Effect of Early versus Delayed Use of Norepinephrine on Short-Term Outcomes in Patients with Traumatic Hemorrhagic Shock: A Propensity Score Matching Analysis

Introduction

Severe trauma is a global public health problem, causing approximately 5.8 million deaths annually, with a mortality rate of more than 10%.¹ Haemorrhagic shock (HS) is a severe complication of trauma and is the primary cause of early death in patients with trauma.^2,3 Guidelines recommend restrictive fluid resuscitation⁴ and permissive hypotension strategies^5–7 for HS until bleeding is controlled. The 2019 European guideline on the management of major bleeding and coagulopathy following trauma recommends the use of norepinephrine (NE) for maintaining target arterial blood pressure in patients with life-threatening hypotension.⁸ However, this guideline does not clearly state the optimal timing for the use of NE. Therefore, the timing of NE use remains unclear.

Rigorous data regarding the efficacy and safety of NE in patients with HS are currently lacking. One multicenter prospective cohort study showed that early use of vasopressors might be hemodynamically detrimental compared with using fluid resuscitation alone and should be used with caution.⁹ However, we found a significantly higher proportion of patients undergoing thoracotomy in the early cohort of this study, which may have influenced patient hemodynamic outcomes. In another prospective study of 518 patients with HS, after propensity score matching (PSM), the early use of NE (eNE) use had no adverse effect on 24 h mortality compared with no NE use.¹⁰ In a recent study of 4253 patients with septic shock, patients with HS in an eNE group had longer survival, shorter durations of NE use and possibly delayed or reversed organ failure.¹¹ This suggests that eNE may benefit patients. However, whether eNE benefits patients with HS is unclear. Therefore, the optimal timing of NE use in patients with traumatic HS requires further investigation.

To date, uniform criteria for the timing of NE initiation in the management of HS have not been established. In this study, we extrapolated previous research results^11–13 and defined eNE as an interval between NE treatment and HS of ≤3 h; delayed NE (dNE) was defined as an NE duration of >3 h. We aimed to investigate the impact of eNE versus dNE on the survival of patients with traumatic HS.

Materials and Methods

Study Population

This was an observational study in which we retrospectively analysed the medical history data of 518 patients with traumatic HS admitted to the emergency intensive care unit (ICU) of the Affiliated Hospital of Yangzhou University with a diagnosis of traumatic HS between March 2017 and April 2021. Traumatic HS was defined as a severely traumatised patient with mean arterial pressure (MAP) of <65 mmHg on admission, requiring surgical control of active bleeding, the transfusion of more than four units of red blood cells (RBCs) within 6 h of admission and the use of NE within 24 h of admission. The exclusion criteria included age <18 years or >65 years, cardiac arrest at admission, severe brain or spinal injury (because of different target blood pressures), death due to haemostatic failure within 6 h of admission and incomplete clinical data. This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Yangzhou University, and informed consent was obtained from all participants (2021-YKL3-01-001).

The vasoactive drug NE was used for preliminary treatment, and the start time of traumatic HS was defined as the first recorded MAP of <65 mmHg. Based on the time of traumatic HS onset and the timing of NE treatment, patients were divided into two groups: an eNE group and a dNE group. Patients were allocated to the eNE group if the timespan was ≤3 h. Patients with an interval of >3 h between NE treatment and HS were allocated to the dNE group. The detailed flowchart of the enrolled patients is shown in Figure 1.

Figure 1 Flowchart of study design and patient selection.

Data Collection

The clinical data of all enrolled patients were extracted from the emergency information system and inpatient electronic medical records. Baseline characteristics were collected within 24 h after admission and included age, sex, Charlson Comorbidity Index (CCI), body mass index (BMI), complications (hypertension, myocardial infarction, congestive heart failure, chronic pulmonary disease, diabetes mellitus, kidney disease, cancer, leukaemia, lymphoma and metastatic cancer), mechanism of injury (blunt), cause of injury (motor vehicles, bikes, pedestrians, falls and other reasons), pre-hospital status (MAP, heart rate [HR], fluid amount, intubation and initial Glasgow Coma Scale [GCS] score), on-admission status (MAP, HR), intubation, initial GCS score, haemoglobin, blood glucose, blood lactate and serum creatinine), severity scores (sequential organ failure assessment [SOFA] score on the first day, injury severity score [ISS] score on the first day and acute physiology, age, chronic health evaluation [APACHE III] score on the first day), NE use (timing, maximum NE dose within 24 h, total dose within 24 h, and target MAP need time), fluid resuscitation within 24 h (RBCs, lyophilised plasma, fibrinogen, platelets, total of non-blood fluid infusion, total of all fluid infusion), damage control surgery, 24 h mortality, in-hospital mortality, acute kidney injury (AKI) within 24 h, continuous renal replacement therapy (CRRT)-free days, invasive mechanical ventilation (IMV)-free days, hospital length of stay (HLOS) and ICU length of stay (ICU LOS).

Study Endpoint

The primary endpoint was 24 h mortality, and the secondary endpoints were in-hospital mortality, incidence of AKI, duration of non-CRRT, duration of non-IMV therapy, HLOS and ICU LOS. The duration of non-IMV therapy and non-CRRT was expressed as 28 d after admission, ie the number of days the patient survived without IMV therapy or CRRT. If the patient died within 24 h, the time of death was used as the endpoint. According to the European guideline on the management of major bleeding and coagulopathy following trauma,⁸ the target MAP for fluid resuscitation was set at 50–60 mmHg. The diagnosis of AKI was based on the Improving the Global Prognosis Guidelines for kidney disease,¹⁴ and AKI was not assessed in patients with end-stage renal disease.

Statistical Methods

Stata 16.0 statistical software was used. The normality of the data was tested using the Shapiro–Wilk method. Normally distributed data were expressed as mean (±SD), and non-normally distributed data were expressed as M (Q1, Q3). Categorical variables were indicated as numbers and percentages. The results were depicted as boxplot diagrams. To reduce bias, PSM was used to obtain a control cohort of patients in the eNE group and the dNE group, with a matching ratio of 1:1 and a calliper value of 0.2, with age, male, CCI, BMI, complications, mechanism of injury, cause of injury, pre-hospital status, on-admission status, severity scores, NE use, fluid resuscitation within 24 h and damage control surgery as covariates without substitution. A Kaplan–Meier survival analysis and a Streg regression model were used to evaluate the relationship between eNE and the 24 h survival rate of patients. The area under the receiver operating characteristic (ROC) curve was calculated to determine the predictive abilities of the timing of NE use for 24 h mortality. A value of P < 0.05 was considered statistically significant.

Results

General Characteristics of the Patients

A total of 518 patients were diagnosed with traumatic HS. Of these, 162 were excluded, including 45 patients aged <18 years or >65 years, 18 patients with cardiac arrest on admission, 62 patients with a severe brain or spinal injury caused by different target blood pressures, 30 patients who died of haemostatic failure within 6 h of admission and 7 patients with incomplete clinical data. Finally, 356 patients met the inclusion criteria. The mean age of the patients was 49.8 ± 14.4 years, and 189 were male (53.1%). The most common injuries were bicycle injuries (143, 40.2%), followed by motor vehicle injuries (82, 23.0%), falls (74, 20.8%), pedestrian injuries (47, 13.2%) and other injuries (10, 2.8%). Ultimately, 176 patients (49.3%) were subordinated to the eNE group, and 180 patients (50.7%) were subordinated to the dNE group. After PSM, the eNE and dNE groups each had 154 patients. Therefore, 308 patients participated in the final analysis (Figure 1).

Before PSM, there were significant differences in age, complications (hypertension), mechanism of injury, pre-hospital status (MAP and initial GCS score), on-admission status (MAP and haemoglobin), first-day ISS score, first-day SOFA score, first-day APACHE III score, timing of NE use, target MAP need time, 24 h total of non-blood fluid infusion and 24 h total of all fluid infusion between the groups (P < 0.05). After PSM, there were significant differences in the timing of NE use, target MAP need time, total of non-blood fluid infusion and total of all fluid infusion between the eNE and dNE groups (P < 0.05) (Table 1, Figure 2).

Table 1 Comparison of Baseline Data of Patients Between Early Norepinephrine and Delayed Norepinephrine Before and After Propensity Score Matching

Figure 2 Comparison of the characteristics of patients in the early group and the delayed group. The timing of norepinephrine use (A); Target mean arterial pressure need time (B); APACHE III score 1st day (C); SOFA score 1st day (D); The total of non-blood fluid infusion (E); Total of all fluid infusion (F). ###Compared with dEN, P<0.001. Abbreviations: MAP, mean arterial pressure, APACHE, acute physiology, age, chronic health evaluation. SOFA, sequential organ failure assessment. eNE, early norepinephrine; dNE, delay norepinephrine.

Primary Study Endpoint

Before PSM, the 24 h mortality rate in the eNE group was lower than that in the dNE group (54, 30.7% versus 45.0%; P < 0.001). After PSM, the 24 h mortality rate in the eNE group was still lower than that in the dNE group (46, 29.9% versus 69, 44.8%, P < 0.001) (Table 2). The ROC analysis demonstrated that a 4.4 h cut-off point for the timing of NE use gave the optimal predictive value for 24 h mortality, with a sensitivity of 95.52%, a specificity of 81.33% and an AUC of 0.9272; these were better than other potential risk factors, such as the ISS score (0.6859), APACHE III score (0.7232), SOFA score (0.7961), total of non-blood fluid infusion (0.8103) and total of all fluid infusion (0.8045) (Figure 3).

Table 2 Comparison of Clinical Outcomes of Patients Between Early Norepinephrine and Delayed Norepinephrine Before and After Propensity Score Matching

Figure 3 Receiver operating characteristic (ROC) curves of ISS score (A), APACHE III (B), SOFA score (C), Total of non-blood fluid infusion (D), Total of all fluid infusion (E), and Timing of NE use (F) for 24h mortality in patients with THS. Abbreviations: ISS, injury severity score; APACHE, acute physiology, age, chronic health evaluation; SOFA, sequential organ failure assessment; NE, norepinephrine.

The Kaplan–Meier survival analysis of 24 h mortality showed that the survival rate of the eNE group was higher than that of the dNE group (P < 0.001) (Figure 4). The Streg regression model showed that the scores for ISS, APACHE III and SOFA; initial blood lactate, 24 h total of non-blood fluid infusion and dNE were significantly associated with 24 h survival (P < 0.05) (Table 3).

Table 3 The Streg Regression Model Analysis Based on Traumatic Hemorrhagic Shock Patients with 24 Hour-Mortality

Figure 4 Kaplan-Meier survival estimates based on 24h mortality. After propensity score matching (A); Before propensity score matching (B).

Secondary Study Endpoint

Regardless of PSM, compared with the dNE group, there was no significant difference in AKI incidence, HLOS, ICU LOS, duration of non-CRRT and non-IMV therapy and in-hospital mortality in the eNE group (P > 0.05) (Table 2).

Discussion

Early NE may be beneficial for the prognosis of patients with HS. However, the optimal timing of NE administration remains unclear. Our study showed that dNE was associated with a significant increase in 24 h mortality (OR = 1.30, P < 0.001). In addition, the Kaplan–Meier survival analysis of the pre-PSM and post-PSM cohorts showed that the patients in the eNE group had a higher survival rate after admission than those in the dNE group. The multivariate Streg regression analysis also showed that dNE was associated with a lower 24 h survival rate.

It has been found that trauma-induced haemorrhage and hypovolemia can trigger an intricate neurohormonal response.¹⁵ Thus, trauma-induced hypotension is associated not only with hypovolemia but also with sympathetic suppression-induced vasodilation.¹⁶ Vasopressor administration plays an important role in treating vascular paralysis and sustaining adequate perfusion pressure among patients with trauma and hypotension. Recent research has supported the biological plausibility of using NE for patients with trauma and HS.¹⁰ Haemorrhage is a time-dependent process, and its early recognition and management are critical. Our findings showed that eNE was associated with decreased mortality, which was consistent with previous studies. Poloujadoff et al¹⁷ found that NE infusion at a rate of 50 µg·100 g−1·h−1 within 75 minutes of traumatic HS significantly improved the survival rate of rats at 210 minutes. A recent study also showed that eNE was associated with increased short-term survival rates in patients with sepsis.¹⁸ Another retrospective study demonstrated that if the time from the onset of shock to the use of NE was more than 2 h, the 28 d mortality rate was significantly increased, and for each additional hour, mortality increased by 5.3%.¹⁹ Preliminary animal studies have shown that NE mainly acts as a vasoconstrictor, which can constrict arterial vessels and activate venous α-adrenergic receptors.²⁰ This induces venous vasoconstriction, diverting splanchnic blood volume to the systemic circulation, while the activation of β₂-adrenergic receptors reduces venous resistance and increases venous return.²¹ Recent data from an animal model showed improved survival after NE infusion, irrespective of a lower or higher blood pressure target.²²

Therefore, we hypothesised that using eNE to improve hemodynamic status might have a positive effect on survival time. However, a few clinical trials have shown that eNE has no positive effect on the survival time of patients with traumatic HS¹⁰ or is even harmful.⁹ We believe that there might be selection bias, as the increased proportion of thoracotomies performed affects the hemodynamic status of patients and negatively impacts survival time. Additionally, other studies examined the combined exposure to any vasopressor, including phenylephrine, dopamine, vasopressin and NE. Furthermore, the grouping of the study population or the concentration of vasoactive drugs might have influenced the trial results. Singer et al²³ found that higher maximum doses of NE were associated with increased mortality and that patients with trauma who commenced NE more than 24 h after injury may have a dire prognosis. Therefore, our study used a PSM analysis to reduce bias as much as possible and borrowed from the grouping method used by most studies.^11–13

Our study found that eNE was not associated with a shorter ICU LOS, a shorter HLOS and a longer duration of non-IMV therapy. Animal studies have shown that the early administration of NE reduced blood loss and fluid requirements during MAP-directed fluid resuscitation in rats with HS.²⁴ Other studies have also demonstrated eNE to be associated with less fluid infusion and improved outcomes.^25,26 This is because, in critically ill patients, the higher the positive fluid balance, the worse the possible prognosis.^17,27–30 Although there may be several reasons for the lower mortality in patients receiving eNE, the rapid restoration of blood flow in combination with lower fluid accumulation could restore tissue perfusion rapidly and avoid the harm caused by fluid overload.³¹ Our study found that eNE could reduce the time of target MAP need and reduce the 24 h total of all fluid infusion, especially that of 24 h total of non-blood fluid infusion. However, eNE was not beneficial in terms of lowering the risk of pulmonary oedema and congestive heart failure, improving respiratory function, shortening HLOS and reducing the duration of IMV therapy.

Our study also found that eNE did not reduce the incidence of AKI or shorten the duration of CRRT. Domizi et al³² found that high doses or a high frequency of NE could lead to serious complications, such as AKI or arrhythmia. A recent double-blind prospective study found that eNE neither caused AKI or serious cardiovascular events nor increased the duration of renal replacement therapy, although it might be beneficial for early fluid resuscitation in patients with shock.³³ This interpretation was basically consistent with our findings. In addition, we also found that blood lactate levels were significantly reduced with eNE. Bai et al¹⁹ and Hernandez et al³⁴ also found that after HS, blood lactate levels were significantly reduced at each time point of eNE.

Our results showed that higher SOFA and APACHE III scores, initial blood lactate levels, total non-blood fluid infusion and dNE were independent risk factors for 24 h mortality in patients with traumatic HS. This conclusion was basically consistent with those of recent studies.^31,35,36

The highlights of our study are as follows: First, our research was the first to compare the effects of eNE versus dNE on the short-term outcomes of patients with traumatic HS. Second, we applied PSM to minimise selection bias and make the data from the early and delayed groups more comparable. Third, because the proportional hazards assumption of the Cox model did not hold, we used a Streg regression analysis to assess the association between eNE and 24 h survival.

Limitations

Our study has some limitations. First, the sample size of the study population was small, which might have led to selection bias. Second, although this study controlled for confounding factors by using PSM and a regression analysis, there might still be confounders. Finally, this was a retrospective study, although it was based on synthetic and abundant clinical data from high-level research university hospitals.

Conclusions

The use of NE within the first 3 h was associated with higher 24 h survival rates. The use of eNE appears to be a safe intervention that benefits patients with traumatic HS. Considering the conflicting evidence in the literature, there is a need for large-scale randomised controlled trials to investigate and clarify the potential clinical association of eNE use with survival among patients with traumatic HS.