Association between maximum norepinephrine dosage and mortality risk in neonates with septic shock (2024)

Sepsis accounts for about one-third of global neonatal mortality, and the World Health Organization has reported neonatal sepsis as a major future global health threat^1,2. Statistics show 2,824 cases of sepsis per 100,000 live births. Septic shock is the most critical stage of sepsis progression and requires vasopressor treatment to maintain blood pressure despite adequate fluid resuscitation; the condition incurs a mortality rate of up to 40%^3,4,5. Early identification of infants at risk of mortality holds significance in medical resourse allocation and enables early intervention to improve the prognosis.

Recommended as the first-line vasoactive agent in the treatment of pediatric septic shock by the latest international management guidelines, norepinephrine (NE) is extensively used in clinical practice⁶. In recent years, results from adult studies revealed that the use of high-dose NE was associated with poor outcomes in septic shock^7,8. Martin et al. reported that an NE dosage of 1ug/kg/min was associated with an ICU death rate of 90% and suggested that a dosage of NE greater than 1ug/kg/min was an independent factor associated with mortality in adults with septic shock⁹. However, the correlation between the NE dosage and prognosis in neonates with septic shock remains unclear. This study aimed to evaluate the correlation between NE dosage and neonatal septic shock mortality.

Subjects

The study retrospectively analyzed neonates diagnosed with septic shock and treated with NE in the Neonatal Intensive Care Unit (NICU) of Guangdong Women and Children Hospital from January 1, 2019, to December 31, 2021. The diagnostic criteria for sepsis followed the guidelines of the expert consensus on the diagnosis and management of neonatal sepsis (version 2019) revised by the Chinese Medical Association¹⁰. The inclusion criteria were neonates with septic shock^6,11 and NE treatment. The exclusion criteria were congenital heart diseases (except patent foramen ovale and non-hemodynamically significant patent ductus arteriosus), disabling congenital malformations, or suspected congenital metabolic diseases. The study was approved by the Guangdong Women and Children Hospital Research Ethical Committee (No. 202301008). Informed consent was obtained from all subjects and/or parents or their legal guardians for study participation. All methods were performed in accordance with the relevant guidelines and regulations.

Methods

The study retrospectively collected data on gender, gestational age, birth weight, perinatal conditions, and initial laboratory results post-septic shock diagnosis, including serum albumin (ALB), base excess (BE), lactate (LAC), platelet count (PLT), and white blood cell count (WBC). The worst values of LAC, BE, cardiac index during shock, maximum dosage of vasopressor, vasoactive-inotrope score (VIS), and septic shock score (SSS) were also recorded and analyzed. The VIS was calculated as follows: VIS = (dobutamine + dopamine in mcg/kg/min) + (milrinone in mcg/kg/min) × 10 + (epinephrine + norepinephrine in mcg/kg/min) × 100 + (vasopressin in IU/kg/min) × 10,000. The bedside SSS (bSSS) refers to a scale ranging from 0 to 5 points, with 1 point attributed for a LAC > 8 mmol/L, 1 point for VIS > 200, and 3 points for the presence of severe cardiomyopathy, as defined by a cardiac index < 2.2L/min/m² or a left ventricle ejection fraction < 25%. The computed SSS (cSSS) was calculated as follows: cSSS = 1.1^LAC + 1.001^VIS + 18 (in the presence of severe cardiomyopathy)¹².

Statistical analysis

Data were analyzed using SPSS 22.0. Normally distributed data were expressed as mean (standard deviation) and compared using two-sample t-tests; non-normally distributed data were expressed as median (interquartile range) and compared using the Mann–Whitney U test; categorical data were expressed as frequencies and percentages and compared using the Chi-square test. The receiver operating characteristic (ROC) curve was used to assess the optimal cutoff for maximum norepinephrine dosage (MND) to evaluate the risk of mortality in neonatal septic shock. The optimal cutoff was determined by identifying the point having the largest sum of sensitivity and specificity. The MND was then converted into categorical variables using this cutoff. The multivariate logistic regression analysis identified independent risk factors for mortality. After adjusting for confounding factors, the OR value of the correlation between MND > 0.3µg/kg/min and mortality was analyzed by multivariate logistic regression. Spearman rank correlation analysis was performed to assess the correlation between MND and indicators of poor prognosis. In this study, a P-value < 0.05 was considered statistically significant.

Ethics approval and consent to participate

The study was approved by the Guangdong Women and Children Hospital Research Ethical Committee (No. 202301008). Informed consent was obtained from all subjects and/or parents or their legal guardians for study participation. All methods were performed in accordance with the relevant guidelines and regulations.

Perinatal conditions and laboratory results

Of the 137 neonates initially identified, 14 were excluded (nine with hemodynamically significant patent ductus arteriosus, four with congenital malformations, and one suspected of having a genetic metabolic disorder or chromosomal disease). Ultimately 123 neonates were included in the analysis, who were further divided into the survival (n = 106) and death (n = 17) groups. (Fig.1).

The median time of onset of septic shock was 2 days after birth. A total of 12 neonates exhibited late-onset septic shock (9.8%). In addition, 21 out of the 123 infants had blood culture- positive sepsis. Compared to the survival group, the death group had a significantly lower birth weight (p = 0.022) and 1min Apgar score (p = 0.005). (Table 1). In contrast, no significant differences were found in gestational age, gender, 5min Apgar score, maternal pregnancy, and childbirth conditions (p > 0.05). The death group showed significantly lower ALB (p < 0.001) and BE (p = 0.001) levels but higher LAC (p = 0.009) levels after being diagnosed with septic shock. No significant differences in PLT, WBC < 5 × 10⁹/L, and positive blood culture rates were observed (p > 0.05). (Table 2).

Predictive value of MND for mortality in neonates with septic shock

The ROC curve for predicting neonatal septic shock mortality using MND showed an area under the curve of 0.775 (95% CI, 0.63–0.92, p < 0.001). The optimal threshold for MND was 0.3µg/kg/min, with a sensitivity of 82.4%, specificity of 75.5%, positive predictive value of 82.4%, and negative predictive value of 75.5%. (Fig.2).

Multivariate logistic regression analysis for mortality in neonates with septic shock

Neonatal septic shock mortality was set as the dependent variable and birth weight, 1min Apgar score, MND > 0.3µg/kg/min, and initial levels of ALB, LAC, and BE were included as variables in the multivariate logistic regression analysis. The results indicated that MND > 0.3µg/kg/min (OR, 12.08, 95% CI, 2.28–64.01) was an independent risk factor for mortality. (Table 3).

Spearman rank correlation analysis indicated that the worst values of LAC (r = 0.252, p = 0.005) and VIS (r = 0.836, p < 0.001) during septic shock were positively correlated with MND, whereas BE (r = -0.311, p = 0.001) was negatively correlated. No correlation was found with SSS (p > 0.05). (Table 4).

Despite advances in the understanding of the pathogenesis and therapeutic principles of neonatal septic shock, mortality rates remain high. Identifying of factors that contribute to an increased risk of mortality could aid in improving survival rates in neonates with septic shock. High doses of NE have been associated with mortality in adults with septic shock^7,13, but the evidence supporting this association in children is limited. To the best of our knowledge, the present study is the first to demonstrate a significant correlation between MND > 0.3µg/kg/min and neonatal septic shock mortality, showing high sensitivity, specificity, and predictive values for mortality prediction.

Current international guidelines for pediatric sepsis and septic shock recommend NE as the first-choice vasopressor for children but explicitly exclude preterm infants⁶. These guidelines acknowledge that neonates, compared to older children, may require different vasopressor support strategies in septic shock¹⁴. Until now, dopamine has been recommended as the first-line vasopressor for neonatal septic shock¹¹. However, growing evidence suggests that dopamine, especially in high doses, may also raise the mortality and adverse event rates in shock patients¹⁵. Recently, NE has been increasingly used in neonatal septic shock. Studies have revealed that NE significantly improves cardiac output, blood pressure, organ perfusion, and urine output in neonates with septic shock while reducing the dosage of dopamine and shortening the duration of vasopressor use^16,17,18. Nonetheless, high doses of NE may induce oxidative stress and myocardial cell insult¹⁹.

Recent studies demonstrate a significant independent correlation between high-dosage NE and mortality risk in septic shock adult patients^7,13. Research indicates that NE dosages ≥ 0.6µg/kg/min within 24h are significantly related to 7-day mortality in septic shock patients, which is likely due to sympathetic overstimulation causing myocardial damage^7,20. A previous study reported that every 10µg/min increase in NE dosage let to a 20.7% increase in mortality¹³. The findings of our study suggest that MND > 0.3µg/kg/min is a significant independent predictor of mortality in neonates with septic shock. This threshold demonstrates high sensitivity, specificity, and positive and negative predictive values all exceeding 75% in forecasting mortality in neonates with septic shock. Furthermore, MND is associated with poor prognostic indicators of septic shock, including BE, LAC, and VIS.

Limitations

Nevertheless, the limitations of the present study should be acknowledged. This single-center retrospective analysis of NE dosage was adjusted based on clinical decisions rather than a prospective protocol. Moreover, the small sample size for the death group (n = 17) was the primary limitation of this study. Hence, even statistically significant results should be interpreted with caution and should be validated by studies with larger sample sizes. Finally, the current study only collected the early and the worst indicators of patients and did not analyze vasopressor therapies other than NE, which may potentially impact the assessment of mortality.

ALB:

Serum albumin

BE:

Base excess

IQR:

Interquartile range

LAC:

Lactate

MND:

Maximum norepinephrine dosage

NE:

Norepinephrine

NICU:

Neonatal intensive care unit

PLT:

Platelet count

ROC:

Receiver operating characteristic

SSS:

Septic shock score

SD:

Standard deviation

VIS:

Vasoactive-inotropic score

Authors and Affiliations

1. Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou, China

   Junjuan Zhong,Jing Zhang,Yingyi Lin,Dongju Ma,Jing Mo&Xiuzhen Ye

Contributions

J.Z., J.Z., Y.L., and D.M. helped in the study design, collected and analyzed the data, and drafted the manuscript. J.M. and X.Y. planned the study, supervised the collection and analysis of data, and were responsible for the critical revision and finalization of the manuscript.

Corresponding author

Correspondence to Xiuzhen Ye.

Competing interests

The authors declare no competing interests.

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