The Acute Respiratory Distress Syndrome (ARDS) remains a considerable contributor to morbidity and mortality after critical injury. Several authors have hypothesized gender as accounting for differences in outcomes following trauma, particularly in animal models5, 6, 8, 10, 22, 23
, but few studies have specifically evaluated the relationship between gender and secondary outcomes such as ARDS. Our objective was to describe the relationship between gender and ARDS, and to relate any observed differences to sex hormone levels. We hypothesized that the pro-inflammatory properties of estrogens would predispose females to developing ARDS.
Gender differences in the prevalence of asthma are well described with females being at a higher risk24
. In a recent analysis of patients hospitalized for an asthma exacerbation in England, women had a higher death rate25
. Female gender has also been identified as a risk factor for hospitalization in COPD patients26
. Our data adds support to the hypothesis that the female lung is more prone to injury and the deleterious effects of inflammation. The effect of female gender on the development of ARDS was independent of the older age and differing injury patterns in these patients. Despite higher rates of ARDS, females with ARDS did not die more frequently than their male counterparts with ARDS.
The fact that females are more prone to ARDS following trauma supports the hypothesis that sex hormones may contribute to the propensity to develop lung injury. Estrogens have diverse and extensive immunologic properties22, 27, 28
, giving plausibility to the fact that the pro-estrous state would be associated with exaggerated inflammation and ARDS. Our data confirms that higher levels of endogenous estrogens are associated with higher rates of ARDS in both genders. However, these differences do not fully explain the difference in ARDS rates by sex since females have a higher incidence of ARDS at all estradiol levels than males.
There is similar biologic plausibility for the association between lower testosterone and higher rates of ARDS since testosterone is generally considered immune depressing. Also, global hypothalamic-pituitary-gonadal axis suppression, and therefore, testosterone depression is related to illness severity. Our data confirms this relationship in both genders. This conflicts with an earlier report by Gee et al29
who correlated high testosterone levels with the development of ARDS. Differences in patient populations may explain this contradiction since only 62 patients were enrolled in the study by Gee, with only 21 of these being mechanically ventilated and only 12 developing ARDS. The strengths of this study lie in its large sample size and the use of a standard case definition for ARDS. We did not rely on administrative coding, but rather systematically reviewed clinical data, including chest radiographs, to more accurately classify patients according to ARDS. Previous studies have reported significantly lower ARDS rates in blunt trauma (4.5%), most likely from relying on retrospective coding rather than actual review of the radiographs and clinical records30
Intriguingly there was no difference in ventilator days between patients who did and did not develop ARDS (approximately 3 days in each group). Although this was not a study pertaining to the management of ARDS and patient management was at the discretion of the treating physician, it is noted that ventilator strategies to minimize barotrauma were consistent among the patients. We believe that strict adherence to a high PEEP, low tidal volume (6mls/kg) ARDS management strategy definitely contributes to limiting the impact of ARDS. Furthermore, there are both direct pulmonary and indirect non-pulmonary causes of acute lung injury and ARDS. Therapies directed to the underlying etiology would shorten the inflammatory burden leading to ARDS.
The lack of a statistical difference in mortality between ARDS and severe ARDS was probably due to the relatively small numbers of patients who developed severe ARDS. There was no difference between the genders with relation to the risk of developing severe ARDS (13% versus 14%), or the associated mortality of severe ARDS (30% versus 37.5%; p=0.9). We postulate that this reflects a gender discrepancy with relation to the inflammatory environment which predisposes to the risk of developing ARDS. However, other factors are clearly involved with relation to the severity of the ARDS once it develops.
Despite these strengths, there are several important limitations. Conclusions regarding sex hormones are based on a single assay at study entry (48 hours after admission). We do not fully understand the relative importance of trends in sex hormones, nor whether absolute values or changes in sex hormones are most important. In this study it is impossible to determine whether or not estrogens specifically cause ARDS, or merely severe as a biomarker for injury or severity of illness. Another limitation is that while patients are cared for according to standard practice management guidelines, we cannot account for differences in fluid resuscitation or ventilator management that may influence rates of ARDS on a per patient level. While practice management guidelines support low tidal volume ventilation strategies and judicious use of fluids, we did not capture detailed information regarding these strategies. Presumably any differences in these strategies would be non-differential with respect to gender and sex hormones. The study was not designed to assess the association between duration of ARDS and gender or hormonal levels. Although others authors employ duration to establish the diagnosis of ARDS, we followed the definition as outlined be Ware et al which neither includes duration nor requires repeat PaO2/FiO2 ratios. Furthermore, once the diagnosis of ARDS was established the data were de-identified. This limited our ability to review medical records to re-assess repeated arterial blood gases, determine the duration of the acute lung injury or ARDS, and thus distinguish relatively short versus prolonged respiratory failure.