Materials and Methods

The present single-center, prospective, observational study was performed in the Emergency Department (ED) of Emam Khomeini Educational Hospital in Sari, Iran, from July 2018 to September 2019. This hospital is a tertiary care center in Sari with referrals from all hospitals in Northern Iran. The ED of this center is equipped with five beds in the intensive care unit (ICU) called ED-ICU [9]. The critically ill patients requiring intensive care, including those that should undergo mechanical ventilation, and need invasive hemodynamic monitoring or critical observation, are admitted to this unit. The present single-center, prospective, observational study was performed on all patients with septic shock admitted to the ED-ICU during the study period. Septic shock was diagnosed in the present study based on the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) [1]. All the patients aged above 18 years diagnosed with septic shock and referring to ED were included in the study. Patients who were excluded from the study included those with known chronic kidney disease, those undergoing abdominal radiotherapy or dialysis, patients with trauma, those undergoing cardiopulmonary resuscitation, those who died within the six hours of follow-up, and patients without a clear ultrasound view. In the present study, patient’s information, including age, gender, past medical disease, physiological scoring, vital signs (Vital signs were measured by sphygmomanometer, heart rate monitoring, and pulse oximeter), and paraclinical findings, were collected prospectively. Vital signs, RRI, UO, and central venous pressure, were measured, and the interpretation of arterial blood gases was performed during the study period. Finally, the mortality rate of the patients was assessed after 30 days.
All the subjects underwent standard treatment according to the Guidelines of the American College of Critical Care Medicine [10], including early goal-directed resuscitation in the first six hours of septic shock. A urinary catheter and an internal jugular or subclavian venous catheter were inserted for the subjects. All patients with CVP≥ 8 and without any changes in hemodynamic status after receiving one liter of crystalloid fluid were considered non-volume-responsive. Those who were non-volume-responsive were given a maintenance crystalloid fluid of one liter in 8 hours and a minimum effective dose of a vasopressor (3 microgram/minute) to maintain MAP at 65 mmHg [11]. Norepinephrine was the only vasopressor used in the current study. All patients were followed up for six hours, during which their body temperature, heart rate, blood pressure, respiration rate, UO, central venous pressure, and blood gas were measured on arrival, as well as 30 and 120 minutes, and six hours after the treatment onset. Age and gender were recorded; moreover, their simplified acute physiology score (SAPS) II and acute physiology and chronic health evaluation (APACHE) II were determined. The RRI was determined by Doppler ultrasound (Sonosite EDGE) of renal interlobular veins performed by an emergency physician who was qualified in using a 2-5-MHz curved probe (Figure 1). The RRI was measured at baseline (RRI0), as well as 30 (RRI30) and 120 (RRI120) minutes and six hours (RRI6h) after the treatment onset.
The right kidney is observed on the monitor if the 2-5MHz curved prop is placed on the right side midaxillary line, as the transducer dot facing upwards, and the interlobular artery of the kidney a13re then identified using the color option. Using continuous-wave Doppler, the interlobular artery is detected in the same place. The gain adjustment is also used for greater clarity of images and waves. An image with three clear continuous waves is considered ideal, and the frozen image and RI are calculated as peak systolic velocity-end diastolic velocity/peak systolic velocity. All three continuous waves on the monitor are used to calculate RI and, the mean value is considered the overall RI for all patients [12]. RRI changes were assessed and evaluated within six hours of the treatment process.


Figure 1. Doppler ultrasound of interlobular veins was performed on the right kidney. Date were expressed in five consecutive waves with IR=0.67

Based on the Kolmogorov-Smirnov test results, the hypothesis of the normality of continuous variables was confirmed (P=0.05). Therefore, independent samples t-test was used to compare continuous variables and the Chi-square test was utilized for qualitative variables. Continuous variables were expressed as mean±standard deviation and qualitative variables were presented as median (interquartile range). The repeated measures ANOVA was employed to compare RRI levels at different time points between the two groups of patients
surviving more than 30 days (the survival group) and those dying before 30 days (the non-survival group). To compare RRI values at different time points, the Friedman nonparametric test was employed. the logistic regression model was used to investigate its effect during the study. Data analysis was performed using SPSS (version 13.0), STAT, and R software packages.

Results

To calculate the significance level, the Bonferroni correction was used as  . Therefore, in Table 3, differences between the groups with a P<0.008 were considered significant. Therefore, there was a significant difference in RRI levels between the time points of (0 and 120), (0 and six hours), (30 and 120 minutes), and (30 minutes and six hours). The RRI level decreased at 120 minutes compared to RRI on arrival, at six hours compared to zero minutes, at 120 minutes compared to 30 minutes, and at six hours compared to 30 minutes. Using logistic regression, the Omnibus tests of model coefficients illustrated that RRI had no significant effect on achieving the treatment goal of MAP ≥65 mmHg and CVP ≥8 mmHg. The P-values were 0.54 on arrival, 0.26 at 30 minutes, 0.40 at 120 minutes, and 0.54 after six hours.
Discussion
In the study, the RRI value decreased significantly only 120 minutes after the treatment onset in the group achieving the treatment goal, compared to those not achieving; however, on arrival, as well as 30 minutes and six hours after the treatment onset, the RRI value had no significant changes; nonetheless, in general, RRI value decreased during the study period. Studies pointed out  that with increasing blood pressure from 65 to 85 mmHg, the RRI value significantly decreased [8], pointing to the  negative (inverse) relationship of MAP value with RRI at 30 and 120 minutes, as well as a positive (direct) relationship after six hours. Using Pearson correlation, the correlation between MAP and RRI was confirmed (). The MAP increase and RRI decrease during the study indicated an inverse relationship between the two variables and similar results were also observed in a study demonstrating that the increase in pressure was accompanied by a decrease in the kidney [14]. Some studies also highlighted a weak and inverse relationship between the two variables in patients with septic shock without acute kidney injury, and RRI alone cannot indicate hemodynamic changes in such patients to reflect optimal MAP [15, 16]. In the study by Deruddre S and et al., RRI was used as a marker of renal perfusion in the management of patients with septic shock [8]. Given that in the present study, the RRI value decreased during the study, it can be used as a volume and hemodynamic assessment index. In some studies, the hemodynamic changes caused by fluid challenges did not lead to changes in RRI [17]. The presence of underlying diseases, such as diabetes and hypertension, was significantly higher in those who died; in some studies, since such diseases affect vascular compliance, they eventually led to an increase in RRI [18]. Critically ill patients with septic shock admitted to ICU had a higher RRI than their counterparts without septic shock (19), and in the present study, the subjects who died had a higher RRI than those who survived. Increased RRI was strongly associated with multiple organ failure [20,21]. In the present study, the RRI value was significantly higher in those who died or were critically ill based on SAPS II and APACHE II criteria.  Some studies revealed that higher RRI increased the need for mechanical ventilation in patients with sepsis [22]. A high renal resistance index is a sign of failure to reach the treatment goals and deterioration of the patient's condition. In some studies, RRI was the best predictor of acute kidney injury in septic shock [23]. Nevertheless, in the present research, the mortality rate was higher in those undergoing mechanical ventilation. Based on the results, RRI was 0.73±0.06 in those undergoing mechanical ventilation and 0.70±0.03 in the subjects not undergoing invasive airway management; the difference between the groups was statistically significant (). The use of both RRI and CVP had a higher predictive value than using one alone to diagnose acute renal failure caused by sepsis [24]. However, in those with a CVP of <8 mmHg, the mean scores of disease severity based on SAPS II and APACHE II scores were 51.60±22.52 and 23.47±11.49; nonetheless, they were 49.01±21.18 in SAPS II and 23.21±10.14 in APACHE II in those with a CVP of ≥8 mmHg, illustrating a statistically significant difference. However, factors, such as age, are directly correlated with RRI (), and in some studies, aging was associated with vascular changes, and decreased renal vascular compliance affected RRI value [25]. Although some conditions, such as DM and HTN, are known as diseases causing AKI [26], these conditions had no correlations with RRI value in the present study (). Among the notable limitations of this study, we can refer to the lack of patients’ follow-up after six hours (). Moreover, the small sample size and the lack of enrolment of those who died during the study were other limitations of the study. Nearly double the number of patients were intubated in the non-survivor group. It is conceivable that PPV would affect RRI. A multicenter study with a larger sample size and prolonged follow-up course to determine whether RRI can be used as a marker of volume assessment in patients with septic shock is recommended.

Conclusion

Ethical Considerations

Compliance with ethical guidelines

Funding

Authors' contributions

Conflicts of interest

Acknowledgments

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