A Vasoactive Inotropic Score Predicts the Severity of Hypotensive Shock and Mortality in Preterm Infants

Objective: To validate the prediction of the severity of hypotensive shock and mortality using the vasoactive inotropic score in preterm infants. Methods: In this retrospective study we calculated the vasoactive inotropic score (VIS) and cumulative exposure to cardiovascular medications over time (VISct) in a cohort of preterm infants with hypotensive shock who received a cardiovascular support. Receiver operator curve was constructed to predict the primary outcome which was death due to hypotensive shock. Results: VIS had an area under the curve of 0.73 (95% CI 0.85-0.98, p < 0.001). A VIS cut off of 25 has sensitivity and specicity of 66% and 92%, and positive and negative predictive values of 78.5% and 83%, respectively. Conclusion: High VIS predicts high mortality rate due to irreversible shock in preterm infants


Introduction
Management of hypotension is an unresolved challenge to neonatal intensive care practitioners (1). The concern about hypotension in preterm infants and the main rationale of neonatologists to treat, is the detrimental effect on end-organ perfusion (2). Hypotension has been associated with several adverse effects that re ect the cardiovascular instability and end-organ injury; the most common detrimental short term clinical consequences are intraventricular hemorrhage (IVH) and periventricular leukomalacia, necrotizing enterocolitis (NEC), and nally death (3). Between 16 to 98 % of preterm infants receive cardiovascular medications during admission (4).
Preterm infants who are both hypotensive and in shock -de ned as low blood pressure with either lactic acidosis or oliguria -will probably have a high mortality. We hypothesized that a preterm infant with hypotension unresponsive to a certain dose of a cardiovascular drug as represented by the vasoactive inotropic score (VIS) can represent a marker at which the treating team should reassess the management strategy rather than continuing to increase the cardiovascular drug dosage or adding more drugs in the absence of clinical improvement. Blood pressure has never been proven to be a sensitive marker re ective of end organ blood ow especially when relying solely on mean blood pressure (MABP) and ignoring the physiologic values of systolic and diastolic blood pressures (5,6). VIS may be useful as an independent predictor of poor short-term outcome after cardiothoracic surgery (7,8) and predicts eventual morbidity and mortality in post-operative congenital heart surgery with cardiopulmonary bypass (9). The aim of this study was to validate the value of VIS for prediction of the severity of hypotensive shock and mortality in preterm infants < 33 weeks. We hypothesized that a higher VIS score would be associated with high mortality in preterm infants < 33 weeks gestation.

Methods
All infants who were admitted to the 2 tertiary NICUs in Winnipeg, Canada between 2011-2015 who received cardiovascular medications were identi ed using pharmacy's electronic records. Preterm infants < 33 weeks were identi ed and a retrospective chart review was undertaken. Elligibility criteria was premature babies < 33 weeks who had Clinical evidence of compromised systemic circulation with at least one of the following: low mean arterial blood pressure (MABP) as de ned by less than the lower 95% con dence interval (CI) for the corrected gestational age with considering invasive BP measurement as the standard monitoring, oliguria less than 1 mL/kg/h for at least 12 hours, or lactic acidosis greater than 2.8 mmol/l, and received cardiovascular medication (1,10). Infants with congenital or chromosomal anomalies were excluded. In this study we calculated the (VIS) as follows [Dopamine (mcg/kg/min) + Dobutamine (mcg/kg/min) + Epinephrine (mcg/kg/min) ×100 + Norepinephrine (mcg/kg/min)×100 + Vasopressin (IU/kg/min)×10000 + Milrinone (mcg/kg/min)×10] (7,9). We considered the highest dose for each drug if continued for > 6 hours. We calculated the cumulative vasoactive inotropic (VISct) exposure to the cardiovascular medications by multiplying the (VIS) of each drug with the exposure time in hours.
Demographic and clinical data were abstracted from the chart review. Those data included antenatal steroids, gestational age (GA), birth weight, sex, Apgar scores at 5 and 10 minutes, con rmed sepsis, and IVH. The cumulative time of compromised systemic circulation (CSC) during NICU admission was considered as marker of disease severity. CSC was considered present if the infant had one or more of the following: hypotension as described above, oliguria < 1ml/kg/hour for at least 12 hours beyond the rst postnatal 12 hours, or lactic acid > 2.8mmol/dl(5, 6). The study period was before the targeted neonatal echocardiography was introduced in our units as a standared of care for assessment of infants with refractory shock; the cardiovasculr medications were prescribed empirically starting with dopamine with the addition of dobutamine or epinephrine as second or third line, plus the administration of multiple empirical normal saline boluses. Our primary outcome was death due to hypotensive shock.
Ethics approval was obtained from University of Manitoba Research Ethics Board.

Statistical analysis:
SPSS v 24 (SPSS Inc, Chicago, Illinois) was used to perform the statistical analysis. Data are presented as median with interquartile range or frequencies. Comparisons between groups were analyzed by Mann-Whitney U test; Frequencies were analyzed using Chi-square; p < 0.05 was considered signi cant. The primary outcome for infants with hypotensive shock was evaluated using Cox proportional hazards regression model. Multivariate and adjusted multivariable analysis between groups was also performed using the general linear model to test effects between subjects and analyzed by multi-way ANOVA with Tukey's multiple comparisons test; p values < 0.05 were considered signi cant. A receiver operating characteristic (ROC) curve was constructed, and predictive values were calculated. Pearson correlation was used to correlate VIS ≥ 25 associated with death with other variables, with relevant graphs created by GraphPad program.

Results
One hundred and seventeen preterm infants < 33 weeks GA who had signi cant hypotension were enrolled in the study; 38 (32.5%) died and 79 (67.5%) survived. Table 1   survival and non survival group (p = 0.9, partial ŋ 2 =0.0001). Figure 2 shows Cox proportional of death of infants with VIS ≥ 25 compared to infants with VIS < 25 and in relation to exposure time to cardiovasculr drugs. Table 2 and Fig. 3 show the assoctation beween infants with VIS who either dead or survived with the following variables:, lactic acid, urine output, systolic blood pressure, diastolic blood pressure, mean blood pressures, serum cortisol levels, gestational age, and Apgar scores, there was signifcant correlation with lactic acid, urine output, systolic blood pressure, gestaional age, and serum cortisol level. Higher percent of cases underwent delayed cord claming was assocaited with VIS < 25, which was not the case with the percent of cases with con rmed infection Fig. 4.

Discussion
We have examined the predictive value of the vasoactive inotropic score in preterm infants with hypotensive shock aiming to predict irreversible shock early which might alert the clinical team to consider different management strategy or consider to formulate a physiologic based medical recommendation by utilizing the new emerging techniques like targeted neonatal echocardiography and near infrared spectroscopy as an alternative to empiric approach (5,6,11). This study was conducted before implementing the physiologic based integrated hemodynamic approach, which might explain the high VIS in signi cant number of cases (5). The formulated medical recommendation could be either discontinuation of a cardiovascular medication causing side effects more than supporting systemic circulation, or consider more investigations to elucidate the pathophysiologic mechanism (12,13). We found that VIS ≥ 25 was associated with higher mortality in preterm infants with hypotensive shock and is an alert number to start considering other modalities of treatment based on further imaging (TNE) Targeted Neonatal Echocardiography to assess underlaying pathophysiologic mechanism (14,15). This is the rst study to our knowledge describing the value of VIS in this population but it has been validated in older children with shock(8).
Current research con rms that the measurement of blood pressure does not re ect either tissue perfusion or oxygen delivery(16, 17), and current therapeutic interventions for hypotension are not associated with improved in-hospital outcomes or neurodevelopmental outcomes (18,19). This could be related to lack of insight regarding the signi cance of physiologic markers which re ect variations in blood ow, together with adopting empirical cardiovascular support without assessment of the underlying pathophysiology (12,20). Identifying whether CSC a result of impaired preload, afterload, contractility, or the oxygen-carrying capacity (or a combination of those factors) can facilitate a more targeted and more meaningful approach to management, we analysed the preterm infants with CSC before implementing our hemodynamics protocol, which could explain high VIS in signi cant number of cases (21)(22)(23). We reported the impact of integrated evaluation of hemodynamics on clinical outcomes including VIS, and the time to clinical recovery and both were signi cantly lower in the group managed with the formulated pathophysiologic medical recommendation compared to infants managed with empiric approach(5). It is not uncommon that in refractory hypotensive shock, the number and/or dose of cardiovascular medications is empirically increased. this approach may overlook the detrimental side effect of these drugs, which may increase the risk of death in some situations (5,6). VIS has been validated in neonates post cardiothoracic surgery and it was predictive of poor short-term outcomes (7,24). The strengths of this study are using the VIS score as a marker of impending and irreversible shock and validating VISct which re ects the impact of the cumulative doses of cardiovascular drugs used before death or discharge. The limitations of this study are small sample size and the retrospective design and the lack of comparison with similar cases managed with physiologic approach.
Conclusions VIS maybe useful in predicting severity of the hypotensive shock and mortality in preterm infants, we found that VIS ≥ 25 was associated with higher mortality in preterm infants. This is the rst study to our knowledge describing the value of VIS in this population. Con icts of interest: The authors have no nancial relationships to disclose and no con ict of interest.
Ethics approval: was obtained from University of Manitoba Research Ethics Board Cox proportional of death of infants with VIS ≥ 25 compared to infants with VIS < 25 and in relation to exposure time to cardiovascular drugs