Organ Dysfunction Score for Obstetric Patients

INTRODUCTION The Sequential Organ Failure Assessment (SOFA) score was initially developed in a consensus meeting organized by the European Society of Intensive Care in 1996. The aim of the score was to quantify and objectively describe the degree of organ dysfunction or failure in critically ill patients (1). The SOFA score describes a continuum process from normality to dysfunction and failure for six organ systems (respiratory, hematologic, hepatic, cardiovascular, neurologic and renal) (1). Although primary objective of SOFA score was descriptive, numerous studies have proven its prognostic value as well. There is a strong association between SOFA, number of dysfunctions upon admission and SOFA trends in the first 48h and ICU mortality (2, 3).

The SOFA score is a key component of the last definition of sepsis. In 2016, the European Society of Critical Care and the American Society of Critical Care developed and validated a new definition of sepsis. Sepsis was then considered as a life-threatening organ dysfunction caused by a dysregulated host response to infection (3). SOFA score was chosen to identify organ dysfunction due to its simplicity and widespread use. Organ dysfunction was defined as a change in total SOFA score of ≥ 2 points (3). This definition was validated by many studies of different countries, including Argentina (4, 5).

The SOFA score was developed and validated in a population of adult critically ill patients. Thus, its calibration for other populations with particular physiological changes, such as children or obstetric patients, could be inadequate. While some scores, like the PELOD (6, 7) or modified SOFA (8) were developed and validated for pediatric patients, there is no one suitable for obstetric patients yet. General SOFA score was associated with mortality among obstetric patients (9-12) but its predictive validity could be improved if adjustments to pregnancy were performed. Although two groups proposed modified SOFA scores adjusted to obstetric patients, these scores presented clear deficiencies and were not validated (13, 14). The development of an adjusted and calibrated organ dysfunction score for obstetric patients, would improve the validity of the score to predict ICU mortality, and would provide a reliable tool to be incorporated into the definition of maternal sepsis (15, 16). Obstetric sepsis account for 11% of global maternal mortality and for 19%, when abortion-related deaths are added, as most of them are due to sepsis (17). Developing a validated instrument to define sepsis in this population, would improve its recognition and would eventually promote its early treatment, which is associated with better outcomes (18).

Barriers for using the non-adjusted SOFA score to diagnose sepsis in obstetric patients are mainly related to renal and cardiovascular systems. SOFA score sets a creatinine of ≥1.2 mg/dl as the lower cut-off point to identify kidney dysfunction (1). However, pregnant patients and those in early puerperium, present an increased in cardiac output, in renal plasma flow and in glomerular filtration rate, which in turn decrease normal creatinine levels to \<0.9 mg/dl in any trimester of pregnancy (19, 20) and in the first 2 weeks postpartum (20-22). Thus, a non-adjusted SOFA score underestimates renal dysfunction in obstetric patients. In terms of cardiovascular dysfunction, mean arterial pressure (MAP) normally decreases during the second trimester of pregnancy, up to approximately 65 mmHg. However, for the general SOFA score any value of MAP ≤70 mmHg is considered abnormal, which will overestimate hemodynamic dysfunction during that trimester (1). In addition to the abovementioned required adjustments, respiratory evaluation of SOFA is usually lacking among obstetric patients. This evaluation is performed through the paO2/FiO2 ratio, which requires an arterial blood gas (ABG) extraction (23, 24). ABG measurement could be unavailable in some low-resource settings, but also could be missing due to a deliberate physician decision of avoiding arterial gas extraction in these patients (24). Using the relationship between the peripheral oxygen saturation over the inspired fraction of oxygen (spO2/FiO2) could address this deficiency. The spO2/FiO2 ratio is a validated, widely available and non-invasive surrogate of paO2/FiO2 ratio to evaluate respiratory performance (25, 26). The use of a paO2/FiO2 ratio surrogate, such as the spO2/FiO2, improves SOFA score specificity compared to the decision of considering the missing value as normal (24) and it is a key factor when SOFA score is used to define sepsis (15).

The main objective of this study is to develop and validate an organ dysfunction score adjusted to obstetric patients (SOFA-OBS) to predict ICU mortality among pregnant and early postpartum patients requiring ICU admission.

I. Background and significance There were two previous attempts to adapt the SOFA score to the obstetric population. In 2016, Blanco Esquivel et al. (13), developed a SOFA score adjusted to obstetric patients; however, the variable chosen to be modified was questionable. The authors proposed lowering normal cut-off point for paO2/FiO2 and SaO2/FiO2, assuming pregnant patients have lower paO2 levels due to a decreased total lung capacity (TLC). However, pregnant patients neither present a reduction in TLC nor a decrease in oxygenation; thus, SOFA score cut-off values for respiratory evaluation should not be modified (27). Moreover, pregnancy renal and hemodynamic changes were not considered. In 2017, the Society of Obstetric Medicine of Australia and New Zealand proposed an obstetric SOFA. This score removed scores of 3 and 4 in each category for simplification and reduced creatinine cut-off point to 1 mg/dl (14). However, this creatinine value is still higher than the expected for obstetric patients. In addition, no adjustments were done for MAP during the second trimester and no validation of the modified obstetric SOFA was performed.

The SOFA-OBS score proposed in this study would be the first adjusting creatinine and MAP to the obstetric population in a prospective and multicenter study, using the best evidence available (28, 29). In addition, it would be the first study evaluating SpO2/FiO2 calibration among these patients, which might improve the specificity and predictive validity of the score. The development and validation of an obstetric SOFA score to be used in the diagnose of maternal sepsis, would contribute to its early recognition and prompt treatment, which instead would hopefully reduce maternal mortality associated with sepsis.

II. Objectives

Primary objective:

\- To develop an obstetric SOFA score (SOFA-OBS) adjusted to physiological changes of pregnancy and to validate the SOFA-OBS during the first 24h in ICU (SOFA-OBS24h) to predict ICU mortality among obstetric patients.

Secondary Objectives:

* To validate the SOFA-OBS to predict maternal sepsis among obstetric patients requiring ICU admission * To validate SOFA-OBS to predict sepsis associated mortality among obstetric patients requiring ICU admission * To evaluate the mean SOFA-OBS (SOFA-OBS mean) to predict mortality among obstetric patients requiring ICU admission * To evaluate the maximum SOFA-OBS (SOFA-OBS max) to predict mortality among obstetric patients requiring ICU admission * To evaluate the impact of SOFA-OBS trend during the first 48 h in ICU (SOFAΔ48) (increase, decrease, no changes) on ICU mortality * To evaluate the relationship between the presence of each organ dysfunction/failure during the first 24h in ICU and ICU mortality * To evaluate the relationship between the number of organ dysfunctions/failures during the first 24h in ICU and ICU mortality * To evaluate the validity of the conventional septic shock definition (15) to predict mortality among obstetric patients admitted to ICU using the SOFA-OBS to define dysfunction * To evaluate the validity of the second trimester septic shock definition (2T-SS) to predict ICU mortality among obstetric patients using the SOFA-OBS to define dysfunction

Null Hypothesis:

* SOFA-OBS does not have higher predictive validity for ICU mortality among obstetric patients requiring ICU admission than non-adjusted SOFA

Alternative Hypothesis:

\- SOFA-OBS has higher predictive validity for ICU mortality among obstetric patients requiring ICU admission than non-adjusted SOFA

III. Material y Methods This study will consist in a development phase and a validation phase of an obstetric SOFA (SOFA-OBS). The investigators will follow TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis) guidelines and TRIPOD check-list (30). Following, investigators describes elements not covered elsewhere.

Sample size calculation:

The sample size was estimated considering the main objective, which includes validity assessment of an organ dysfunction score modified to obstetric patients (SOFA-OBS), through the AUROC. The investigators considered information published by Oliveira Neto et al. (31), which reports an obstetric mortality of 2.6% in a 673 patients cohort. In order to detect an AUROC of 0.9, an alpha error of 5% and a power of 80%, 130 patients are required (4 presenting the outcome and 126 not presenting it). Statistical package pROC of the statistical software R was used to calculate sample size.

Theoretical and operational variables definitions:

Outcome variables:

1. Obstetric patients ICU mortality: defined elsewhere. This outcome cannot be blinded to in site researchers; however, it is a definite outcome, not requiring any interpretation. Moreover, the final data analysis will be performed by a separate team from the one collecting them. 2. Sepsis-related obstetric ICU mortality: defined elsewhere Although ICU mortality is an objective outcome, as previously mentioned, the attribution of sepsis as cause of death requires some interpretation. This outcome variable cannot be blinded, but the investigators will use an accepted and concise definition supported by objective variables, such as a change in SOFA score of at least 2 points and a suspected infection triggering cultures or antibiotics administration. The final data analysis will be performed also by a separate team from the one collecting data.

Predictor variables:

1. Sequential Organ Failure Assessment (SOFA) and modified SOFA scores (obstetric SOFA: SOFA-OBS):

The investigators decided to adapt the Sequential Organ Failure Assessment (SOFA) score to the obstetric population. The SOFA score is used worldwide and is simple. It also has high predictive validity for mortality among critically ill patients in general and critically ill obstetric patients, in particular. However, it was not calibrated for obstetric patients.

The SOFA score is a key component of last sepsis definition (15). Although sepsis is an important cause of maternal mortality, a SOFA score adjusted to obstetric patients, which could be incorporated in sepsis definition, is still unavailable.

SOFA score will be measured according to its original version. Six organ systems (respiratory, hematologic, hepatic, cardiovascular, neurologic and renal) are evaluated (1). The worst value for each organ on a day is recorded and a score of 0 to 4 is assigned to each value according to predefined ranges (1, 2). Normal values are assigned 0 points and abnormal values are assigned 1 to 4 points (from least to most abnormal); where 1 and 2 represents organ dysfunction and 3 and 4 represents organ failure (2). Total SOFA score is the results from the sum of the score of each organ (1, 2).

The obstetric SOFA (SOFA-OBS) adjusts renal and cardiovascular variables to physiological changes of pregnancy. Moreover, it simplifies respiratory evaluation, in terms of replacing arterial blood gases (ABG) for peripheral oxygen saturation/fraction of inspired oxygen (spO2/FiO2), when ABGs were not av