The Impact of Early Norepinephrine Use on Outcomes in Patients with Septic Shock: A Retrospective Study Based on the MIMIC IV Database

doi:10.21203/rs.3.rs-3753916/v1

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The Impact of Early Norepinephrine Use on Outcomes in Patients with Septic Shock: A Retrospective Study Based on the MIMIC IV Database

https://doi.org/10.21203/rs.3.rs-3753916/v1

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Background

Septic shock is a life-threatening condition that requires timely and effective hemodynamic support. Norepinephrine is a preferred vasopressor in the treatment of septic shock, but there is still controversy regarding the optimal timing of its use. This study aims to assess the impact of norepinephrine administration in the early management of septic shock on short-term and medium-term outcomes.

Methods

A retrospective analysis was conducted on 3642 septic shock patients from the MIMIC IV 2.2 database. Patients were divided into four groups based on the timing of norepinephrine initiation (within 1 hour, within 3 hours, within 6 hours, and after 6 hours). Mortality rates at 28 days, 90 days, and 180 days, as well as secondary outcome measures such as ICU and hospital length of stay, duration of mechanical ventilation, and urine output were compared among the groups. Survival analysis was employed to evaluate survival rates among different groups.

Results

Primary Outcome: Survival curves showed that the group receiving norepinephrine within 3 hours had the highest survival rate at 28 days, while the group receiving norepinephrine within 6 hours had the highest survival rates at 90 and 180 days (logrank chi2 25.51, p < 0.001). Secondary Outcome: The group receiving norepinephrine within 1 hour had the shortest ICU length of stay (P < 0.001) and hospital length of stay (P < 0.001). This group also had the shortest duration of mechanical ventilation (P < 0.001) and the least fluid administration (P < 0.001). There was no significant difference in total norepinephrine usage among the groups (P > 0.05).

Conclusion

Early norepinephrine use, especially within 3 hours, may be associated with lower short-term mortality in patients with septic shock, while initiation within 6 hours may be associated with improved medium-term survival. Early norepinephrine use may also contribute to reduced hospital length of stay, decreased fluid administration, and improved renal perfusion. These findings support considering norepinephrine use in the early management of septic shock, but further research is needed to optimize the timing of its administration.

Septic shock

Norepinephrine

Mortality

Shock is a life-threatening condition characterized by inadequate delivery of oxygen to tissues [1]. Septic shock is one of the most common causes of shock in the ICU [2]. Septic shock, as the most severe form of sepsis, is a clinical emergency associated with high mortality rates worldwide. It is typically caused by infection and is characterized by tissue hypoperfusion and organ dysfunction. According to the latest clinical guidelines, the diagnosis of septic shock depends on evidence of infection and persistent hypotension, even after adequate fluid resuscitation, necessitating the use of vasoactive medications. Globally, the incidence and mortality rates of septic shock remain high [3], posing significant challenges to clinicians. In the management of septic shock, norepinephrine is the preferred vasoactive medication [4]. It increases vascular constriction through α-adrenergic receptor stimulation, thereby raising blood pressure and improving organ perfusion. Despite extensive research on the vascular mechanisms of norepinephrine, there is still significant controversy regarding its optimal timing of use, especially in the early stages of shock. In recent years, increasing evidence has suggested a close relationship between the timing of norepinephrine initiation and treatment outcomes in septic shock patients. Some studies have indicated that early initiation of norepinephrine may be associated with lower mortality [5], while others have shown different results[6]. Therefore, systematic studies investigating the relationship between the initiation of norepinephrine at different time windows and patient outcomes are crucial. This study aims to utilize a large sample of patients from the MIMIC IV 2.2 database[7, 8] to explore the impact of early norepinephrine use in the early stages of septic shock on short-term and medium-term outcomes. By categorizing patients based on the timing of norepinephrine use (within 1 hour, within 3 hours, within 6 hours, and after 6 hours), this research aims to provide deeper insights and scientific evidence for clinical treatment decisions.

Study Design and Data Source: This study is a retrospective cohort study, and the data were obtained from the publicly available MIMIC IV 2.2 database.

Patient Selection: Inclusion criteria encompassed all adult patients diagnosed with septic shock. Exclusion criteria included patients under 18 years of age, non-first-time ICU admissions, ICU stays less than 24 hours, and patients with missing key data such as the timing of norepinephrine use (Fig. 1).

Grouping Method: Patients were divided into four groups based on the timing of norepinephrine use: within 1 hour was Group 1; 1 to 3 hours was Group 2; 3 to 6 hours was Group 3; and after 6 hours was Group 4.

Data Collection: Collected data included patients' baseline characteristics (such as age, gender, comorbidities, SOFA score, APSIII score, etc.); key variables during treatment (such as fluid infusion, norepinephrine dosage, urine output); and treatment outcomes (28-day, 90-day, and 180-day mortality rates; ICU length of stay, hospital length of stay, and duration of mechanical ventilation).

Statistical Analysis

Descriptive statistical analysis was conducted to summarize the baseline data. Group differences between primary and secondary outcome measures were assessed. Survival analysis was employed to investigate the relationship between the timing of norepinephrine administration and patient survival rates at 28 days, 90 days, and 180 days. Visual representation of differences in secondary outcome measures was achieved using box plots and violin plots. A two-sided p-value less than 0.05 was considered statistically significant.

Baseline Characteristics (Table 1)

Table 1

Baseline Characteristics
Variables	Septic Shock (n = 3642)	NE ≤ 1h (n = 1626)	1h<NE ≤ 3h (n = 799)	3h<NE ≤ 6h (n = 491)	NE >6h (n = 726)	p
Age (yr)	67.17(15.05)	68.98(15.22)	67.93(14.87)	67.69(14.60)	66.94(15.11)	0.016
Male(%)	2010(55.19%)	913(56.15%)	435(54.44%)	273(55.60%)	389(53.58%)	0.664
SOFA Score	10.22(3.88)	10.00(3.90)	10.09(3.86)	10.23(3.76)	10.86(3.86)	0.000
APSIII Score	64.12(24.74)	61.86(24.38)	64.71(26.02)	63.95(23.44)	68.67(24.33)	0.000
Temperature (℃)	36.93(0.67)	36.91(0.67)	36.92(0.65)	36.96(0.69)	36.95(0.69)	0.514
R rate (bpm)	21.04(4.21)	21.04(4.13)	21.00(4.45)	20.88(4.04)	21.19(4.25)	0.633
Heart rate (bpm)	91.13(17.30)	90.09(16.83)	91.31(17.63)	90.97(16.63)	93.40(18.20)	0.000
MAP (mmHg)	71.57(7.01)	72.05(7.06)	71.80(6.98)	71.55(6.63)	70.24(7.03)	0.000
Myocardial infarct	715	334	147	103	131	0.341
Congestive Heart failure	1376	613	301	193	269	0.883
Cerebrovascular disease	372	173	61	47	91	0.014
Renal disease	1013	466	208	138	201	0.600
Chronic pulmonary disease	1074	477	224	150	223	0.655
Malignant cancer	628	126	123	108	134	0.008
Severe liver disease	314	120	62	39	93	0.000
AIDS	54	25	10	8	11	0.940
Data are presented as median (interquartile range), or number of patients(%)
NE norepinephrine; SOFA sequential organ failure assessment; APSIII Score acute physiology score iii;R rate respiration rate; MAP mean arterial blood pressure. AIDS Acquired Immune Deficiency Syndrome

Age: The mean ages for the four groups were 68.98 years, 67.93 years, 67.69 years, and 66.94 years, with the group using norepinephrine within 1 hour (NE ≤ 1h) having a slightly higher age, but the overall difference was not significant (p = 0.016).

Gender: The proportion of males was similar among the four groups, with no significant difference (p = 0.664).

SOFA Score and APSIII Score: The group with norepinephrine use exceeding 6 hours (NE > 6h) had the highest SOFA and APSIII scores, indicating potentially more severe illness in this group (SOFA p = 0.000, APSIII p = 0.000).

Mean Arterial Pressure: The group using norepinephrine (NE ≤ 1h) had the highest mean arterial pressure, with a significant difference (p = 0.000).

Outcome Measures (Table 2)

Table 2

Outcomes
Variables	Septic Shock (n = 3642)	NE ≤ 1h (n = 1626)	1h<NE ≤ 3h (n = 799)	3h<NE ≤ 6h (n = 491)	NE >6h (n = 726)	p
Los hospital(day)	14.49(15.23)	13.08(14.05)	14.53(14.10)	16.36(16.71)	16.32(17.46)	0.000
Los ICU(day)	6.55(6.88)	5.93(6.63)	6.49(6.30)	7.04(7.71)	7.67(7.27)	0.000
Death within 28 days(%)	1137(31.22)	500(30.75)	221(27.66)	137(27.90)	279(38.43)	0.000
Death within 90 days(%)	1476(40.53)	653(40.16)	300(37.55)	174(35.44)	349(48.07)	0.000
Death within 180 days(%)	1664(45.69)	735(45.20)	341(42.68)	203(41.34)	385(53.03)	0.000
Input amount(ml)	7714(5212)	7193(4758)	8150(5546)	8312(5751)	7999(5324)	0.000
Duration (hour)	97.58(109.45)	88.94(106.54)	98.84(105.03)	100.92(119.13)	111.83(111.66)	0.000
NE amount(ml)	38.64(70.94)	38.92(78.08)	40.81(72.44)	34.71(57.96)	38.26(59.53)	0.512
Urine output(ml)	1499.16(1301.57)	1627.37(1382.14)	1453.15(1279.75)	1438.71(1231.37)	1323.35(1150.55)	0.000
Los length of stay

28-day Mortality Rate: The group using norepinephrine within 3 hours (NE ≤ 3h) had the lowest 28-day mortality rate, suggesting that initiating norepinephrine within this time window may be associated with lower short-term mortality.

90-day and 180-day Mortality Rates: The group using norepinephrine within 6 hours (NE ≤ 6h) had the lowest 90-day and 180-day mortality rates, indicating an important association between norepinephrine use time and long-term survival rates. This suggests that using norepinephrine within 6 hours may help improve medium to long-term patient outcomes (logrank chi2 25.51, p < 0.001) (Fig. 2).

Length of Hospital Stay and ICU: The group using norepinephrine within 1 hour had the shortest length of hospital stay in both the hospital and ICU, while the group with use exceeding 6 hours had the longest stay, implying that early norepinephrine use may shorten the duration of hospitalization (Fig. 3, 4).

Duration of Mechanical Ventilation: The group using norepinephrine within 1 hour had the shortest duration of mechanical ventilation, indicating that early norepinephrine use may expedite respiratory function recovery (Fig. 5).

Norepinephrine Dose: There were no significant differences in the total norepinephrine doses among the groups, suggesting individualized treatment and pursuit of specific hemodynamic goals (Fig. 6).

Fluid Administration: There was a significant difference in the total volume of fluid administration within 24 hours among the groups (p < 0.001), with the group using norepinephrine within 1 hour having the least fluid administered (Fig. 7).

Urine Output: The group using norepinephrine early had higher urine output, possibly reflecting better renal function and hemodynamic status (Fig. 8).

Septic shock is a life-threatening clinical condition, and the survival of patients depends on early intervention and effective treatment. This study explores the relationship between the timing of norepinephrine administration and the severity of illness and outcome measures in patients with septic shock. It is noteworthy that the treatment of septic shock has evolved continuously, especially concerning the use of vasopressor agents. Traditionally, vasopressors were considered after fluid resuscitation, but recent research and clinical guidelines have advocated for the early use of norepinephrine to improve patient outcomes.

In this study, baseline characteristics of the four groups included age, gender, SOFA score, APSIII score, and mean arterial pressure. Age showed slight differences among the groups, but the overall difference was not significant. Gender distribution was similar across the four groups, with no significant differences. However, it is worth noting that the group with norepinephrine use exceeding 6 hours exhibited higher SOFA and APSIII scores, indicating potentially more severe illness in these patients. Additionally, the group using norepinephrine within 1 hour showed higher mean arterial pressure, possibly reflecting a positive impact of early norepinephrine use on hemodynamics.

The primary outcome measures in the study included 28-day, 90-day, and 180-day mortality rates. The study found that the group using norepinephrine within 3 hours had the lowest 28-day mortality rate, while the group using norepinephrine within 6 hours had the lowest 90-day and 180-day mortality rates. These results suggest that early norepinephrine use within specific time windows may be associated with lower short-term and long-term mortality rates. This association may be related to early intervention, improved hemodynamic stability, and reduced risk of multi-organ failure.

Secondary outcome measures included length of hospital stay, duration of mechanical ventilation, urine output, and total norepinephrine dose. The group using norepinephrine within 1 hour had the shortest hospital and ICU stays, the shortest duration of mechanical ventilation, and higher urine output. These results suggest that early norepinephrine use may contribute to shorter hospitalization, expedited respiratory function recovery, and potentially better renal function and hemodynamic status. Additionally, the study indicated no significant differences in total norepinephrine doses among the groups, highlighting the individualized nature of treatment and the pursuit of specific hemodynamic goals.

The advantages of early norepinephrine use include rapid restoration of perfusion pressure, prevention of treatment delay, improved response to fluid resuscitation, prevention of cardiovascular collapse, and synergy with appropriate fluid management. These factors contribute to maintaining adequate tissue perfusion, reducing the risk of multi-organ dysfunction, and improving patient survival. Furthermore, studies [9] have indicated a synergistic effect of norepinephrine and fluids in increasing cardiac output by improving preload and cardiac contractility, further enhancing hemodynamic stability. This synergy may help reduce the total fluid volume required for initial resuscitation of patients with septic shock, thereby reducing mortality.

However, uncertainty remains regarding the optimal timing of early norepinephrine use, and some research results are contradictory. Some studies [10] support early norepinephrine use in reducing fluid requirements and improving survival, while others [11] suggest that early use may increase mortality. Therefore, treatment strategies should be individualized based on the specific patient's condition, striking a balance between early intervention and appropriate fluid management.

It is essential to recognize the complexity of septic shock treatment, which requires consideration of multiple factors. Early norepinephrine use is likely a crucial component in improving the outcomes of patients with septic shock, but more research is needed to further validate this notion and determine the best treatment strategy. Personalized treatment and clinical monitoring remain critical to successfully managing septic shock [12].

Despite some findings regarding early norepinephrine use, it is essential to acknowledge the limitations in current research, which pose challenges in understanding and guiding clinical practice. Most evidence regarding early norepinephrine use comes from observational studies, introducing potential observational biases and confounding factors that complicate establishing causality. More randomized controlled trials are needed to validate these observational findings [13]. To assess the effectiveness of early norepinephrine use more accurately, more randomized controlled trials should be conducted. These trials should use standardized definitions and treatment protocols to ensure comparability of results. Moreover, future research should prioritize the development of predictive models to identify which patients are most likely to benefit from early norepinephrine use.

Early administration of norepinephrine, particularly within 3 hours, may be associated with lower short-term mortality rates in patients with septic shock, while its use within 6 hours may be linked to improved medium- to long-term survival rates. Early norepinephrine administration may also help reduce hospitalization duration, decrease fluid requirements, and improve renal perfusion. However, further research is needed to determine the optimal timing of administration definitively. Our findings support the adoption of individualized norepinephrine use strategies in the early treatment of septic shock to optimize patient clinical outcomes.

Authors' Contributions

Zhaokun Fan: Responsible for data extraction and manuscript preparation.

Yinyin Shen: Modified the code.

Chengen Li: Analyzed the data.

Ruqin Yi: Optimized the tables and figures.

Wei Chen and Wen Feng: Carried out literature search.

Zhirong Zhang: Supervised and revised the final draft.

Funding

No funding was received for this study.

Availability of Data and Materials

The original data for this study are available from the corresponding author upon reasonable request. Publicly available datasets were analyzed in this study. The data can be found here: https://physionet.org/content/mimiciv.

Ethics Approval and Consent to Participate

The project was approved by the Institutional Review Boards of Beth Israel Deaconess Medical Center (BIDMC) and the Massachusetts Institute of Technology (MIT). The waiver of informed consent was approved by the Institutional Review Board of BIDMC due to the de-identification of all protected health information. One author, Zhao kun Fan, completed the online course on Data or Specimens Only Research and gained access to the database for data extraction after passing the Collaborative Institutional Training Initiative (CITI) exam (Record ID: 55,303,422). All relevant guidelines and regulations were followed during the study.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

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No competing interests reported.

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The Impact of Early Norepinephrine Use on Outcomes in Patients with Septic Shock: A Retrospective Study Based on the MIMIC IV Database

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Abstract

Background

Methods

Results

Conclusion

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Introduction

Materials and Methods

Statistical Analysis

Results

Baseline Characteristics (Table 1)

Outcome Measures (Table 2)

Discussion

Conclusion

Declarations

References

Additional Declarations

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