign: Management of Septic Shock and Sepsis-related Organ 
Dysfunction in Children. " 
efficacy evaluation 
The main efficacy indicators: hospitalization time and cumulative 
hospitalization time, mortality.  
Secondary efficacy indicators: cumulative fluid volume during 
fluid resuscitation, use of vasoactive drugs and mechanical 
auxiliary gas. 
Safety evaluation index: Mortality. 
statistical method 
Measurement data and count data were expressed as mean ± 
standard deviation [ or median ( interquartile range ) ] and 
percentage ( % ), respectively. Normal and non-normal distribution 
data were analyzed by two independent sample t test and 
Mann-Whitney U test, respectively. The chi-square test was used 
to compare the count data rates between groups. Kaplan-Meier 

 
3
method was used to draw the survival curve, and Log-rank test was 
used to compare the difference of 28-day cumulative survival rate 
between the two groups. Baseline covariates were adjusted in the 
Cox proportional hazards model to calculate the hazard ratios 
( HRs ) and their 95 % confidence intervals. Logarithmic conversion 
was performed on hospital stay and organ support time and linear 
regression analysis was used to calculate a 95 % confidence 
interval for reporting. No data with missing information is 
interpolated. The above statistical analysis was performed using 
R software, and the test was bilateral, and p < 0.05 was considered 
statistically significant. 
Research period 
January 1, 2022 - December 31, 2023 
 

 
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一、Research background 
Sepsis, especially the development of septic shock, is one of the most important causes 
of neonatal morbidity and mortality [ 1 ]. Although the understanding of the 
pathophysiology of septic shock continues to evolve, the treatment of neonatal septic shock 
remains challenging ; although considerable progress has been made in treatment, failure is 
still common [ 2 ]. In particular, the particularity of neonatal physiological development [ 3, 
4 ] makes the tolerance of neonatal septic shock much lower than that of adults. However, 
the research progress in the field of neonatal septic shock is far behind that of adults [ 2, 5 ]. 
At present, non-invasive monitoring and clinical experience are mainly used to judge the 
organ function and volume status of patients and then treat them in clinical practice. 
However, empirical diagnosis and treatment can lead to insufficient volume or excessive 
fluid, which in turn leads to impaired function of important organs [ 6 ]. Ultrasound 
examination integrates structural and functional assessment, problem goal orientation, 
quantitative and qualitative combination, and dynamically evaluates volume status, volume 
responsiveness and organ function changes, so as to guide fluid resuscitation and positive 
inotropic drug use in a timely and accurate manner. It is an ideal medical tool for 
hemodynamic management in patients with septic shock [ 7, 8 ]. However, there is still a 
lack of relevant research in the field of fluid resuscitation in neonatal septic shock. 
The incidence of neonatal sepsis varies with gestational age and onset time ( 35 % of 
live births ) [ 10-13 ]. Sepsis neonates may develop or progress to septic shock, which is 
initially manifested as cardiovascular dysfunction requiring fluid resuscitation or muscle 
strength support [ 14 ]. If the development of infection cannot be prevented, the possibility 
of terminal organ damage and death will be greatly increased, especially in premature 
infants, sepsis has become an important source of morbidity and mortality. [ 2 ]. Although 
the exact incidence is not clear, a recent retrospective cohort study of 3800 newborns 
admitted to the Neonatal Intensive Care Unit ( NICU ) during the three-year period reported 
that the incidence of septic shock was 1.3 %, and the peak mortality rate associated with 

 
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very low birth weight ( birth weight < 1000g ) was 71 % [ 15 ]. 
Septic shock refers to life-threatening organ dysfunction caused by the body 's 
uncontrolled response to infection, accompanied by severe circulatory, cellular and 
metabolic abnormalities. The in-hospital mortality rate is as high as more than 40 % [ 16 ], 
and the proportion is higher in newborns [ 15 ]. In the early stage of septic shock, in order to 
maintain the stability of circulation, a large amount of fluid resuscitation treatment is usually 
needed. The effective circulating blood volume of the body is supplemented by intravenous 
infusion and other means, and the increase of stroke volume and cardiac output is promoted, 
so as to restore the perfusion of tissues and organs, improve their hypoxic state, and then 
correct septic shock [ 17 ]. Therefore, appropriate volume resuscitation is an important 
measure for clinical treatment of septic shock. How to effectively monitor the volume status 
of patients and reasonably guide clinical treatment has become the focus of clinical workers. 
The ' Save Sepsis Campaign ' emphasizes that sepsis and septic shock are clinical 
emergencies and require early comprehensive treatment. It is recommended to guide late 
fluid therapy through repeated hemodynamic monitoring after timely initial fluid 
resuscitation [ 18,19 ]. Hemodynamic monitoring in patients with septic shock is mainly 
used to evaluate whether continuous fluid infusion can improve organ perfusion and assist in 
deciding whether positive inotropic drugs are needed [ 17 ]. At present, non-invasive 
monitoring and clinical experience are mainly used to roughly judge the organ function, 
volume status and resuscitation effect of patients. ' Detachment after heavy irrigation ' has 
become a clinical norm, while empirical diagnosis and treatment can lead to insufficient 
volume or excessive fluid. Volume overload is often ignored until clinical signs or imaging 
signs of organ dysfunction occur, and continuous positive fluid balance will significantly 
increase the complications and mortality of patients [ 20,21 ]. Therefore, it is an important 
way to improve the therapeutic effect and prognosis quality of septic shock by establishing 
accurate and objective organ function monitoring methods in the process of diagnosis and 
treatment, carrying out appropriate fluid management optimization under the guidance of 

 
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scientific dynamic monitoring of disease, correctly evaluating the circulatory function of 
different stages of shock to adjust the treatment plan, and supporting organ tissue perfusion 
with the least amount of fluid and the least physiological cost. 
In the past few decades, hemodynamic monitoring technology has developed from 
discontinuity to continuity, real-time, and less invasive, and the number and characteristics 
of indicators provided have also been continuously improved [ 22 ]. At present, the 
commonly used monitoring tools in clinical practice are divided into invasive and 
non-invasive. Among them, transpulmonary thermodilution method and pulmonary artery 
catheter are considered as invasive advanced hemodynamic monitoring methods, which can 
continuously and dynamically evaluate the cardiac volume and pressure status and systemic 
oxygenation status of critically ill patients, and are called the ' gold standard ' of 
hemodynamic monitoring [ 23 ]. However, it cannot be used as a routine monitoring tool due 
to its cumbersome operation, many complications, lack of evidence of benefits for patients, 
and inability to evaluate cardiac diastolic function. Early fluid resuscitation is the key to the 
treatment of septic shock, but so far, there is no unified guidance for fluid resuscitation. 
Blind fluid replacement can lead to insufficient fluid or excessive fluid, which can lead to 
acute heart failure, pulmonary edema and other complications [ 6 ]. Therefore, it is 
extremely important to establish an accurate and objective organ function monitoring 
method in the process of diagnosis and treatment, and correctly evaluate the circulatory 
function of different stages of shock to adjust the treatment plan. The traditional 
hemodynamic methods, including pulmonary artery floating catheter, pulse indicator 
continuous cardiac output and other monitoring techniques are invasive operations, and the 
clinical application process has high technical requirements, relatively many complications, 
and high prices [ 23 ]. In view of the characteristics of severe neonatal septic shock, poor 
consciousness and low cooperation, these invasive monitoring have certain difficulties, and 
the ideal non-invasive monitoring system should be accurate, economical and efficient, with 
few complications, easy to use and explain, with high specificity and sensitivity, and can be 

 
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widely used [ 24 ]. 
At present, non-invasive monitoring and inspection methods have broad application 
prospects in the field of fluid management of septic shock. Monitoring cardiac output in the 
ICU has become part of routine patient management, helping doctors assess patients ' 
clinical status and track their response to various interventions. Non-invasive cardiac output 
monitoring ( NICOM ) is a non-invasive cardiac output detection method that detects 
hemodynamic indicators by bioelectrical impedance method. NICOM can dynamically and 
conveniently detect the hemodynamic characteristics of patients on a non-invasive basis in 
real time. In recent years, NICOM has been gradually applied in pediatric NICU, especially 
in the treatment of neonatal septic shock patients, and has achieved certain results [ 24 ]. In 
addition, among various monitoring methods, ultrasound technology can provide 
cardiovascular system-related information from both functional and structural aspects, and is 
an important tool for hemodynamic monitoring in adult patients with septic shock [ 25 ]. 
More and more evidence shows that severe ultrasound-guided fluid resuscitation can 
improve the prognosis of critically ill patients, and was written into the 2015 ' Severe 
Hemodynamic Therapy-Beijing Consensus ' [ 26 ]. Ultrasound technology has the 
characteristics of non-invasive, real-time and repeatable, and integrates structural and 
functional assessment, problem goal orientation, quantitative and qualitative combination, 
dynamic assessment of volume status ( cardiac function ), volume responsiveness ( inferior 
vena cava diameter ) and organ function changes ( lung ultrasound ), so as to timely and 
accurately guide fluid resuscitation and positive inotropic drug use. It is an ideal medical 
tool for hemodynamic management in patients with septic shock and has been integrated 
into the diagnosis and treatment of adult septic shock [ 25, 27 ]. In particular, ultrasound 
diagnosis of pulmonary edema depends on the discovery of characteristic B lines, and has a 
high consistency with CT diagnosis. If the patient 's B line under lung ultrasound monitoring 
is significantly increased, suggesting increased lung water, increased lung permeability, such 
as reduced cardiac function and inferior vena cava dilatation, at this time, the presence of 

 
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excessive lung water volume load should be considered. Increases should begin to make 
adjustments in fluid therapy and respiratory therapy that are most suitable for patients [ 28 ]. 
However, previous studies are basically aimed at adults, and the number of studies in 
neonates is very limited. In clinical studies, due to the particularity of neonatal anatomy and 
physiology, there is a lack of research on the application of severe ultrasound technology in 
fluid resuscitation of neonatal septic shock. [ 29 ] There is an urgent need for an effective 
non-invasive monitoring method to assist fluid resuscitation in children with septic shock. 
At present, the fluid resuscitation methods used in our department for neonates with 
septic shock mainly include : conventional fluid resuscitation, severe ultrasound-guided 
fluid resuscitation and NICOM-assisted fluid resuscitation. In this prospective observational 
study, children with neonatal septic shock diagnosed in the neonatal intensive care unit of 
Guangdong Second People 's Hospital from January 1,2022 to December 31,2023 were 
included in the study. According to the different monitoring methods used in shock treatment, 
30 cases of severe ultrasound-assisted fluid resuscitation, 30 cases of NICOM-assisted fluid 
resuscitation and 30 cases of conventional fluid resuscitation were collected, a total of 90 
cases. The hemodynamic differences, NICU hospitalization time, renal replacement therapy 
/ mechanical ventilation, and 28-day mortality were compared among the three groups to 
comprehensively evaluate the application value of cardiopulmonary ultrasound and 
non-invasive cardiac output in fluid resuscitation of neonatal septic shock. Improve the 
therapeutic effect of neonatal septic shock, enrich the application field of clinical ultrasound, 
and promote the cross-fusion of ultrasound and pediatrics, and provide clinical basis for 
subsequent prospective studies. 
二、research objective 
1. Main Objective: To study the application value of severe ultrasound and 
non-invasive cardiac output technique in fluid resuscitation of neonatal septic shock.  
2.Secondary purpose: To promote the therapeutic effect of neonatal septic shock and 
enrich the application field of clinical ultrasound technology. 

 
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三、Research Design Types, Principles, and Test Procedures 
1. Research Design 
In this study, children with neonatal septic shock diagnosed in the neonatal intensive care unit of 
the Second People 's Hospital of Guangdong Province from January 1,2022 to December 
31,2023 were included. According to the different monitoring methods used in routine / clinical 
shock treatment, 30 cases of severe ultrasound-assisted fluid resuscitation, 30 cases of 
NICOM-assisted fluid resuscitation and 30 cases of routine fluid resuscitation were collected. 
The demographic data, blood examination and microbiological examination data of the three 
groups at admission were collected. The fluid volume, blood lactic acid, blood pressure, 
vasoactive drugs ( such as dopamine and epinephrine / norepinephrine ), mechanical ventilation, 
renal replacement therapy and antibiotic use before fluid resuscitation were collected. The 
cumulative fluid infusion volume during fluid resuscitation ( 6 hours ), and the use of vasoactive 
drugs and mechanical ventilation for 6 hours were collected. NICU hospitalization time, 
cumulative hospitalization time and mortality were collected. 
四、case selection 
1. Inclusion criteria: 
1 Born less than 28 days on admission; 2 Conform to the diagnostic criteria for neonatal 
septic shock in the ' 2020 International Guidelines for Saving Sepsis Campaign: 
Management of Septic Shock and Sepsis-related Organ Dysfunction in Children; 3 For 
children diagnosed with septic shock, fluid resuscitation should be performed according to 
the routine diagnosis and treatment. 4 The legal guardian has signed the informed consent. 
2. excluded criteria: 
1 combined with neurogenic shock, trauma and hemorrhagic shock; 2 symptomatic 
patent ductus arteriosus; 3 combined with congenital heart disease; 4 give up treatment or 
death within 24 hours of admission; 5 The legal guardian refused to participate in the study; 
6 Key information and information missing. 
3. Elimination criteria  

 
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Subjects who have been enrolled in the study but meet one of the following criteria 
should be excluded :  
( 1 ) After inclusion, those who did not meet the inclusion criteria or met the exclusion 
criteria were found.  
( 2 ) Those who have not used test drugs / interventions. 
4. Standard for suspension of research  
( 1 ) If the following conditions occur during the experiment : cardiac arrest, intestinal 
perforation, intracranial and other serious complications ; ( 2 ) the need for rescue is not 
suitable for experimental related operators ; ( 3 ) The competent physician believes that the 
clinical condition is not suitable for continuing the experiment ; ( 4 ) If the clinical 
symptoms and other auxiliary examinations are inconsistent with the relevant non-invasive 
examination results ; ( 5 ) Parents did not agree to continue the experiment during the 
experiment. 
4. Drop-out / exit criteria  
Expulsion / withdrawal criteria : ( 1 ) the competent physician believes that the clinical 
condition is not suitable for the continuation of the experiment ; ( 2 ) If the clinical symptoms 
and other auxiliary examinations are inconsistent with the relevant non-invasive examination 
results ; ( 3 ) Parents did not agree to continue the experiment during the experiment. 
    五、research method 
In this study, children with neonatal septic shock diagnosed in the neonatal intensive care 
unit of the Second People 's Hospital of Guangdong Province from January 1,2022 to 
December 31,2023 were included. According to the different monitoring methods used in 
routine / clinical shock treatment, 30 cases of severe ultrasound-assisted fluid resuscitation, 
30 cases of NICOM-assisted fluid resuscitation and 30 cases of routine fluid resuscitation 
were collected. The demographic data, blood examination and microbiological examination 
data of the three groups at admission were collected. The fluid volume, blood lactic acid, 
blood pressure, vasoactive drugs ( such as dopamine and epinephrine / norepinephrine ), 

 
11
mechanical ventilation, renal replacement therapy and antibiotic use before fluid 
resuscitation were collected. The cumulative fluid infusion volume during fluid resuscitation 
( 6 hours ), and the use of vasoactive drugs and mechanical ventilation for 6 hours were 
collected. NICU hospitalization time, cumulative hospitalization time and mortality were 
collected. 
六、Observation items and detection time points 
( 1 ) The demographic data, blood examination and microbiological 
examination data of the three groups at admission were collected.  
( 2 ) The fluid volume, blood lactic acid, blood pressure, vasoactive drugs 
( such as dopamine and adrenaline / norepinephrine ), mechanical ventilation, 
renal replacement therapy and antibiotic use before fluid resuscitation were 
collected.  
( 3 ) The cumulative fluid infusion volume during fluid resuscitation ( 6 
hours ), and the use of vasoactive drugs and mechanical ventilation for 6 hours 
were collected.  
( 4 ) NICU hospitalization time, cumulative hospitalization time and 
mortality were collected. 
七、standards for efficacy appraisal 
The main efficacy criteria : NICU hospitalization time and cumulative 
hospitalization time, mortality.  
Secondary efficacy criteria : cumulative fluid volume during fluid 
resuscitation ( 6 hours ), and use of vasoactive drugs and mechanical 
ventilation for 6 hours. 
八、Observation of adverse events  
Observation of adverse events : Clinicians should evaluate the fluid resuscitation of 
children at any time during the experiment. If the clinical symptoms and other auxiliary 
examinations ( such as heart rate, liver size, mental state, X-ray, blood gas analysis, etc. ) are 

 
12
inconsistent with the relevant non-invasive examinations, the experiment should be 
terminated immediately and the superior physician should be found in time to assist. 
九、Data security monitoring  
Clinical research will develop a corresponding data security monitoring plan based on 
the size of the risk. All adverse events were recorded in detail, properly handled and tracked 
until they were properly resolved or stable. Serious adverse events and unexpected events 
were reported to the ethics committee, competent authorities, sponsors and drug supervision 
and management departments in a timely manner according to the regulations. The main 
researchers regularly conduct a cumulative review of all adverse events, and if necessary, 
convene a meeting of researchers to assess the risks and benefits of the study ; research that 
is greater than the minimum risk will arrange independent data monitors to monitor the 
research data, and high-risk research will establish an independent data security supervisory 
committee to monitor the accumulated security data and effectiveness data to make 
recommendations on whether the research will continue. 
十、Statistical processing  
Measurement data and count data were expressed as mean ± standard deviation [ or 
median ( interquartile range ) ] and percentage ( % ), respectively. Normal and non-normal 
distribution data were analyzed by two independent sample t test and Mann-Whitney U test, 
respectively. The chi-square test was used to compare the count data rates between groups. 
Kaplan-Meier method was used to draw the survival curve, and Log-rank test was used to 
compare the difference of 28-day cumulative survival rate between the two groups. Baseline 
covariates were adjusted in the Cox proportional hazards model to calculate the hazard ratios 
( HRs ) and their 95 % confidence intervals. Logarithmic conversion was performed on 
hospital stay and organ support time and linear regression analysis was used to calculate a 
95 % confidence interval for reporting. No data with missing information is interpolated. 
The above statistical analysis was performed using R software, and the test was bilateral, 
and p < 0.05 was considered statistically significant. 

 
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十一、Ethics in clinical research  
Clinical research will follow the World Medical Congress ' Helsinki Declaration ' and 
other relevant provisions. Before the study began, the clinical study was carried out after the 
ethics committee approved the test plan. Before each subject is selected for this study, the 
researcher has the responsibility to fully and comprehensively introduce the purpose, 
procedure and possible risks of this study to the subjects or their agents, and to sign a written 
informed consent form. The subjects should be informed that they have the right to withdraw 
from the study at any time. Informed consent should be retained as a clinical research 
document for review. The personal privacy and data confidentiality of the subjects will be 
protected during the study. 
十二、Research progress  
January 1, 2022 - March 31, 2022 : Pre-project preparation, harmonization of data 
collection standards, training of personnel  
From April 1,2022 to May 31,2023 : the specific implementation stage of the 
experiment, case data were collected.  
From June 1,2023 to December 31,2023 : Write scientific research papers and project 
summary reports 1 Organize research data and conduct statistical analysis ; 2 writing and 
submission of scientific research papers ; 3 Summarize the research results and write the 
project summary report. 
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