Vasoactive Inotropic Score compared to the sequential organ failure assessment cardiovascular score in intensive care

The cardiovascular component of the sequential organ failure assessment (cvSOFA) score may be outdated because of changes in intensive care. Vasoactive Inotropic Score (VIS) represents the weighted sum of vasoactive and inotropic drugs. We investigated the association of VIS with mortality in the general intensive care unit (ICU) population and studied whether replacing cvSOFA with a VIS‐based score improves the accuracy of the SOFA score as a predictor of mortality.


| INTRODUCTION
The sequential organ failure assessment (SOFA) score 1 is commonly used to quantify the severity of organ dysfunctions in intensive care (Table S1).3][4][5] Thus, scoring of cardiovascular dysfunction should be updated.
[8] Vasopressors, such as norepinephrine, epinephrine, and vasopressin, along with inotropes, including dobutamine, dopamine, milrinone, and levosimendan, provide the foundation of vasopressor/inotropic support aiming to maintain sufficient perfusion of vital organs.Norepinephrine is currently the most used vasopressor, although there is no definitive evidence of superiority of any one agent over others. 9,10e amount of vasopressor/inotropic support needed may be used as an indirect measure of cardiovascular failure.2][13] Using conversion factors to make doses of different drugs comparable, VIS reflects the sum of doses of most common intravenous drugs used for acute cardiovascular failure.
[16][17][18] Moreover, the value of VIS as an outcome predictor has been confirmed in adult cardiac surgery patients. 19,20However, the usefulness of VIS in general adult intensive care unit (ICU) patients is unknown.
In this study, we evaluated the association of VIS with mortality in a general adult ICU population and examined whether replacing the cvSOFA score with a VIS-based score improves the predictive accuracy of the total SOFA score.

| Study population and eligibility criteria
We performed a single-centre retrospective study on patients admitted to the ICU at Kuopio University Hospital in Kuopio, Finland.We extracted data on all patients admitted between January 1st 2013 and December 31st, 2019.The research ethics committee of the Northern Savo hospital district reviewed and approved the study protocol, and permission to use the data for research was granted by the hospital administration (reference number: 478/2021).The need for consent of the patients was waived due to the retrospective nature of the study.
We extracted data on the doses of inotropes and vasopressors administered during the first 24 h after ICU admission from the electronic health record system.Data on clinical characteristics, the SOFA score recorded during the first 24 h after ICU admission, and length of stay (LOS) in the ICU and hospital had been prospectively validated and documented in the Finnish ICU quality register, Finnish Intensive Care Consortium. 21 excluded all elective (non-emergency) postoperative admissions and all cardiac surgery patients.Regarding the 24-h SOFA score, we excluded all patients with missing data on any SOFA score component (respiratory, cardiovascular, renal, coagulation, and neurological) from the first 24 h after ICU admission except for hepatic function, which we assumed to be normal in case of missing data.The reasoning for this assumption of normality was that determination of hepatic score is based on the serum concentration of bilirubin, which is not routinely measured at KUH for all patients with no clinical suspicion of hepatic problems.For patients with recurrent ICU admissions during the same hospitalisation, only the first ICU admission was included.Patients admitted for the sole purpose of possible organ donation after brain death were excluded.

| VIS-based variables
We defined two separate VIS-based variables: the maximum (VIS max ) and mean (VIS mean ) values.We used data from the first 24 h after the ICU admission to calculate these values.To make doses of different vasopressor/inotropic medications comparable, we multiplied the doses of medications with inotropic/vasopressor-specific coefficients as previously suggested 12,13 also including levosimendan as suggested by Favia et al. 13 to capture most vasopressors and inotropes commonly used in clinical practice.We calculated VIS as the coefficientadjusted sum of intravenously administered vasopressor/inotropic medications.Unlike Gaies et al., who reported the vasopressor/ inotropic medications in dopamine equivalents, 12 we used norepinephrine equivalents in reporting (Table 1).We defined VIS max as the sum of the highest coefficient-adjusted infusion rates per kilogram per minute of each vasopressor/inotrope.To calculate VIS mean , we first calculated the total amount of each medication administered during the first 24 h after ICU admission.We then divided this

| Categorising VIS
We determined VIS max and VIS mean as presented in Table 2.The cutoff values for VIS max and VIS mean were determined by visually inspecting a scatterplot of the relationship between mortality and VIS together with the resulting frequencies in the VIS categories.We aimed at cutoff values that (1) are easy to remember and thus practical in clinical practice, (2) result in a rather linear VIS-mortality relationship and (3) result in categories with a comparable distribution of patients compared to other SOFA component scores (i.e., decreasing proportions of patients in more severe organ failure categories). 5Moreover, we searched for 'natural' cutoffs with cubic spline analysis (Figures S3 and S4).

| Statistical analysis
For statistical analyses, we used R, Version 4.

| Outcomes
Our primary outcome was a change in AUROC depending on whether we used cvSOFA-or VIS-based scores as the cardiovascular component in SOFA score predicting 30-day mortality.The secondary outcomes were differences in AUROC of these scores predicting ICU and in-hospital mortality.

| Study population
The number of ICU patients meeting the inclusion criteria was 8079 (Figure 1).The median age was 61 (interquartile range [IQR] 49-70) years, and the majority of the patients (62%) were male.ICU mortality was 7.0%, in-hospital mortality 11.4% and 30-day mortality 13.7%, respectively.The most frequent causes of admission were neurologic non-operative causes (19.4%), including intracranial haemorrhage, subarachnoid haemorrhage, central nervous system infection and seizures, followed by non-operative cardiovascular causes and nonoperative respiratory causes (Table 3).The data on ICU, in-hospital and 30-day mortality were complete.
The age and sex-adjusted odds ratios for 30-day mortality, ICU mortality and in-hospital mortality for increasing cardiovascular (cv) SOFA and VIS categories.Category 0 of each score was used as reference.The solid line (balls) represents the odds ratios for increasing cvSOFA categories, dotted line (triangles) for increasing VIS max categories and dashed line (squares) for increasing VIS mean categories.The error bars represent 95% confidence intervals.The odds of death were consistently higher for higher VIS categories but not for higher cvSOFA categories.The odds ratio for ICU mortality in cvSOFA category 2 was not calculable because this category contained only eight patients who all survived to ICU discharge.ICU, intensive care unit; SOFA, sequential organ failure assessment; VIS max , maximum Vasoactive Inotropic Score; VIS mean , mean Vasoactive Inotropic Score.Our study confirms that a VIS-based cardiovascular score is a better alternative to the conventional cardiovascular component of the SOFA score.According to our results, either VIS max or VIS mean could be used for this purpose.Since VIS max requires less calculation, it would be a simpler choice.An additional advantage of the VIS-based SOFA score would be the adjustability in the case of introduction of new vasopressor/inotropic agents to clinical practice in the future: in that case the whole scoring does not need to be changed, but only a conversion factor for the new agent needs to be determined. 25an arterial pressure (MAP) below or above 70 mmHg is the current distinctive criterion between 0 and 1 cvSOFA points.[28] Hence, it would make sense to score 0 cardiovascular SOFA points to patients who do not receive any vasopressor/inotropic agents and to use the scale of 1-4 points to categorise the magnitude of vasopressor/inotropic medication needed.In our study, one third of patients received any vasopressor/inotropic support which is in line with previous studies done in ICU patients without preceding cardiac surgery. 29,30eviously Yadav et al. 32 proposed a modified cvSOFA based on Shock Index, lactate measures and infusion rates of dopamine, epinephrine and norepinephrine.In their observational cohort study, they found a statistically significant difference in discrimination between conventional SOFA score and modified SOFA score with substituted cvSOFA as predictors of 28-day mortality (AUROC 0.822 vs. 0.836; difference = 0.014).However, the scoring should be ideally based on a simple measurement instead of a mix of laboratory results, physiologic findings, and drug infusion dosages.In a retrospective study by Bosch et al., 33 the ratio of norepinephrine equivalent doses (NEQ) and MAP was associated with in-hospital mortality.The patients were given 0-2 points according to the NEQ/MAP ratio.The NEQ/MAP was more accurate than the conventional cvSOFA score and the modified cvSOFA score by Yadav et al. 32 in predicting in-hospital mortality.In this study, the scoring had, however, three categories and it was not implementable in the full SOFA score.
Previous studies on VIS have focused on paediatric or neonatal patients or on cardiac surgical patients.

| Strengths and limitations
Our study population was a heterogenic group of critically ill adult patients treated in a mixed medical-surgical ICU.This increases the generalisability of the results.The data on administered infusions and 30-day mortality were complete.
The main limitation is that the study was a single-centre study.
Differences in local practices in administering vasopressor/inotropic agents in different countries and healthcare systems may affect the VIS values.Some of the medications included in VIS in this study have not been included in all previous VIS studies.Levosimendan has been part of VIS only in studies on adult patients and the coefficient used for its dose is disputable. 13,19However, the controversies of conversion factors concern not only levosimendan but also other vasopressor/inotropic agents to some degree. 34r VIS max , we were unable to track the highest concomitant infusion rates of the vasopressors and inotropes.Instead, we used the highest infusion rates of each drug during the first 24 h at the ICU.The use of concomitant rates might be a more accurate measure for cardiovascular dysfunction but less useful in clinical practice: it would require calculations from multiple time points to determine where the highest VIS score is reached.Moreover, our study did not take into account possible mechanical cardiovascular support (e.g.veno-arterial extracorporeal membrane oxygenation or intraaortic balloon pump).However, during the study period (2013-2019), these interventions were seldom used in our hospital in other patient groups than post-cardiac surgical patients.The increasing use of mechanical cardiovascular support devices must be taken into consideration if an update of the cardiovascular SOFA score is planned in the future. 24e major limitation is that the observation is limited to the first 24 h after ICU admission.Future studies should focus on the dynamic nature of SOFA score and observe how daily increase/decrease in VIS-based cvSOFA is associated with outcomes.
To the best of our knowledge, this study is the first one to evaluate the association of increasing VIS with mortality in a general ICU population.It is obvious that more studies validating the usefulness of VIS are needed before it can be considered for use in clinical practice.

| CONCLUSION
In contemporary intensive care, the cardiovascular component of the SOFA score is no longer an optimal metric of cardiovascular failure.
coefficient-adjusted sum of infusions by 1440 to get the mean dose in μg/kg/min.For vasopressin, we used U/kg/min as the unit of infusion rate.The VIS mean value for patients with LOSs less than 24 h was calculated for the true length of ICU stay.F I G U R E 2 A scatterplot presenting the relationship between VIS and mortality.The turquoise line represents the mean (VIS mean ) and red line represents the maximum (VIS max ) VIS value recorded during the first 24 h at the ICU.The turquoise and red areas represent the standard error.ICU, intensive care unit; VIS max , maximum Vasoactive Inotropic Score; VIS mean , mean Vasoactive Inotropic Score.F I G U R E 3 The distribution in VIS categories and cvSOFA scores.cvSOFA, cardiovascular sequential organ failure assessment; VIS, Vasoactive Inotropic Score.
, several proposals have been made to replace cvSOFA with an alternative score.Vacheron et al. proposed a cvSOFA component score based on cumulative dosages of vasopressor/inotropic agents (limited to norepinephrine, epinephrine and dopamine) as part of a suggested full renewal of the SOFA score.31The discrimination ability of their fully renewed SOFA score proposal was significantly better compared to the conventional SOFA score in prediction of 28-day mortality.They used only three categories for each of the six organ systems included in SOFA, but their findings are in line with ours, supporting the feasibility of an approach based on vasopressor/ inotropic dosages in generating an updated version of the cvSOFA.
The cutoff values for VIS max and VIS mean .Characteristics of the study population, stratified according to 30-day outcome.
T A B L E 2 F I G U R E 1 Flowchart of patient selection.
We compared differences of each baseline variable in groups of survivors and non-survivors at 30 days with the non-parametric Mann-Whitney test for continuous variables and Fisher's exact test or Pearson chi-square test, as appropriate, for categorical variables.
1.1, Vienna, Austria and IBM SPSS Statistics for Windows, Version 26.0, Armonk, NY: IBM Corp. max -and VIS mean -based alternative SOFA scores.Then, we assessed the AUROC for these predicted probabilities to evaluate the discrimination ability of cvSOFA score, VIS max and VIS mean categories, SOFA score, and alternative VIS max -and VIS mean -based SOFA scores.In the alternative SOFA scores, the cvSOFA was replaced with F I G U R E 4 The 30-day, ICU and in-hospital mortalities in VIS max , VIS mean and cvSOFA score categories.cvSOFA, cardiovascular sequential organ failure assessment; ICU, intensive care unit; VIS max , maximum Vasoactive Inotropic Score; VIS mean , mean Vasoactive Inotropic Score.VIS max -or VIS mean -based scores, as follows: patients in the VIS category 0 score 0 points and patients in other categories score points corresponding to each category, the maximum score being 4 points for category 4. The difference between these scoring methods in discrimination was assessed with DeLong test.P value under 0.05 was considered as statistically significant in all statistical tests.
19re than one third of the patients needed cardiovascular support with infusion of intravenous vasopressor/inotropic medications during the first 24 h.This is far less than in patients with preceding cardiac surgery.However, our results are comparable to those of Koponen et al.,19who studied cardiac surgical patients: VIS is associated with outcome both in general ICU patients and in patients admitted after cardiac surgery.