Development of an Artificial Intelligence Algorithm to Predict Hypotension Risk After Induction in Cesarean Sections With Spinal Anesthesia
Conditions: Spinal Anesthesia Induced Hypotension, Caeserian Section
Sponsor: Hacettepe University

NCT06158542                                                                                                                                      
12.01.2023 
 
 
Development of an Artificial 
Intelligence Algorithm to Predict 
Hypotension Risk After Induction in 
Cesarean Sections With Spinal 
Anesthesia                       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCT06158542                                                                                                                                      
12.01.2023 
1.Study Type: Non-Interventional Single-Center Prospective Observational Clinical 
Study 
 
2.Location of the Study: 
Evaluation of patients for eligibility for the study, recording of preoperative 
demographic information and vital signs, collection of blood samples, and 
administration of spinal anesthesia: Hacettepe University Hospital, Section 81 
Delivery Room 
Evaluation of blood samples: For all samples except Syndecan-1, Hacettepe 
University Adult Hospital, Department of Biochemistry Central Laboratory; for 
Syndecan-1 samples, Hacettepe University Faculty of Medicine, Department of 
Biochemistry Laboratory will be used. 
Recording, defining, and cleaning of data: Hacettepe University Faculty of Medicine, 
Department of Anesthesiology and Reanimation 
 
3.Timing of the Study:  
Ethical approval for the project has been granted by the Hacettepe University Non-
Interventional Clinical Research Ethics Committee as of January 25, 2023. The study 
is planned to be conducted between December 2023 and March 2024. 
 
4.Universe, Sample, and Research Group of the Study: 
4.1. Inclusion criteria: 
- Being 18 years of age or older 
- Having an American Society of Anesthesiologists (ASA) physical status of I, II, or III 
- Being at a gestational age of 37 weeks or more 
- The patient having received spinal or combined spinal-epidural anesthesia 
 
4.2. Exclusion criteria: 
- The patient's refusal to participate in the study 
- Multiple pregnancy 
- Emergency cesarean 
- The patient being preeclamptic 

NCT06158542                                                                                                                                      
12.01.2023 
- Preoperative systolic blood pressure equal to or greater than 140mmHg 
(hypertensive patient) 
- Having a contraindication to spinal anesthesia or failure of spinal anesthesia 
 
5. Methods and Data Collection Tools of the Study: 
Data from patients meeting the inclusion criteria in Section 81 Operating Room will 
be obtained from the results of routine tests sent after hospitalization for cesarean 
section, preoperative nurse observation forms, and records of vital signs monitored 
by anesthesia during surgery. After the patient is taken to the operating room, the 
"Data Collection Form" under the title "Appendix-1" will be filled out by the 
anesthesiologist. The duration of hypotension after spinal anesthesia in pregnant 
women starts immediately after the anesthesia application and reaches the lowest 
level within approximately 10-15 minutes. Then, it is known to return to normal within 
20-30 minutes. However, the duration of hypotension can vary depending on the 
gestational week, anesthesia dose, the patient's general health condition, and other 
factors. Especially in pregnant women with high blood pressure or those who receive 
high doses of anesthesia, the duration of hypotension can be longer. Therefore, the 
duration of hypotension should be evaluated separately for each patient. However, 
for this study, it has been preferred to observe for the first 15 minutes. This choice 
has been made because the algorithm is intended to predict hypotension induced by 
spinal anesthesia based on preoperative characteristics. With an extended 
observation period, it is clear that hemodynamics become a complex situation 
influenced by multiple independent factors, such as childbirth, increased cardiac 
output, and the initiation of oxytocin infusion during surgery. The data collection 
process will end after the first 15 minutes. Hypotension data developing after the 16th 
minute will not be recorded, and the study-specific observation will be terminated. 
 
6.Data Collection for the Study: 
The number of patients needed to develop an artificial intelligence algorithm can vary 
depending on the characteristics of the data sources used, the complexity of the 
algorithm, and the projected accuracy level. However, larger and more diverse data 
sets generally provide more accurate results. Many studies in the literature 
emphasize the importance of large data sets in the development of artificial 
intelligence algorithms. For this purpose, the frequency of hypotension after spinal 
anesthesia in cesarean sections varies in the literature, but it has been observed that 
the frequency does not exceed 75%. In light of these studies, the sample size of the 
study has been calculated using power analysis based on the following formula: 
𝑍1−α/2
2 × 𝑝× (1 −𝑝)
𝑑2
 

NCT06158542                                                                                                                                      
12.01.2023 
Z:  Standard normal deviation. (For a type 1 error of 5% (P<0.05), it is 1.96, and for a type 1 
error of 1% (P<0.01), it is 2.58). In this study, it has been determined as (P<0.05). 
P: The expected ratio, based on previous studies or pilot studies, has been determined as 
75%, as explained in the literature. 
d: The absolute error or precision has been determined as 0.05. 
 
Based on this information, the minimum number of patients to be included in the 
study has been determined to be 280, with a type 1 error rate below 5%, a disease 
addition rate of 75%, and an absolute error of 0.05. 
Before the patients are taken to the operating room, enough blood will be separated 
from the routine pre-delivery blood samples for the blood parameters listed in the 
"Data Collection Form" under the title "Appendix-1." Other parameters in the blood 
parameters besides Syndecan-1 are routinely tested in the biochemistry laboratories 
of Hacettepe University Hospital. 
A commercial kit will be used for the mentioned Syndecan-1 molecule. To detect 
Syndecan-1 in serum, samples will be taken in yellow-capped, gel tubes and allowed 
to clot at room temperature for 10-20 minutes. Then, the transport to the Hacettepe 
University Department of Biochemistry Laboratory will take place, and after 
centrifugation at 3000 g for 10 minutes, the serum will be separated and aliquoted 
into eppendorf tubes in appropriate volumes and stored at -80 °C until the day of the 
ELISA study. Before the ELISA study, the samples will be thawed, and dilution will be 
done using 0.9% NaCl as deemed appropriate by the kit. 
 
6.1 Routine Obstetric Spinal Anesthesia Practice 
No specific intervention will be made regarding the amount of preoperative fluid, but 
the administered fluid will not be of colloid character (the amount of fluid will be 
noted). Preoperative fluid loading has been shown to damage the endothelial 
glycocalyx. Standardized fluid loading has the potential to affect the results of 
syndecan-1 released into circulation as a result of endothelial glycocalyx damage. 
The duration of oral fasting is routinely applied worldwide for at least 6-8 hours. This 
duration will not be specifically standardized, but the 6-8 hour rule will be followed. 
There will be no intervention in the oxytocin dosage given by the Obstetrics and 
Gynecology department during the management of the delivery process, and if 
preoperative oxytocin infusion is given, it will be noted. When the procedure starts, a 
stopwatch will be started, and the duration of spinal anesthesia will be recorded. 
 
After the patient is taken to the operating room, standard monitoring will be 
performed with electrocardiogram, non-invasive blood pressure, and pulse oximetry; 

NCT06158542                                                                                                                                      
12.01.2023 
the patient's initial pulse, non-invasive blood pressure, saturation values, vertebral 
column, and abdominal circumference lengths will be recorded. Since patients 
usually come to surgery with an intravenous line in place, a bolus of 10 ml/kg fluid 
and maintenance fluids (a total of 1000 ml crystalloid administration) will be given 
through the existing vascular access. After standard monitoring, the patient will be 
positioned sitting for marking and anesthesia application. The highest line connecting 
the right and left iliac crests (Tuffier's line) is determined as the entry site for the L3-
L4 interspinous space or L2-L3 space through conventional palpation of anatomical 
landmarks. In patients with successful spinal entry, spinal anesthesia is achieved with 
LA doses and types shown in Table 1, appropriate for the patient (intrathecal 10-12 
mg bupivacaine and 15-25 mcg fentanyl added). The block level is determined by the 
ice test/pin prick test 10 minutes after the procedure is completed and the patient is 
placed in the supine position. Blocks reaching the T4-T6 level are considered 
successful, and surgery is started. 
 
The type and dose of local anesthetic to be used during spinal anesthesia are shown 
in Table 1: 
Length (cm) 
Bupivacaine 
0.5% 
(Izobaric) 
(mg) 
150-160 
8 
160-180 
10-12.5 
>180 
12.5-15 
Table 1: Local anesthetics to be used in cesarean delivery performed with subarachnoid 
block. 
 
At the start of spinal anesthesia, the patient will begin to receive a crystalloid fluid 
between 1000 ml (co-load) that will end during the operation.  Only this fluid will be 
given during the operation, and in case of hypotension, treatment will be done with 
ephedrine as a vasopressor. IV boluses of 5-10 mg will be given until hypotension is 
corrected, and if necessary, hypotension will be intervened with an infusion of 1-5 
mg/min[32]. The decision for ephedrine or other treatments will not be influenced by 
the data collection process. The patient will be observed for 15 minutes from the time 
of supine placement, and hypotension will be noted when it occurs. The definition of 
hypotension for this study is made as any of the following conditions: 
 
 
 Mean arterial pressure dropping below 65mmHg 
 Systolic Blood Pressure dropping below 80 mmHg 
 Systolic Blood Pressure dropping below 75% of the baseline value 

NCT06158542                                                                                                                                      
12.01.2023 
 The emergence of hypotension symptoms such as dizziness, increased 
salivation, dyspnea, nausea, vomiting. 
During the study, there will be no changes in treatment approach based on the data 
for algorithm development. In the process of developing artificial intelligence, no 
patient's treatment will be influenced by this process. There will be no changes in 
anesthesia management with the study. Routine anesthesia management will be 
performed, and only the results will be observed. 
 
6.2. Analysis of Syndecan-1 in Patient Serums: 
Syndecan is a proteoglycan molecule, and its serum levels will be measured using 
the enzyme-linked immunosorbent assay (ELISA) method with a commercial kit. 
In the sandwich ELISA method to be used, there is a two-step binding process. The 
first is between the primary antibody covalently bound to the solid surface of the 
measurement plate and the antigen (Syndecan-1). After a washing process to 
remove unbound molecules, the second stage of binding is completed by adding a 
secondary antibody solution specific to the primary antibody. This second antibody is 
conjugated with the horse radish peroxidase enzyme, and quantification is targeted 
through spectrophotometry by adding 3,3′,5,5′-tetramethylbenzidine as a substrate. 
The absorbance reading on the measurement plate will be performed with the 
SpectraMax-M2 (Molecular Devices, USA) device located in the Department of 
Medical Biochemistry and then serum Syndecan-1 levels will be calculated using the 
GraphPad Prism program based on the standard graph. 
In a study measuring serum Syndecan-1 levels in a healthy population, the median 
value was found to be 0.3 ng/mL[34]. Syndecan-1 levels increase during pregnancy, 
reaching levels of 38 ng/mL in the last period of pregnancy. 
The Syndecan-1 ELISA measurement kit to be used in this study will be carefully 
chosen to be sensitive enough for the study in serum and the coefficient of variation 
in repeated measurements will be below 10%. 
 
7. Analysis of Data: 
The Python Programming Language will be used in all stages of algorithm 
development. The "Guidelines for Developing and Reporting Machine Learning 
Predictive Models in Biomedical Research: A Multidisciplinary View." guideline will be 
followed in the process of developing the artificial intelligence algorithm. The stages 
are as follows: 
7.1. Data Collection: Data will be recorded by filling out the "Data Collection Form." 

NCT06158542                                                                                                                                      
12.01.2023 
7.2. Data Processing: After data collection, the data will be processed, randomly 
divided into training data and internal validation data. The data will be cleaned of 
artifacts and incorrect readings. 
7.3. Labeling (Annotation): Data will be labeled for classification by artificial 
intelligence, and the definition of hypotension will be made (Annotation). Studies will 
be conducted to determine the potential of artificial intelligence in detecting 
hypotension. 
7.4. Feature Selection: Features that predict annotated events at the highest rate 
will be selected. One or more feature selection algorithms will be used for this 
process, and features will be used based on the success achieved in the models. 
7.5. Building the Model: The most related features in the data will be selected, and 
a model will be developed. After the formation of the data in the study, basic 
performance rates will be obtained using basic classification algorithms such as K-
nearest neighbors, Support Vector Machines (SVM), Decision Trees, Random Forest, 
which are used for classification processes in the literature. Then, a deep learning 
method will be developed. The performance difference between the proposed 
method and the basic methods will be examined.  
 
7.6.Cross-Validation: The performance of the first version of the model will be 
subjected to cross-validation repeatedly with subsets of data that the model has 
never seen before. Thus, the performance changes of the proposed method due to 
data variation will be examined, and the model's success will be determined. 
Depending on the number of data, either 10-Fold Cross-Validation or 5-Fold Cross-
Validation method will be used. 
 
7.7. Test of the Model: The predictive performance of the algorithm trained with 
training data will be demonstrated with internal validation data that it has never seen 
before . 
In addition to the algorithm development process, if the variables are normally 
distributed, the analysis of the monitored numerical variables will use "ANOVA", 
"Student's t-test", and "Mann Whitney U test" depending on the number of groups 
compared and the analysis of normal distribution of variables. For the relationship 
between hypotension values and other continuous parameters, "Pearson Correlation 
Analysis" and "Spearman Correlation Analysis" will be used depending on the 
analysis of normal distribution of variables. Moreover, the predictability of the system 
will be tested with sensitivity, specificity, positive predictive value (PPV), negative 
predictive value (NPV), odds ratio (OR), risk ratio (RR), area under the receiver 
operating characteristic curve (AUROC), and Pearson correlation coefficient (r) tests. 
The level of statistical significance will be accepted as p<0.05. For statistical analysis, 

NCT06158542                                                                                                                                      
12.01.2023 
Statistical Packages for the Social Sciences v26.0 (SPSS Inc., Chicago, IL) software 
will be used. 
 
8. Accuracy Metrics 
Sensitivity, specificity, and accuracy are commonly used metrics to measure model 
performance in classification problems in the medical field. These metrics play a 
significant role in the detection of diseases such as hypotension. 
 
8.1. Sensitivity: Sensitivity is the true positive rate and is the percentage of true 
positive predictions out of the total positives. It shows how many of those with the 
disease are correctly identified. Sensitivity is important for minimizing false negative 
predictions. 
8.2. Specificity: Specificity is the true negative rate and is the percentage of true 
negative predictions out of the total negatives. It shows how many of those without 
the disease are correctly identified. Specificity is important for minimizing false 
positive predictions. 
8.3. Accuracy: Accuracy is the ratio of correct predictions to the total number of 
samples and shows how accurately a model makes predictions. It shows how many 
of those with and without the disease are correctly identified. However, accuracy can 
be misleading in situations such as imbalanced class distribution. 
In the detection of hypotension, sensitivity and specificity metrics are of great 
importance. Sensitivity ensures the correct identification of patients with hypotension 
and minimizes false negative predictions. Specificity ensures the correct identification 
of patients without hypotension and minimizes false positive predictions. 
For example, when developing a machine learning model for hypotension detection, 
evaluating sensitivity and specificity metrics is important. High sensitivity and 
specificity values indicate a model with better performance in hypotension detection. 
However, having high values for only one of these metrics can sometimes conflict 
with each other. Therefore, a balance point must be found, and both metrics should 
have optimum values. 
 
 
APPENDIX 1  

NCT06158542                                                                                                                                      
12.01.2023 
 
 
DATA COLLECTION FORM 
1. 
PREOPERATİF DEĞERLENDİRME 
 
A.DEMOGRAPHIC INFORMATION 
 
Patient’s Code:                                     
Age:                                                 Height(cm):                                                  Weight(kg): 
 
Comorbidities:  
 
YES 
NO 
COPD:  
 
Gravidity:                                              Paridity:                                  Gestational Age(weeks) : 
 
 
 
Yes 
 
No 
 
Unknown 
Did hypotension develop in the previous cesarean 
section?         
 
 
AREA 
 
LENGHT(cm) 
Columna Vertebralis                              
 
Abdominal Circumference 
 
 
Medications:   
B. VITAL SIGNS  
 
 
HR(pulse/min) 
 
Blood Pressure(mmHg) 
 
Temperature(0C
) 
 
Sp02(%) 
 
 
 
 
 
 
 
 
 
 
 
Date: 
Time: 

NCT06158542                                                                                                                                      
12.01.2023 
C.VOLUMe INFORMATION 
 
 
Fasting Duration (hours)                                             
 
 
Fluid Intake in the Last 8 Hours Preop (ml) 
 
 
Fluid Bolus preoperatively(ml) 
 
 
Oxytocin Dose Administered in the Last 8 
Hours (IU) 
 
 
 
 
Urine output just before the surgery (ml) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCT06158542                                                                                                                                      
12.01.2023 
D. BLOOD PANEL 
 
 
Hb (g/dL) 
 
 
Hct (g/dL) 
 
 
Eritrosit (x106/ 
/μL 
 
 
MCV ( fL) 
 
 
ESR (mm/sa) 
 
 
RDW (%) 
 
 
WBC ( x103/μL) 
 
 
Plt ( x103/μL) 
 
 
Ferritin (ng/mL) 
 
 
Transferrin 
Saturation(%) 
 
 
Total Iron 
Binding 
Capacity 
(µg/dL) 
 
 
Iron (µg/dL) 
 
 
 
ALT (U/L) 
 
 
AST (U/L) 
 
 
ALP (U/L) 
 
 
GGT (U/L) 
 
 
Bilirubin, direkt 
(mg/dL) 
 
 
Bilirubin, total 
(mg/dL) 
 
 
Albumin (g/dL) 
 
 
Protein (g/dL) 
 
 
Creatinine(mg/dL) 
 
 
Uric Acid (mg/dL) 
 
 
K+ (mEq/L) 
 
 
Na+ (mEq/L) 
 
 
Mg++ (mEq/L) 
 
 
Cl- (mEq/L) 
 
 
Glucose (mg/dL) 
 

NCT06158542                                                                                                                                      
12.01.2023 
 
 
aPTT (sn) 
 
 
INR  
 
 
D-dimer (ng/mL) 
 
 
 
Fibrinogen(mg/dL) 
 
 
 
 
Syndecan-1(SDC-1) 
(ng/mL) 
 
 
 
 
pH 
 
 
Pv02(mmHg) 
 
 
PvC02(mmHg) 
 
 
BE  
 
 
Ca++ (mmol/L) 
 
 
Laktat  (mmol/L) 
 
 
 
 
 
 
 
 
CRP (mg/dL) 
 
 
Procalcitonin (ng/mL) 
 
 
Transferrin(mg/dL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCT06158542                                                                                                                                      
12.01.2023 
 
2.SPINAL ANESTHESIA CHARACTERISTICS 
Observation period is the first 15 minutes after induction. Terminate data collection after the 16th minute. 
 
DRUG 
 
VOLUME 
 
DOSE 
Bupivakain heavy 
 
 
Fentanil 
 
 
Other 
 
 
 
Duration of Spinal Anesthesia Application (seconds): 
 
Puncture Site:                                                             Number of Punctures : 
 
Block Level: 
Type and Gauge of Needle:  
 
Experience of the Practitioner (Junior Resident/Senior Resident/Attending): 
Received Sedation: 
 
Type and Dose of Sedation Medication: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCT06158542                                                                                                                                      
12.01.2023 
 
 
 
3.POST-INDUCTION CHARACTERISTICS 
 
 
The Lowest Systolic Blood Pressure 
 
 
 
The Lowest Diastolic Blood Pressure 
 
 
MAP(Mean Arterial Pressure) 
 
Symptome 
 
At which Minute? 
 
When did the skin incision occur after induction? 
 
When was the baby delivered after induction? 
 
 
Hypotension Decision 
 
Yes 
 
No 
 
Hypotension Treatment: Ephedrine / Other /Dose