Original Contribution

The analysis of risk factors of impacting mortality rate in severe Multiple trauma patients with posttraumatic acute respiratory distress syndrome

Junsong Wu MD^a, Lei Sheng MD^b, Yuefeng Ma MD^a,?, Jun Gu MD^c, Mao Zhang MD^a,

Jianxin Gan MD^a, Shaowen Xu MD^a, Guanyu Jiang MD^a

^atrauma centre of Emergency Department, The Second Affiliated Hospital of Zhejiang University School of Medicine,

Hangzhou, Zhejiang Province 310009, China

^bNursing Faculty of Zhejiang College of Medicine, Hangzhou, Zhejiang Province 310053, China

^cDepartment of Orthopaedics of Red Crossing Hospital, Hangzhou, Zhejiang Province 310003, China

Received 14 March 2007; revised 25 June 2007; accepted 28 June 2007

Abstract

Objective: We hypothesize that not all of the traditional risk factors of impacting mortality rate in commonly traumatic populations with posttraumatic Acute respiratory distress syndrome are independently associated with those patient populations identified with severe multiple trauma. Rather, we postulate that there may exist significantly different impacting degrees of specific risk factors in stratified patients (surviving beyond 24 and 96 hours)–more severe multiple trauma with higher injury score and long-term mechanical ventilation as well.

Methods: This is a retrospective cohort study regarding trauma as a single cause for emergency intensive care unit admission. Twenty-two items of potential risk factors of impacting mortality rate were calculated by univariate and multivariate logistic analyses to find distinctive items in these severe multiple trauma patients.

Results: The unadjusted odds ratio and 95% confidence intervals of mortality rate were found to be associated with 6 (out of 22) risk factors, namely, (1) Acute Physiology and Chronic Health Evaluation II score, (2) duration of trauma factor, (3) aspiration of gastric contents, (4) sepsis, (5) pulmonary contusion, and (6) duration of mechanical ventilation. Significant results also appeared in stratified patients.

Conclusions: Impact of pulmonary contusion and Acute Physiology and Chronic Health Evaluation II score contributing to prediction of mortality may exist in the early phase after trauma. Sepsis is still a vital risk factor referring to systemic inflammatory response syndrome, infection, secondary Multiple organ dysfunction, etc. Discharging trauma factors as early as possible becomes the critical therapeutic measure. Aspiration of gastric contents in emergency intensive care unit admission could lead to incremental mortality rate due to Aspiration pneumonia. Long-standing mechanical ventilation should be constrained because it is likely to cause severe refractory complications.

(C) 2008

* Corresponding author. Tel.: +86 571 87783921.

E-mail address: [email protected] (Y. Ma).

0735-6757/$ – see front matter (C) 2008 doi:10.1016/j.ajem.2007.06.032

Introduction

acute respiratory distress syndrome is nowadays described as respiratory failure symptoms with distinctive pattern of clinical and radiographic findings [1]. Some known risk factors in onset of ARDS include sepsis, aspiration, pneumonia, multiple transfusions, disseminated intravascular coagulation, etc. [2]. Although the reported incidence rate varies widely, studies indicate that trauma is one of the strongest risk factors for the development of ARDS [3-5]. In addition, studies have suggested that there are associations with higher rates of hospital mortality and morbidity and reduced long-term pulmonary function and quality of life among patients with posttraumatic ARDS [6-9].

Because of the rapid development in traffic and building industries, work- and traffic-related injuries rise as well. In contrast to traditional trauma definition (ie, single anatomical site injury), most of these trauma patients with posttraumatic ARDS have severe multiple traumas. Study methods on severe multiple trauma populations may lead to more realistic and vital findings. Although numerous studies have focused on risk factors, especially in mortality in posttraumatic ARDS [10,11], with wide variations secondary to differences in disease definition, patient population, and study design, most of those patient populations in these studies had single trauma; and none of them were absolutely identified as with multiple trauma. Our work on multiple trauma patient populations has demonstrated that character- istic kinds and different degrees of certain risk factors may be responsible for mortality in posttraumatic ARDS.

In our study, 22 traditional risk factors have been selected as measures and listed in Table 1, together with sorting criteria where applicable, and also selected as potential risk factors in our study.

We hypothesized that not all 22 of these could be independently associated with mortality in posttraumatic ARDS in patient populations identified as having severe multiple trauma, as proposed in previous prospective studies [12-22].

Rather, we wanted to sieve distinctive ones from those risk factors that could be specific for multiple trauma patients. We further hypothesized that there may exist significantly different impacting degrees of risk factors in stratified patients (eg, surviving beyond 96 hours, more severe multiple trauma with higher injury score, and long- term mechanical ventilation).

Patients and methods

All patients admitted to the emergency intensive care unit (EICU) of the Second Affiliated Hospital of Zhejiang University in China, a level 1 academic emergency trauma center, and 4 other local hospitals‘ EICUs because of trauma

Variables

Sex Male or female Age >=60 or b60 y Smoking Yes or no Alcohol abuse Yes or no; alcohol abuse was defined as insobriety for more than thrice a week Diabetes Yes or no Duration of trauma >=1 or b1 h, interval from trauma factor occurring to trauma factor discharged; trauma factor was defined as the cause of producing early injury (eg, continuous crush) APACHE II score >=20 or b20 Pulmonary contusion Yes or no, diagnosed by CT scan Nonchest trauma Yes or no; nonchest trauma was defined as several anatomical site injuries instead of chest Traumatic shock >=0.5 or b0.5 h Multiple blood >=10 or b10 U transfusions in 24 h Operation Yes or no Traumatic Yes or no pancreatitis Hepatic inadequacy Yes or no Renal inadequacy Yes or no Gastrointestinal Yes or no hemorrhage Aspiration of gastric Yes or no contents Sepsis Yes or no, sepsis is defined as presence of SIRS with positive cultures Glucocorticoid dose Urbason >=160 or b160 mg/d Duration of >=3 or b3 d glucocorticoid use Duration of >=7 or b7 d mechanical ventilation PEEP parameter >=10 cm H2O or b10 cm H2O

CT indicates computed tomographic; PEEP, positive end-expiratory pressure.

as a single cause between May 2000 and April 2006 were included in the study.

Table 1 The 22 risk factors are listed below together with sorting criteria where applicable

Information on patients’ demographic characteristics, treatment procedures, and injury severity was collected at the time of admission. The criteria used for ARDS diagnosis conformed to the definition of the American-European Consensus Conference [1], which included a partial pressure of arterial oxygen to fraction of inspired oxygen ratio of less than 200, characteristic bilateral infiltrates on chest radio- graphy, and a pulmonary artery occlusion pressure of less than or equal to 18 mm Hg or no clinical evidence of cardiogenic pulmonary edema. In the absence of a pulmonary artery catheter, the diagnosis of exclusion of pulmonary edema was made by the supervising critical care

attending physician. The commonly accepted definition of multiple trauma was consistent with both several injury sites (generated from 2 or more Anatomical sites) and life- threatening injury in at least one anatomical site. Severity of injury was quantified by the simplified Acute physiology and chronic health evaluation II score at

Table 3 Unadjusted ORs of risk factors impacting EICU mortality in multiple trauma patients with posttraumatic ARDS surviving beyond 24 hours of hospital admission

Duration of mechanical ventilation

PEEP parameter

0.709 2.032 1.059-3.900 .033

0.219 1.244 0.638-2.428

.522

Variables	?	OR	95% CI	P
Sex	0.313	1.368	0.704-2.655	.355
Age	-0.948	0.388	0.142-1.062	.065
Smoking	-0.230	0.795	0.419-1.507	.481
Alcohol abuse	0.664	1.942	0.883-4.271	.099
Diabetes	-1.946	0.143	0.039-0.530	.004
Duration of trauma factor	1.133	3.106	1.390-6.940	.006
APACHE II score	0.961	2.056	1.058-3.997	.034
Pulmonary contusion	0.812	2.253	1.137-4.462	.020
Nonchest trauma	-0.254	0.776	0.405-1.485	.443
Traumatic shock	-4.243	0.016	0.004-0.069	.000
Multiple blood	-1.575	0.207	0.085-0.504	.001
transfusions in 24 h
Operation	-0.539	0.583	0.307-1.109	.100
Traumatic pancreatitis	0.779	2.179	0.859-5.527	.101
Hepatic inadequacy	-1.745	0.175	0.087-0.351	.000
Renal inadequacy	-2.646	0.071	0.033-0.154	.000
Gastrointestinal	-4.291	0.014	0.003-0.060	.000
hemorrhage
Aspiration of gastric	0.680	1.973	1.035-3.761	.039
contents
Sepsis	1.341	3.822	1.950-7.493	.000
Glucocorticoid dose	0.013	1.013	0.513-2.002	.971
Duration of	-0.087	0.917	0.467-1.798	.800
glucocorticoid using

24 hours of EICU admission [23]. We included adult patients (age >=18 years) with an EICU length of stay longer than 48 hours and treated with mechanical ventilation for more than 24 hours.

Patients who were readmitted to EICU or transferred to EICU after acute injury beyond 24 hours were excluded. Patients with pretraumatic pathophysiological dysfunction and those meeting the following partial injury causes were also excluded: (1) near-drowning in peritrauma, (2) blast injury complicating poisonous gas inhalation, (3) drug or oxygen intoxication, (4) extracorporeal circulation treatment in hospital stay, (5) cardiovascular diseases or chronic hepatopathy, and (6) uncured pulmonary infection or long- term pulmonary dysfunction.

All patients were treated with standard protocols (eg, antibiotic use according to cultures, glucocorticoid use, and mechanical ventilation). Mortality was assessed at hospital discharge.

Patients, divided into surviving group and nonsurviving group, were statistically compared by using ?2 for categorical variables and Student t test for continuous variables (data normally distributed). The 22 risk factors

were evaluated by univariate logistic analyses, and results with a value of less than .05 were entered into the forward conditional multivariate logistic regression model. Signifi- cance of individual interaction among these terms was determined using likelihood test. However, none of the interaction terms was significant (P b .05); and there was no significant correlation between any of the independent variables. Goodness of fit in regression model was evaluated by Hosmer-Lemeshow test (P b .05). Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistical analyses were performed using SPSS 11.0 for Windows (SPSS, Chicago, IL). Statistical significance was set at P less than .05 (2 tails).

Table 2 Demographic characteristics of multiple trauma patients with posttraumatic ARDS surviving after 24 hours of hospital admission, stratified according to surviving group/ nonsurviving group during EICU stay

Variable	Surviving group	Nonsurviving group	P a
No. of patients	168	212	–
surviving N24 h
Sex (male [%])	124 (74)	136 (64)	N.05
Age (y)	45.10 +- 15.99	41.66 +- 12.03	b.01
Ethnicity (n [%])
Asian	168 (100)	212 (100)	–
Others	–	–
APACHE II score	29 +- 12.96	25 +- 9.58	b.05
Blunt injury (n [%])	124 (74)	100 (47)	b.05
Interval injury to
EICU admission
Hours	1.68 +- 0.57	1.82 +- 0.60	N.05
Range	1-3	1-3
Interval injury to
ARDS
Days	2.44 +- 0.68	2.39 +- 0.76	N.05
Range	1-4	1-4
Continuous variables are presented as mean (SD); categorical variables are presented as frequency (%). a Student t test for continuous variables; Pearson ?2 test for categorical variables.

The study was approved by the institutional review board of Zhejiang University, and need for informed consent was waived.

Results

During the 6-year study period, 546 patients identified with severe multiple trauma were admitted to EICU. However, 106 patients not meeting the criteria described earlier were excluded, leaving 440 patients with ARDS

Variables	?	OR	95% CI	P
APACHE II score	0.909	2.481	1.237-4.976	.010
Duration of trauma	1.391	4.020	1.771-9.124	.001
factor
Pulmonary contusion	-0.829	0.437	0.213-0.893	.023
Aspiration of gastric	0.831	2.295	1.154-4.563	.018
contents
Sepsis	-1.429	0.225	0.110-0.459	.000
Duration of mechanical	0.635	1.887	0.951-3.745	.069
ventilation

Variables	?	OR	95% CI	P
APACHE II score	0.784	2.189	0.879-5.456	.093
Duration of trauma	0.981	2.667	0.869-8.185	.086
factor
Pulmonary contusion	0.559	1.748	0.666-4.588	.257
Aspiration of gastric	0.159	1.196	0.500-2.748	.714
contents
Sepsis	1.002	2.964	1.135-6.535	.025
Duration of mechanical	–	–	–	–
ventilation

available for the analysis. In the cohort of surviving beyond the first 24 hours, 380 patients (86%) were finally included into our study. Demographic characteristics of the patient population are shown in Table 2. No significant difference was noted between the surviving group and the nonsurviving group with respect to race, sex, interval from injury to EICU admission, and interval from injury to ARDS. Compared with the surviving group, the nonsurviving group had a higher APACHE II score, blunt injury rate, and age.

Table 4 Adjusted ORs of risk factors impacting EICU mortality in multiple trauma patients with posttraumatic ARDS surviving beyond 96 hours of hospital admission

Table 6 Adjusted ORs of risk factors impacting EICU mortality in multiple trauma patients with posttraumatic ARDS excluding those patients with duration of mechanical ventilation less than 7 days

Among survivors beyond the first 24 hours of EICU admission, the unadjusted ORs were associated with duration of trauma factor (OR, 3.106), pulmonary contusion (OR, 2.253), aspiration of gastric contents (OR, 1.973), sepsis (OR, 3.822), duration of mechanical ventilation (OR, 2.032), and APACHE II score (OR, 2.056) (Table 3). Based on our previous clinical experience and the results of data collected in this study, and because most of the Severe trauma patients developed ARDS within 96 hours after injury, the model was consequently refitted to exclude patients who died within 96 hours of admission to enhance the comparability. There was incremental mortality associated with duration of trauma factor (OR, 4.020), aspiration of gastric contents (OR, 2.295), and APACHE II score (OR, 2.481) (Table 4). When we eliminated patients who acquired APACHE II score b20, leaving more severe multiple trauma patients (APACHE II score >=20) available for analysis, predicted distinct increase

Table 5 Adjusted ORs of risk factors impacting EICU mortality in multiple trauma patients with posttraumatic ARDS excluding those patients with APACHE II score less than 20

Variables	?	OR	95% CI	P
APACHE II score	–	–	–	–
Duration of trauma factor	1.157	3.182	1.363-7.426	.007
Pulmonary contusion	0.592	1.808	0.904-3.617	.094
Aspiration of gastric	0.580	1.786	0.918-3.475	.088
contents
Sepsis	1.349	3.853	1.914-7.758	.000
Duration of mechanical	0.969	2.636	1.318-5.275	.006
ventilation

of ORs in risk factors was not observed; only mild augmentation of adjusted ORs was manifested in duration of trauma factor (OR, 3.182), sepsis (OR, 3.853), and duration of mechanical ventilation (OR, 2.636). On the contrary, the adjusted OR in aspiration of gastric contents (OR, 1.786; P N .05) declined (Table 5). To confirm the assumption that long-term mechanical ventilation possibly promotes other risk factors to induce higher mortality in multiple trauma, patient population with mechanical ventila- tion >=7 days was brought into further analysis, with significance of adjusted OR only in sepsis (OR, 2.964) as shown in Table 6.

Discussion

To enlarge sieving extent, we included these potential factors that are all associated with mortality or development of ARDS in previous studies and also included clinically important indications that may impact outcomes, for example, glucocorticoid dose, positive end-expiratory pres- sure, and duration of mechanical ventilation. In this retro- spective cohort study, we evaluated the effect of 22 high-risk items impacting mortality within severe multiple trauma populations with posttraumatic ARDS. Our results suggest that for those patients admitted to EICU, increase of the overall mortality is associated with several risk factors out of

22 items, especially including duration of trauma factor, aspiration of gastric contents, sepsis, etc.

Pulmonary contusion resulting in disputing lung par- enchyma with rupture of small airways, alveoli, and capillaries may be the most common cause of development of ARDS in previous studies [24]. However, it was not the main impacting factor in mortality in posttraumatic ARDS in our study because significance was not observed in adjusted ORs of surviving beyond 96 hours of hospital admission, APACHE II score >=20, and duration of mechanical ventilation >=7 days. It is possible that pulmonary contusion only indicates acutely short-term worsening oxygenation due

to direct Crush injury, blood spilling intrabronchially into the normal tissue causing airway obstruction, and bronch- ospasm with airway collapse. Its contribution to mortality gradually attenuates in long-term outcomes (surviving beyond 96 hours of hospital admission and duration of mechanical ventilation >=7 days) because of mechanical respiratory support that maintains adequate oxygenation.

The APACHE II score in several studies is taken as the main assessment index of mortality in trauma populations, and there is also a definite relationship between the severity of the injury and the likelihood of subsequent occurrence of ARDS [18,25]. The same conclusions in mortality were made in survivors beyond 96 hours (OR, 2.481), but not in duration of mechanical ventilation beyond 7 days (OR, 2.189; P = .093). Therefore, similar to pulmonary contusion, the impact of APACHE II score calculated at 24 hours of EICU admission on posttraumatic mortality probably exists in the early phase after severe trauma. Multiple Therapeutic measures, such as immediate damage-control operations to mitigate secondary injury, defensive ventilation strategy to prevent ventilator-associated lung injury, and correctly treating infections, were enforced to relieve severe multiple traumatic injury. Results in Table 5 appear to suggest that unlike other conclusions in past studies [26,27], the single item of APACHE II score may not be the optimal index in assessing mortality within multiple trauma population during the entire EICU treatment period.

Duration of trauma factor determined the degree of injury and outcomes in EICU admission in our past experience, longer duration generally determining higher mortality. In our trial aimed at severe multiple trauma populations, the long-term consequence of duration of trauma factor was indicated in both duration of mechanical ventilation >=7 days (OR, 2.667) and surviving beyond 96 hours of hospital admission (OR, 4.020); the mortality rate markedly rose 3 to 4 times. The results suggest that it is vital to discard trauma factors as early as possible.

The reported rate of mortality from ARDS ranges from 31% to 74% depending on the specific patient mix, with most deaths occurring as a consequence of sepsis and multiple organ failure [28,29]. Findings of our study also indicated that sepsis still was the main risk factor of mortality (in APACHE II score >=20 and duration of mechanical ventilation >=7 days), particularly regarding severe multiple trauma populations. These results were consistent with previous conclusions in unclassified trauma patients as well. Mortality due to sepsis far exceeds all other causes of EICU deaths and equals the number of deaths due to acute myocardial infarction [30]. It appeared that nearly all enrolled multiple trauma patients in EICU had Systemic Inflammatory Response Syndrome by virtue of their severe injury. Sepsis was present when SIRS was accompanied by a known or suspected infection [31]; and secondary organ dysfunction, hypotension, and hypoperfu- sion ensued.

Infection could actually be considered a manifestation of

SIRS as well as the cause of it [32]. Insight into inflammatory

response, endothelial injury, and coagulation cascade corre- lated to sepsis suggests promising new Treatment regimens that markedly decrease mortality and morbidity [30].

Aspiration of gastric contents in EICU is constantly correlated to severe aspiration pneumonia and is also attributable to an increase in mortality in previous literature [33-36]. The same conclusion was demonstrated in severe multiple trauma patients with surviving beyond 24 hours (OR, 1.973) and 96 hours (OR, 2.295). Nevertheless, similar results did not occur in more severe multiple trauma patients with APACHE II score >=20 (P = .088). In contrast, when uniform analysis was manipulated in those patients with mechanical ventilation beyond 7 days expected to acquire more severe complications, the absence of aspiration leading to augmentation of rate of mortality appeared. There may be several reasons to explain this difference. Aspiration of gastric contents resulting in severe complications in EICU was gradually noticed. More attention was then paid to this complication; and necessary immediate actions such as accepted suction treatment, routine semireclining position, and enforcing infection prevention therapy were adminis- tered to critically ill patients.

In regard to mechanical ventilation treatment, those

severe multiple trauma patients (APACHE II score >=20) with ventilation beyond 7 days had a higher risk rate (OR, 2.636). Long-standing mechanical ventilation necessarily led to ventilation-associated complications such as sepsis and barotrauma, ultimately resulting in increased mortality.

This study has several potential limitations. Over a 6-year period, we collected large amounts of data related to severe multiple trauma with posttraumatic ARDS in only 5 centers. Findings may not be generalized to other clinical settings and may be biased by time-related changes in medical strategy, including new lung-protective ventilation therapy, new perceptions in curing sepsis, etc. Although we used the commonly accepted diagnostic criteria for ARDS, these definitions may be less stringent; and moreover, there may be a risk of misclassification [12,28]. Overly exclusive standards may lead to a bias by the exclusion of patients with pretraumatic pathophysiological dysfunction. The decrease in penetrating trauma observed during the investi- gation period was another confounding factor that was not controlled. It is also attributable to an increased mortality in the early phase than blunting trauma. Finally, specific or primary causes of death were not collected in our data; and hence, we could not analyze deaths primarily due to ARDS in relation to other causes.

Conclusions

In summary, we have retrospectively demonstrated the impact of several risk factors on mortality rate of posttrau- matic ARDS in severe multiple trauma patients. In contrast to the traditional trauma definition in single anatomical site

or generally unclassified trauma populations, we conclu- sively noted different outcomes regarding multiple trauma populations in emergency trauma circumstances. Impact of pulmonary contusion and APACHE II score contributing to prediction of mortality may exist in the early phase after trauma. Consistent with previous studies, sepsis is still a vital risk factor with reference to SIRS, infection, secondary multiple organs dysfunction, etc. Duration of trauma factor overly impacting long-term mortality deserves increased attention. Therefore, promptly discharging trauma factors becomes the critical therapeutic measure. Aspiration of gastric contents in EICU leading to incremental mortality rate due to severe aspiration pneumonia should not be ignored. Long-standing mechanical ventilation in severe multiple trauma patients should be constrained to prevent severe refractory complications.

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