SeveriTy of Pulmonary Edema and Timing of Resolution in Patients With Severe Pre-eclampsia and Eclampsia (TIPER): A Physiological and Sonographic Prospective Observational Study
Conditions: Eclampsia, Severe Pre-eclampsia
Sponsor: Doctors with Africa - CUAMM

TIPER Study Protocol 
 
 
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Study Title: SeveriTy of Pulmonary Edema and timing of Resolution in patients with severe pre-eclampsia 
and eclampsia (TIPER) – a prospective observational study 
Short title: Pulmonary edema resolution in severe pre-eclampsia and eclampsia - TIPER 
 
SLERCSRef: 
Date and Version No: Apr 2023, version 3.0 
Coordinating 
investigator/project leader: 
 
Principal Investigator: 
 
Dr Serena Crisci 1 2 
Dr Simone Di Filippo 3 
 
Prof Adetunji Oladeni Adeniji 8 
Co-Principal Investigator: 
Co-Investigators:   
Dr Foday Musa Janneh 8 
Dr Michele Orsi 4 
Dr Luigi Pisani 5 6 7  
Dr Giuseppe Natalini 1 
Dr Nitsuh Tiru 8 
 
Affiliations: 
 
1Department of Anesthesia, Intensive Care and Pain Medicine, 
Fondazione 
Poliambulanza 
Hospital, 
Brescia, 
Italy 
2Department of Anesthesiology and Intensive Care Medicine, Catholic 
University of The Sacred Heart, Rome, Italy. 
3Department of Anesthesia and Intensive Care, University of Insubria, 
Varese, Lombardia, Italy. 
4Mangiagalli Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore 
Policlinico di Milano, Milan, Italy 
5Amsterdam UMC, location University of Amsterdam, Intensive Care, 
Amsterdam, Netherlands 
6Mahidol University, Mahidol–Oxford Tropical Medicine Research Unit, 
Bangkok, Thailand 
7Miulli Regional Hospital, Anesthesia and Intensive Care, Acquaviva delle 
Fonti, Italy 
8Department of Gynaecology and Obstetrics Princess Christian Maternity 
Hospital Freetown, Sierra Leone 
 
Sponsor:  
Correspondence: 
Doctors with Africa Cuamm 
Serena Crisci 
Telephone: +39 3387237228  
E-mail: s.crisci@cuamm.org  
 
Chief Investigator Signature:  The approved protocol should be signed by author(s) and/or person(s) 
authorised to sign the protocol 
 
 
Conflicts of Interests:  
The investigators do not have any conflicts of interest. 

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Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
authorised individuals from the University of Sierra Leone, the Investigator Team and members of 
the  Sierra Leone Ethical Research Committee (SLERCS), unless authorised to do so. 
 
 

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TABLE OF CONTENTS 
 
1. 
SYNOPSIS ............................................................................................................................................... 5 
2. 
ABBREVIATIONS ..................................................................................................................................... 6 
3. 
BACKGROUND AND RATIONALE ............................................................................................................ 8 
3.1 Background .......................................................................................................................................... 8 
4.  OBJECTIVES AND OUTCOME MEASURES .................................................................................................. 9 
5.  STUDY DESIGN ........................................................................................................................................ 10 
5.1.  Study Site ......................................................................................................................................... 11 
6.  PARTICIPANT IDENTIFICATION AND RECRUITMENT .............................................................................. 11 
6.1.  Study Participants ............................................................................................................................ 11 
6.2.  Inclusion Criteria .............................................................................................................................. 11 
6.3.  Exclusion Criteria ............................................................................................................................. 11 
6.4.  Case definitions ............................................................................................................................... 11 
7.  STUDY PROCEDURES ............................................................................................................................... 13 
7.1.  Recruitment ..................................................................................................................................... 13 
7.2.  Informed consent ............................................................................................................................ 13 
7.3.1. Screening demographic and medical history ............................................................................ 13 
7.3.2. Screening physical exam and vital signs .................................................................................... 13 
7.4.  Baseline Assessments ...................................................................................................................... 14 
7.4.1. Demographic and medical history ............................................................................................. 14 
7.4.2. Physical exam and vital signs ..................................................................................................... 14 
7.4.3. Non-invasive investigations ....................................................................................................... 14 
8.  INVESTIGATIONS ..................................................................................................................................... 14 
8.1. Ultrasound Examinations ................................................................................................................. 14 
8.1.1. Lung ultrasound examination .................................................................................................... 14 
8.1.2. Cardiac echocardiographic examination ................................................................................... 14 
10.  STATISTICS AND ANALYSIS .................................................................................................................... 14 
11.  DATA MANAGEMENT ........................................................................................................................... 15 
11.1. Data management .......................................................................................................................... 15 
11.3. Data Handling and Record Keeping ................................................................................................ 15 
12.  QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ............................................................. 15 
13.  ETHICAL AND REGULATORY CONSIDERATIONS .................................................................................... 16 
13.1. Declaration of Helsinki ................................................................................................................... 16 
13.2. Guidelines for Good Clinical Practice ............................................................................................. 16 
13.3. Approvals ........................................................................................................................................ 16 
13.4. Participant Confidentiality .............................................................................................................. 16 

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13.5. Expenses and Benefits .................................................................................................................... 16 
13.6. Reporting ........................................................................................................................................ 16 
13.7. Other Ethical Considerations .......................................................................................................... 17 
13.7.1. Risks ......................................................................................................................................... 17 
14.  FINANCE AND INSURANCE ................................................................................................................... 17 
14.1. Funding ........................................................................................................................................... 17 
15.  PUBLICATION POLICY ............................................................................................................................ 17 

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1. SYNOPSIS 
 
Study Title 
SeveriTy of Pulmonary Edema and timing of Resolution in patients with severe 
pre-eclampsia and eclampsia (TIPER) – a prospective observational study 
Internal ref. no. 
(short title) 
Pulmonary edema resolution in severe pre-eclampsia and eclampsia – TIPER 
Study Design 
A prospective, observational cohort study.  
Study Participants 
Female subjects, hospitalized with severe preeclampsia or eclampsia 
Planned Sample Size 
All eligible patients admitted to PCMH for 1 year 
Study Site 
Princess Christian Maternity Hospital, Freetown, Sierra Leone 
Planned Study Period 
April 2023 to April 2024. 
Inclusion criteria 
All patients with severe pre-eclampsia or eclampsia admitted to hospital PCMH 
during the study period   
Exclusion criteria 
1. Patients with chronic hypertensive disorders  
2. Lung ultrasound not feasible, e.g., due to electricity breakdown, or absence of 
the trained sonographer or presence of subcutaneous emphysema,  
Aim 
The primary aim is to describe the frequency of lung ultrasound consistent with 
pulmonary oedema and the timing of resolution after delivery. 
Secondary aims include the assessment of the frequency of acute respiratory 
failure, other LUS findings beyond pulmonary edema, the assessment of 
oxygenation, the use of respiratory organ support strategies, assessment of 
cardiac function, and quantification of major direct/ indirect obstetric 
complications and of perinatal complications.  
Hypothesis 
1. A high proportion (>20%) of patients show LUS signs consistent with 
pulmonary edema before delivery.  
2. There is incomplete resolution of both clinical and ultrasound signs of 
pulmonary edema 48 hours after delivery.  
 
Objectives 
Outcome Measures 
Primary 
 
Frequency of LUS consistent with 
pulmonary edema 
Frequency 
endpoint: 
proportion 
of 
patients 
with 
a 
LUS 
positive 
for 
pulmonary edema 
Severity: LUS areation score 
 
 
Timing of resolution after delivery 
Categorical: Fraction of patients with 
improvement or resolution of LUS 
findings.  
Numerical: delta LUS score between T1 
and T2 
Secondary 
 
Frequency of acute respiratory 
failure in patients with Severe Pre 
eclampsia and in patients with 
Eclampsia 
Proportion of patients with acute 
respiratory failure 

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Frequency of other LUS findings  
Proportion of patients with  
• 
consolidations 
• 
isolated pleural effusion 
• 
minor LUS findings 
 
Frequency of organ support 
strategies 
 
Fraction of patients that receive oxygen 
and/or 
CPAP 
and/or 
mechanical 
ventilation 
 
Frequency of patients with abnormal 
cardiac function 
Defined as low cardiac index measured 
by ultrasound 
 
Oxygenation assessment 
SpO2 to FiO2 ratio  
 
Frequency of Major Direct Obstetric 
Complications (MDOCs) 
 
Fraction of patients with at least one 
additional MDOC (antepartum 
hemorrhage, postpartum hemorrhage, 
sepsis, uterine rupture, obstructed 
labour) 
 
Frequency of Indirect Obstetric 
complications 
 
Fraction of patients with at least one 
among stroke, severe malaria, acute 
kidney injury and cardiac insufficiency. 
 
Frequency of perinatal complications 
 
Intra uterine fetal death (IUFD), Apgar 
score, Admission to special care baby 
unit (SCBU) 
Procedures 
All procedures are standard of care and routinely performed in critically ill 
patients: 
1. Lung Ultrasound examination 
2. Echocardiography and inferior vena cava ultrasound 
3. Pulse oximetry 
4. Urine output monitoring (when foley catheter inserted by treating team) 
Safety 
The bedside non-invasive procedures pose minimal risk to the patient and do not 
require additional transportation.  
Benefits of study 
The study will evaluate the possibility of early intercepting pre-eclamptic and 
eclamptic patients with pulmonary involvement. This group of patients may 
potentially benefit from the implementation of optimal triage and early 
therapeutic choices in a limited resource setting (e.g. diuretics, escalation to non-
invasive or invasive ventilation, referral to HDU or ICU, dialysis) with a potential 
to reduce unfavourable outcomes. 
 
2. ABBREVIATIONS 
 
ARDS 
Acute respiratory distress syndrome 
PCMH 
Princess Christian Maternity Hospital 
CUAMM 
Doctors with Africa – CUAMM 
HDU 
High Dependency Unit 
FiO2 
Fraction of inspired oxygen 

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LUS 
Lung ultrasound 
SLERC 
Sierra Leonel research ethics committee 
SpO2 
Peripheral oxygen saturation 

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3. BACKGROUND AND RATIONALE 
3.1 Background 
 
Obstetric critical care burden in resource–poor settings  
Maternal mortality from treatable causes concerning the critical care domain in low– income countries 
remains strikingly high (1) . Maternal mortality in Sierra Leone is the highest in the world with 1,360 deaths 
per 100,000 born alive. The burden of obstetric–related critical care morbidity is also extremely high. In 
high–income countries less than 2% of intensive care unit (ICU) admissions relate to obstetric illnesses, but 
these rise to 10% in resource–limited settings. Pre-eclampsia/eclampsia are hypertensive disorders of 
pregnancy, one of the 3 leading causes of maternal morbidity and mortality worldwide(2).  
 
Aims of critical care management  
The aims of critical care management are to stabilize and monitor physiological parameters and support 
failing organ systems, thus allowing time for recovery and implementation of disease–specific therapies. 
Supportive management is classically divided by organ systems and may be guided by invasive or non–
invasive monitoring, globally aimed at adequate oxygen delivery to the tissues. This involves several steps, 
at any of which deficiencies may occur, i.e., oxygen transfer to the blood in the lungs, oxygen transport 
from the lungs to the tissues and finally diffusion from capillary blood to the cells (3). The respiratory 
system is a central in this process; hence early and precise assessment of pulmonary impairment is pivotal. 
 
Pulmonary complications associated with Severe Preeclampsia and Eclampsia 
The reported incidence of eclampsia is 1.6 to 10 per 10,000 deliveries in developed countries, whereas it 
is 50 to 151 per 10,000 deliveries in developing countries (4–6). In addition, low-resource countries have 
substantially higher rates of maternal and perinatal mortalities and morbidities. This disparity in incidence 
and pregnancy outcomes may be related to universal access to prenatal care, early detection of 
preeclampsia, timely delivery, and availability of healthcare resources in developed countries compared 
to developing countries. Because of its infrequency in developed countries, many obstetrical providers and 
maternity units have minimal to no experience in the acute management of eclampsia and its 
complications.  
Respiratory distress and pulmonary oedema are known complications of preeclampsia-eclampsia and their 
insurgence is a hallmark of  severe disease (7,8). Pulmonary oedema is reported as a complication in 2.9% 
of patients with preeclampsia-eclampsia (9). Pulmonary involvement is associated with worse maternal 
and perinatal outcomes (10,11). Incidence is significantly higher in low income countries, rising to 12% due 
to poorer prenatal care and access to hospital care, and suboptimal diagnostic and management processes 
(12). 
A retrospective study showed how the average time to resolution of pulmonary oedema for obstetric 
patients with different primary clinical disorders was 2.4 days (13). The preeclamptic and eclamptic 
patients is characterized by systemic endothelial cell dysfunction, increased systemic vascular resistance 
and increased capillary permeability, all leading to excessive extravasation and as such increasing the risk 
of pulmonary oedema (14,15). This is also why, together with the infectious cause, 
preeclampsia/eclampsia are the leading cause of ARDS in pregnancy (16,17). 
 
Challenges with diagnosis and follow up of pulmonary complications  
In the absence of imaging modalities (chest radiography, computed tomography) and laboratory measures 
(blood gas analysis) it may be difficult to quantify respiratory deterioration, or the pulmonary component 
in a global deterioration. Bedside clinical examination lacks sufficient sensitivity and specificity for 

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pulmonary edema and ARDS. Simple bedside techniques are increasingly available, such as pulse oximetry 
for quantification of oxygenation deficit and lung ultrasound for systemic imaging. 
 
Use of lung ultrasound to detect pulmonary complications  
Point–of–care lung ultrasound (LUS) is a non–invasive, rapid and sensitive method to detect pulmonary 
pathology (18,19). LUS is a bedside practical and easy tool to use, and being a radiation–free investigation 
it can be regularly repeated. LUS may expedite etiological diagnosis in cases of undifferentiated dyspnoea 
(20), both in resource–rich and –poor settings (21,22). Detection of focal consolidation could suggest a 
diagnosis of pneumonia, whereas the visualization of multiple complex patterns could suggest ARDS (23). 
Simultaneous presence of pleural fluid and loss of aeration may point at fluid overload (24). Conversely, a 
normal lung pattern in the presence of respiratory distress would direct the clinician towards alternative 
diagnoses, such as respiratory compensation of a metabolic acidosis, asthma or pulmonary embolism (25). 
 
Additional point-of-care ultrasound applications 
Point-of-care echocardiography also represents a potential valuable adjunct to clinical care in low- and 
middle-income countries, with several ultrasound-based clinical algorithms proposed. Early bedside 
echocardiographic assessment of cardiac function is recommended to guide haemodynamic management 
and when combined with lung ultrasound it provides further clinically relevant information. The basic 
echocardiography examination consists of five standard views and allows the physician to: (i) identify 
imminent life-threatening causes of haemodynamic failure, (ii) recognise coexisting diagnoses that 
complicate management, (iii) follow the evolution of the disease process, and (iv) monitor response to 
treatment. 
 
3.2 Rationale 
Accurate assessment of patients with pulmonary involvement combined with LUS and echocardiography 
could lead to earlier detection of pre eclampsia and eclampsia associated pulmonary oedema, ARDS and 
other pulmonary complications. As there is currently limited evidence regarding the features, severity, 
aetiology and history of pulmonary oedema in this kind of people (26,27), the data from this prospective, 
cohort study might facilitate the early intercepting pre-eclamptic and eclamptic patients with pulmonary 
involvement to implement optimal triage and early therapeutic choices in a limited resource setting 
(diuretics, escalation to non invasive or invasive ventilation, referral to HDU or ICU, dialysis)  could reduce 
unfavourable outcomes. 
 
4.  OBJECTIVES AND OUTCOME MEASURES 
 

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4.1 Hypothesis 
1. A high proportion (>20%) of patients show LUS signs consistent with pulmonary edema before 
delivery.  
2. There is a resolution of both clinical and ultrasound signs after in the 48 hours after delivery.  
 
5.  STUDY DESIGN 
This will be a single centre, prospective, cohort study of patients with severe pre-eclampsia and eclampsia. 
The expected duration of study is 1 year. All patients with suspected severe pre-eclampsia or eclampsia 
will undergo screening upon admission to HDU and the Eclamptic ward. Eligible patients will undergo a 
systematic clinical and LUS examination, straight after admission (before delivery). Clinical examination 
will focus on signs of respiratory, neurologic and cardiac failure. Lung ultrasound will be performed using 
a MyLab™Five ultrasound machine (Esaote Spa, Genova, Italy) and a low frequency (2.5–5 MHz) convex 
probe or a Butterfly ultrasound probe (Butterfly, USA). Lung ultrasound will be performed using the 
Objectives 
 
Outcome Measures 
Primary objective 
 
To describe the frequency of 
LUS abnormalities consistent 
with pulmonary oedema 
Frequency endpoint: proportion of patients with LUS consistent 
with pulmonary edema 
Severity endpoint: LUS aeration score (numerical 0 to 36) 
To describe the timing and 
entity of edema resolution 
after delivery 
Frequency endpoint: Fraction of patients with improvement or 
resolution of LUS findings.  
Quantitative endpoint: delta LUS score between T1 and T2 
Secondary objectives: 
 
To describe the frequency of 
acute respiratory failure in 
patients with Severe Pre-
eclampsia and in patients with 
Eclampsia 
Proportion of patients with acute respiratory failure (see 
definition) 
 
Frequency of other LUS 
findings 
Proportion of patients with:  
• 
consolidations 
• 
isolated pleural effusion 
• 
minor LUS findings 
Calculation of the LUS ARDS score  
Frequency of organ support 
strategies 
Fraction of patients that receive: 
- 
oxygen 
- 
CPAP 
- 
Mechanical ventilation 
Frequency of patients with 
abnormal cardiac function 
Defined as either low cardiac output measured by ultrasound 
Oxygenation assessment 
SpO2 to FiO2 ratio 
Frequency of Major Direct 
Obstetric Complications 
Fraction of patients with at least one additional MDOC (APH, 
PPH, sepsis, uterine rupture, obstructed labour) 
Frequency of Indirect Obstetric 
complications 
Fraction of patients with at least one among stroke, severe 
malaria, acute kidney injury and cardiac insufficiency 
Frequency of perinatal 
complications 
 IUFD, Apgar score, Admission to special care baby unit (SCBU) 

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validated 12-region method, evaluating 2 anterior regions, 2 lateral regions and 2 posterior in each 
hemithorax (18,28,29). As heart failure is a common finding in preeclamptic women, echocardiography 
performed with a cardiac sector probe, will enable real-time assessment of maternal cardiac contractility 
and cardiac output. The same clinical, LUS and echocardiographic assessment will be repeated between 
24 h to 72 h (after delivery). Whenever the pre-delivery timepoint is not feasible due to late arrival, 
emergency scenario or postpartum onset, the after delivery examination only will be performed. 
5.1.  Study Site 
The study will be conducted at a single tertiary care hospital in Freetown, Sierra Leone. The Princess 
Christian Maternity Hospital (PCMH) is a 130-bed referral hospital. Patients will be recruited from the 
Eclamptic ward and the High Dependency Unit. 
5.1.  Sample size calculation 
There is very limited data on the prevalence of pulmonary edema in eclampsia patients. For this explorative 
descriptive study we plan to recruit all eligible patients during a 12 months study period.  
6.  PARTICIPANT IDENTIFICATION AND RECRUITMENT 
6.1.  Study Participants 
Patients hospitalized at PCMH with severe preclampsia and eclampsia will be enrolled if the applicable 
inclusion and exclusion criteria are met.  
6.2.  Inclusion Criteria 
1.  All patients with severe pre-eclampsia or eclampsia admitted to hospital PCMH during the study 
period, defined as by American College of Gynaecology and Obstetrics according to the Government of 
Sierra Leone Ministry of Health and Sanitation. 
6.3.  Exclusion Criteria 
The participant may not enter the study if ANY of the following apply: 
1.  Patients with chronic hypertensive disorders; 
2. LUS not feasible, e.g., due to electricity breakdown, or absence of the trained sonographer or diffuse 
subcutaneous emphysema.  
6.4.  Case definitions 
Acute respiratory failure defined as RR≥30 breaths per minute AND/OR SpO2/fraction of inspired oxygen 
(FiO2) ≤ 315 AND/OR signs of difficult breathing, including the use of accessory muscles or nasal flaring. 
FiO2 will be derived from the amount of oxygen the patient receives in liters.   
 
Clinical pulmonary oedema 
Defined as respiratory distress (respiratory rate >30 breaths/min and/or SpO2 <92% on room air) with 
bilateral fine crepitations on chest auscultation. 
 
Lung ultrasound consistent with pulmonary oedema (categorical) 
The presence of three or more B-lines (any size and any distance apart) in a particular lung region will 
define a positive lung region for interstitial syndrome (30) Pulmonary edema will be defined as the 
presence of ≥2 positive regions per side.  
 
Abnormal lung ultrasound aeration score 

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The LUS aeration score (numerical) will be calculated: each lung field will be scored from 0 to 3 as follows: 
“0,” A-pattern with ≤ 2 B-lines; “1,” more than 2 separated B-lines; “2,” multiple coalescent B-lines; or “3,” 
lung consolidation, defined as anechoic or tissue-like images arising from the pleural line that is limited in 
depth by an irregular border. A global LUS score will be calculated at each time point and ranged from 0 
to 36. 
 
LUS ARDS score 
The three variables included in the final logistic regression model for diagnosis of ARDS are: left LUS 
aeration score (range 0-18), right LUS aeration score (range 0-18), and the number of antero-lateral lung 
regions with an abnormal pleural line (range 0-8). The LUS-ARDS score can range from 0 to 91 and is 
computed with the formula below. (31) 
 
LUS-ARDS score = 2.5 x left LUS aeration score + 1 x right LUS aeration score  
                                   + 3.5 x no. of anterolateral regions with an abnormal pleural line 
 
 
Acute Respiratory Distress Syndrome (ARDS) 
Defined according to the Berlin Definition or Kigali Modification as shown in Table 1.  
 
Table 1. Berlin Criteria for ARDS and Kigali Modification of the Berlin Criteria (19,32) 
Criteria 
Berlin definition of ARDS 
Kigali modification 
Timing 
Within 1 week of a known clinical insult, or new or worsening respiratory 
symptoms 
Oxygenation 
PaO2 /FIO2 ≤300 mmHg 
SpO2 /FIO2 ≤315 mmHg 
PEEP requirement 
Minimum 5 cm H2O PEEP required by 
invasive mechanical ventilation (non-
invasive acceptable for mild ARDS) 
No PEEP requirement, 
consistent with AECC definition 
Chest imaging 
Bilateral opacities not fully explained by 
effusions, lobar/lung collapse, or 
nodules by chest radiograph or CT 
Bilateral opacities not fully 
explained by effusions, 
lobar/lung collapse, or nodules 
by chest radiograph or 
ultrasound 
Origin of oedema 
Respiratory failure not fully explained by cardiac failure or fluid overload 
(need objective assessment, such as echocardiography, to exclude 
hydrostatic oedema if no risk factor present) 
Bilateral opacities on ultrasound will be defined as two or more regions with a B-pattern and/or C-patterns 
per hemithorax bilaterally  (33).  
Abbreviations: ARDS, acute respiratory distress syndrome; PaO2, arterial oxygen tension; FiO2, fraction of 
inspired oxygen; SpO2, oxygen saturation as measured by pulse oximetry; AECC, American-European 
Consensus Conference; CT, computed tomography; PEEP, positive end-expiratory pressure. 
 
Abnormal cardiac function  
Defined as a cardiac index (CI) <2.5 l/min/m2 measured by echocardiography.  
 
Modified Early Warning (MEWS) Score  

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The modified early warning score ranges from 0 to 14 and is calculated as detailed in Table 2 (34) (35). 
Table 2. The Modified Early Warning Score score.  
 
Physiological 
parameters 
Normal values (0 
points) 
Yellow alert (1 point) 
Red Alert (2 points) 
Respirator rate 
10- 20 breaths pwe 
minute 
21- 30 breaths per 
minute 
 
 
 
<10 or >30 breaths per minutes 
Oxygen saturation 
96- 100% 
 
<95% 
Temperature 
36.0- 37.4°C 
35- 36 or 37.5- 38°C 
<35 or >38°C 
Systolic blood 
pressure 
100- 139 mmHg 
150- 180 or 90- 100 
mmHg 
>180 or < 90 mmHg 
Diastolic blood 
pressure 
50- 89mmHg 
90- 100 mmHg 
>100 mmHg 
Heart rate 
50- 99 beats per 
minute 
 
100- 120 or 40- 50 
beats per minute 
>120 or <40 beats per minutes 
Neurological 
response 
Alert 
Voice 
Unresponsive, pain 
7.  STUDY PROCEDURES 
7.1.  Recruitment 
Consecutive admitted patients will be assessed for inclusion and exclusion criteria by a research physician. 
If eligible, the participant will be enrolled in the study. Details of those fulfilling the entry criteria will be 
entered onto a screening form, while reasons for non-eligibility will be added to the eligibility-screening 
log. It is expected that this process will take approximately 30 minutes.  
7.2.  Informed consent   
No ethical concern is attributable to this study due to its observational nature. No direct intervention on 
patient is part of the study design. Personal information (name, age, community, etc.) from registries will 
be anonymized and no patients will be recognizable during the realization or dissemination phases of the 
study. Serial ultrasound examinations are standard of care in obstetric patients, while lung ultrasound is 
routine practice in intermediate and intensive care units, especially in the absence of alternative image 
modalities as chest radiography or computed tomography. For these reasons, a waiver of patient individual 
informed consent is requested to this EC. Sharing of patient data will follow Good Clinical Practice 
guidelines and ethics review committee advice. 
7.3.1. Screening demographic and medical history 
Basic demographic and epidemiological data (i.e. age, sex, medical history of hypertension disease) will be 
obtained to assess eligibility and recorded in the screening log by the study staff.  
7.3.2. Screening physical exam and vital signs 
Vital signs will be conducted by a research physician including Glasgow Coma Scale (GCS), pulse rate, blood 
pressure, respiratory rate, aural temperature (average of left and right ears), and pulmonary auscultation. 
The screening vital signs will be recorded in the screening log by the study staff. 

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7.4.  Baseline Assessments 
Following screening and eligibility confirmation the baseline assessments will be performed as detailed 
below. The duration of time to perform baseline assessment will take approximately 1 hour.  
7.4.1. Demographic and medical history 
A detailed demographic, epidemiologic (i.e. age, sex, address, previous medications) and past-medical 
history will be obtained and recorded in the Case Report Form (CRF) by the research staff. All prescribed 
or over-the-counter drugs, traditional medications and any drug allergies will also be recorded. 
7.4.2. Physical exam and vital signs 
Upon enrolment, a full physical examination will be conducted by a research physician. Vital signs including 
GCS, pulse rate, blood pressure, respiratory rate, SpO2, FiO2, aural temperature (average of left and right 
ears), weight, height and a neurological exam will be recorded in the CRF.  
7.4.3. Non-invasive investigations 
Baseline investigations will include echocardiography and lung ultrasound.  
Briefly, point-of-care ultrasonography will include: (1) lung ultrasound following a 12-region protocol, (2) 
echocardiography. 
8.  INVESTIGATIONS 
8.1. Ultrasound Examinations 
8.1.1. Lung ultrasound examination 
A complete 12-region lung ultrasound examination will be conducted with a standard ultrasound machine 
and a low frequency (2.5–5MhZ) convex probe. The ultrasound machine, the probe and the probe holder 
will be cleaned before and after each use using the dedicated antiseptic detergent indicated by hospital 
guidelines. The patient remains in supine position and the probe will be held perpendicular to the skin. 
Briefly, the 12-rib interspaces will be scanned at the bedside with the ultrasound probe applied 
longitudinally and perpendicularly to the exterior chest wall. The left and right hemi thorax will be assessed 
in six areas: two anterior areas, two lateral areas, and two posterior areas. The anterior chest will be 
delineated as the parasternal to the anterior axillary line and divided into upper and lower halves (zones 
1 and 2). The lateral area will be delineated as the anterior to the posterior axillary line and divided into 
upper and basal halves (zones 3 and 4). The posterior area will be considered as the zone beyond the 
posterior axillary line and divided into upper and lower zones (zones 5 and 6). The lung ultrasound score 
(sum of patterns found on each scanning site) will be recorded (score 0: pattern with less than three B-
lines; score 1: Three or more separated B lines; score 2: multiple and confluent B-lines; score 3: 
consolidation) (36). The global lung ultrasound score will range from 0 to 36. Additional ultrasound findings 
include the assessment of subpleural consolidations, pleural effusions and lung sliding.  
8.1.2. Cardiac echocardiographic examination 
In the supine position, bedside images will be obtained using a with a low frequency (2.5-5 MhZ) sector 
cardiac probe. Focused echocardiographic examination will include two windows of the exterior chest wall: 
the parasternal long axis (PLAX) and the 4-chamber long views (4CLV). The cardiac ultrasound will obtain 
the real-time assessment of maternal cardiac contractility and cardiac output.  
 
10.  STATISTICS AND ANALYSIS 
For descriptive purposes continuous and ordinal variables data will be expressed as median with 
interquartile range. For categorical variables, percentages are calculated. Student’s t-test or analysis of 

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variance (ANOVA) will be used to compare normally distributed numerical variables. Mann Whitney U-
tests and Kruskal-Wallis tests will be used to compare numerical variables when normality cannot be 
assumed, while chi-squared tests will be used to compare categorical variables. Univariate logistic 
regression analyses will be performed to identify potential factors associated with the clinical outcomes 
including, but not limited to, presence of interstitial syndrome, non-resolution of interstitial syndrome at 
48-72h, development of ARDS and death in hospital. Multivariable logistic regression models will be used 
to identify independent risk factors for the same clinical outcomes. A forward and backwards stepwise 
approach will used to include variables into the models, with a limit of P <0.2. 
Inter– observer variability of the lung ultrasound score between the study sonographer and an 
independent expert will be calculated on a random sample of 10 cases (120 lung regions) using Cohen K-
statistics. Statistical analyses will be conducted using R (www.r-project.org). A P-value of <0.05 will be 
considered statistically significant. Analyses will be conducted after the end of patient recruitment and no 
interim analyses are planned. Statistical analysis will be performed with R software (R Foundation for 
Statistical Computing, Vienna, Austria). 
11.  DATA MANAGEMENT 
11.1. Data management 
All patients will be identified with a unique study identification code. A logbook with the matching between 
patient number and name will be stored digitally and in paper. The paper version will be stored behind a 
lock and the digital form will be protected with a password. The logbook will be the only document 
containing patient identifier information. Data will be stored an additional 15 years after the study’s 
completion 
11.2. Access to Data 
Data is collected from the patient medical chart and transcribed onto an Internet– based electronic CRF 
(REDCap – Research Electronic Data Capture (18), www.projectredcap.org). Access to the data–entry 
system is protected by a personalized username and password. The data will be kept on a central secured 
server. Patients are identified with a study identification code, hence there will be no patient identifier 
data transcribed on the online CRF. 
Data derived from this study will be shared with the clinical team directly responsible for patient’s care 
and with hospital leadership and management team for monitoring and/or audit purposes. After 
publication of the primary results, on request the pooled dataset will be available for secondary analysis, 
after judgment and approval of scientific quality and validity of the proposed analysis by the Steering 
Committee. 
11.3. Data Handling and Record Keeping 
The anonymized data will be stored in a secure database to guarantee the privacy of study subjects. Only 
local investigators will have access to the database and matching log–book. A copy of the LUS report will 
be attached to the patient’s clinical chart to be visualized by the clinical team responsible for patient’s 
care. 
12.  QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
The trial will be conducted in accordance with the current approved protocol, GCP, relevant regulations 
and standard operating procedures. 
Regular monitoring will be performed according to GCP. Data will be evaluated for compliance with the 
protocol and accuracy in relation to source documents. Following written SOPs, the monitors will verify 

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that the clinical trial is conducted and data are generated, documented and reported in compliance with 
the protocol, GCP and the applicable regulatory requirements. 
13.  ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (2008). 
13.2. Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with 
Good Clinical Practice. 
13.3. Approvals 
The protocol, ICF, and PIS will be submitted to SLERC, Sierra Leone Ethical Research Committee for written 
approval. The Investigator will submit and, where necessary, obtain approval from the above parties for 
all amendments to the original approved documents. As lung ultrasound is standard of care in critically ill 
patients, especially in a setting lacking other imaging modalities and considered there are no associated 
risks when receiving this examination, a waiver of written informed consent is requeted from the 
committee. This approach was successfully used in the past in the same setting. (18)  
13.4. Participant Confidentiality 
The study staff will ensure that the participants’ anonymity is maintained.  The participants will be 
identified only by a participant ID number on all study documents and any electronic database. All 
documents will be stored securely and only accessible by study staff and authorised personnel. The study 
will comply with the Data Protection Act, which requires data to be anonymised as soon as it is practical 
to do so. 
13.5. Expenses and Benefits 
Expenses 
In-hospital costs of medications and medical supplies will be covered. No other gifts or payments will be 
made upon participation in this study.    
 
Benefits 
Pulmonary oedema is a life-threatening complication of severe preeclampsia and eclampsia, occurring in 
approximately in 2.9% of patients with preeclampsia-eclampsia and it is associated with worse  maternal 
and perinatal outcomes. Accurate assessment of patients with pulmonary involvement combined with LUS 
and echocardiography could lead to earlier detection of pre eclampsia and eclampsia associated 
pulmonary oedema, ARDS and other pulmonary complications. As there is currently limited evidence 
regarding the features, severity, etiology and history of pulmonary oedema in this group of patients, the 
possibility of early intercepting pre-eclamptic and eclamptic patients with pulmonary involvement to 
implement optimal triage and early therapeutic choices in a limited resource setting (diuretics, escalation 
to non-invasive or invasive ventilation, referral to HDU or ICU, dialysis) could reduce unfavourable 
outcomes. 
13.6. Reporting 

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The PI shall submit an Annual Progress Report to SLERC and local ethics committee on the anniversary of 
the date of approval of the study. In addition, the PI shall submit an End of Study Report to SLERC and to 
local ethics committee upon the completion of the study. 
13.7. Other Ethical Considerations 
13.7.1. Risks 
Because all proceedings in the method of this study are based on common clinical practice and ultrasound 
is a non–invasive procedure that cannot injure patients, the risk of this study is considered very low. LUS 
and echocardiographic are standardly performed in intensive and intermediate care units to assess lung 
aeration and presence of pleural effusion and consolidations or cardiac contractility and cardiac output. 
The ultrasound examinations  performed for this study are not charged to the patient or to the hospital 
administration. As this study aims at assessing the frequency of complications in critically ill obstetric 
patients, we cannot choose for another patient population. Patients included in this study may benefit in 
terms of increased serial monitoring events in a setting where no other onsite lung and cardiac imaging 
techniques is available 
14.  FINANCE AND INSURANCE 
14.1. Funding 
The study will be supported by Doctors with Africa – CUAMM using funding by a Wellcome Innovations 
Flagship award (Collaboration for Research, Improvement and Training in Critical CARE in ASIA grant -- 
ref. 215522/Z/19/Z). Waiver for costs for publication based on low–income country status will be sought 
from the relevant international journals.  
15.  PUBLICATION POLICY 
The results of this study will be published in a peer–reviewed medical journal. We have no restrictions in 
publication of outcomes of this study 
 
 

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