Changes in Pulse-Oximetry Perfusion Index Induced by Tidal Volume Challenge Versus Fluid Volume Challenge to Detect Preload Responsiveness in Mechanically Ventilated Patients With Low Tidal Volume: A Prospective Observational Study
Conditions: To Assess the Ability of PI to Detect Preload Responsiveness
Sponsor: Benha University

 
Initial Approval Date: 02/08/2024 
 
 
 
 
Changes in pulse-oximetry perfusion index 
induced by tidal volume challenge versus fluid 
volume challenge to detect preload responsiveness 
in mechanically ventilated patients with low tidal 
volume: A prospective observational study 
 
Protocol of Thesis Submitted for Fulfillment of 
 
PhD degree in Critical Care Medicine By 
Salwa Abbas Awad Eltahawy 
MB.B.Ch, MSc, Critical Care Medicine 
 
Under supervision of: 
 
Prof. Ahmed Mostafa Abd El-Hamid 
 
Professor and Head of Critical Care Medicine Department 
Faculty of Medicine, Benha University 
 
 
Dr. Samar Rafik Mohamed Amin 
 
Assistant Professor of Anesthesia and Intensive Care 
Faculty of Medicine, Benha University 
 
Dr. Mona Sobhy Emara 
 
Lecturer of Anesthesia and Intensive Care 
Faculty of Medicine, Benha University 
 
 
Faculty of Medicine, Benha University 
2024 

 
 
Introduction: 
 
Fluid resuscitation is a critical component in the management of severely ill 
patients, aimed at optimizing cardiac output and improving tissue perfusion. 
However, determining the correct fluid volume can be complex, as both 
insufficient and excessive resuscitation can lead to serious complications. Fluid 
responsiveness, which refers to the ability of cardiac output to rise following a fluid 
bolus, is a key component in directing fluid therapy for both spontaneously 
breathing and mechanically ventilated patients. This approach helps tailor 
treatment to individual patient needs, enhancing outcomes and minimizing risks 
associated with fluid administration. [1] 
Positive pressure ventilation, which is a common practice in critical care settings, 
can reduce cardiac preload by increasing the pressure in the pleural cavity during 
the inspiratory phase of mechanical ventilation. This increase in pleural pressure 
leads to reductions in both cardiac preload and stroke volume. The variations in 
stroke volume that occur between the inspiratory and expiratory phases of positive 
pressure ventilation are known as stroke volume variation (SVV). In human critical 
care medicine, SVV is regarded as a reliable indicator of fluid responsiveness. [2] 
However, patients with atrial fibrillation exhibit variations in pulse pressure, 
deeming it inappropriate to reliably assess their fluid responsiveness by  SVV [3]. 
Moreover, when changes in pleural pressure are minimal during a single 
respiratory cycle, alterations in cardiac preload will also be minor to cause change 
in stroke volume. Small fluctuations in pleural pressure can occur in patients who 
breathe spontaneously, those receiving mechanical ventilation with low tidal 
volumes (such as 6 ml/kg), or in patients with increased chest compliance, like 

 
those with an open chest [4]. Therefore, it is important to be cautious before 
assuming that a patient is not fluid responsive simply because SVV is low, as this 
could lead to a false-negative result.  
Among such conditions, tidal volume (Vt) must be ≥ 8 mL/kg of predicted body 
weight (PBW), as lower Vt values create false negatives. To overcome this 
limitation, the Vt challenge has been described in mechanically ventilated patients. 
It consists in transiently increasing Vt from 6 to 8 mL/kg PBW, and looking for a 
significant increase in PPV, reflecting that the slope of the cardiac function curve is 
steep [5]. However, the Vt challenge has two limitations. First, although it has been 
validated by several studies, the diagnostic threshold they reported is variable. 
Second, it requires an arterial pressure curve, which is usually plotted by using an 
arterial catheter [6] 
The plethysmographic perfusion index (PI) is a valuable parameter in medical 
practice with various emerging applications. PI represents the ratio between 
pulsatile and non-pulsatile components of peripheral circulation, primarily 
influenced by cardiac output and the balance between sympathetic and 
parasympathetic nervous systems. When sympathetic predominance and/or low 
cardiac output occur, PI decreases, making it a useful, non-invasive tool for 
hemodynamic 
monitoring 
as 
well 
as 
predicting 
patient 
outcomes 
in 
anaesthesiology, perioperative and critical care. [7] 
Several studies investigated the use of PI as an alternative to traditional dynamic 
measures in assessing fluid responsiveness. Some demonstrated that PI was a 
reliable surrogate of cardiac index, pulse pressure variation and SVV [8],  while 
others were inconclusive [9]. Whether the use of PI in resuscitation algorithms 
would improve patient outcomes is yet to be explored. 

 
 
Aim of the study: 
The primary goal of this study was to assess the ability of PI changes induced by a 
Vt challenge or fluid challenge test to detect preload responsiveness in critically ill 
adult patients on mechanical ventilation with low-tidal volume.  
The secondary aims were (i) to compare the changes in PI with VTI during a Vt 
challenge test (ii) to compare the changes in VTI and PI during a volume expansion 
challenge test, (iii) to compare the Vt-induced changes in PI to changes induced by 
fluid challenge test, (iv) to compare the Vt-induced changes in VTI to changes 
induced by fluid challenge test. 
 
 
 
 
 
 
 
 
 
 

 
 
Patients and methods 
I-Technical design: 
1. Study design: A prospective observational study 
2. Study setting: The study will be carried out in the department of critical care 
medicine, Benha university hospitals. 
3. Study time: The study time is set to a period of six months from September 
2024 to February 2025. 
4. Study population:  
The study will be conducted on 75 mechanically ventilated patients with 
circulatory failure. 
5. Inclusion criteria: 
• Patients of both genders aged 18 years or older 
• Invasive  mechanical ventilation in assist controlled mode with a Vt of 6 
mL/kg PBW, 
• Patients with circulatory failure  
• Decision by the clinicians in charge to assess preload responsiveness through 
a Vt Challenge and a Fluid Challenge test. 
• Patients in sinus rhythm 
6. Exclusion criteria: 
• 
Open chest 
• 
Pulmonary hypertension 
• 
Poor lung compliance (Crs <30 ml/cmH2O) 
• 
Obesity (BMI≥35) 
• 
Pregnancy 

 
• 
Intraabdominal hypertension 
• 
Prone position 
• 
Atrial fibrillation 
II -Operational design: 
Methods: 
Primarily, a tidal volume challenge (VtC) will be performed. The tidal volume will 
be initially set at 6 ml/kg PBW. Once stability of hemodynamic parameters is 
established, the tidal volume will be increased transiently from 6 ml/kg PBW to 
8 ml/kg PBW for 1 min. Thereafter, the tidal volume will be reduced back to 
6 ml/kg PBW. 
Once hemodynamic parameters have reached their baseline values, a fluid 
challenge (FC) will be performed by administering 4ml/kg crystalloid solution over 
10 minutes. 
Left ventricular outflow tract (LVOT) velocity time index (VTI) as well as the 
plethysmographic perfusion index (PI) will be determined in all patients at the 
baseline, after VtC and after a FC via transthoracic echocardiography (GE 3Sc-RS 
phased array transducer connected to GE LOGIQ F8 Expert R2 ultrasound 
machine) and a pulse oximeter (ChoiceMMed MD300CN310, Beijing Choice 
Electronic technology Co., Ltd.) respectively. 
The patient will be considered a fluid responder if the VTI increased by 10% after 
completion of the fluid bolus. 
The change in VTI (∆VTI) will be calculated as follows: 
1. ∆VTI (%)= (post-VtC VTI – pre-VtC VTI)/pre-VtC VTI. 

 
2. ∆VTI (%)= (post-FC VTI − pre-FC VTI)/pre-FC VTI. 
 
Study measurements: 
Primary outcome:  
The ability of changes in PI (∆PI) to detect fluid responsiveness. 
∆PI = {(PI after VtC or FC – PI at baseline)/PI at baseline} x 100 
Secondary outcomes:  
⚫ Hemodynamic variables: heart rate, mean arterial pressure, central venous 
pressure, and VTI (measured at the baseline, after VtC and 300 mL fluid 
boluses). 
⚫ Perfusion indices: Serum lactate, central venous oxygen saturation (ScVO2), 
and central venous-arterial CO2 gap (CO2 gap), (measured at the baseline, after 
TVC and 300 mL fluid boluses). 
⚫ The use of vasopressors and inotropic agents. 
⚫ Baseline laboratory investigations: hemoglobin level, urea, creatinine, and 
electrolytes. 
⚫ Patient characteristics, including age, sex, source of infection, and the severity 
of the disease [using Acute physiology and chronic health evaluation 
(APACHE II)]. 
 

 
 
 
 
III- Administrative and Ethical design: 
An approval from Research Ethics Committee of Benha faculty of medicine will be 
obtained. 
An informed written consent will be obtained from all patients or first-degree 
relatives before participation. It will include data about aim of the work, study 
design, site, time, subject and methods, confidentiality. 
IV- Data management and statistical analysis: 
The clinical data will be collected, verified, edited, and then analyzed using SPSS 
(statistical program for social science) as follows: 
• Quantitative data will be presented as mean and standard deviation  
• Qualitative data will be presented as numbers and percentages. 
• Comparisons between patients with positive and negative fluid responders 
will  performed by two-tailed Student t or Wilcoxon tests. We will compare 
the percent relative changes of SVV to those of PI by linear regression 
analysis. Correlations will be assessed by the Spearman coefficient. 
• Receiver operating characteristic (ROC) curves will be constructed to predict 
fluid responsiveness. Sensitivities, specificity, positive predictive values 
(PPV), negative predictive values (NPV)  and accuracy by area under the 
curve (AUC). 

 
• P Value < 0.05 will be considered statistically significant.  
• P Value < 0.01 will be considered statistically highly significant. 
 
 
 
Sample Size: 
The sample size was calculated using the MedCalc Software version 18 (MedCalc 
Software bvba, Ostend, Belgium) based on  the assumption that ∆PPI could 
determine fluid responsiveness at an AUC of 0.70, corresponding to a good 
discriminative ability for the diagnostic test, whilst the null hypothesis was 
assumed to be AUC =0.5, and the risk of alpha error at 5% and beta error at 20% 
were accounted for. According to Yang, the ratio of non-responders cases to 
responder cases was supposed to be about 0.7 [10].  The minimum number of 
calculated patients was 63 patients with at least 37 responders and 26 non-
responders. The estimated sample size was corrected to 75 participants in 
consideration of at least a 15% drop-out rate. 
 
 
 

 
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