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Advanced age is associated with worsened outcomes and a unique genomic response in severely injured patients with hemorrhagic shock.

Vanzant EL, Hilton RE, Lopez CM, Zhang J, Ungaro RF, Gentile LF, Szpila BE, Maier RV, Cuschieri J, Bihorac A, Leeuwenburgh C, Moore FA, Baker HV, Moldawer LL, Brakenridge SC, Efron PA, Inflammation and Host Response to Injury Investigato - Crit Care (2015)

Bottom Line: We found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts.Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities.As the general population's age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Molecular Genetics and Microbiology, University of Florida, PO Box 100245, Gainesville, FL, 32610-0245, USA. erin.vanzant@surgery.ufl.edu.

ABSTRACT

Introduction: We wished to characterize the relationship of advanced age to clinical outcomes and to transcriptomic responses after severe blunt traumatic injury with hemorrhagic shock.

Methods: We performed epidemiological, cytokine, and transcriptomic analyses on a prospective, multi-center cohort of 1,928 severely injured patients.

Results: We found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts. However, aged patients had more comorbidities. Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities. Additionally, advanced age was an independent predictor of a complicated recovery and 28-day mortality. Acutely after trauma, blood neutrophil genome-wide expression analysis revealed an attenuated transcriptomic response as compared to the young; this attenuated response was supported by the patients' plasma cytokine and chemokine concentrations. Later, these patients demonstrated gene expression changes consistent with simultaneous, persistent pro-inflammatory and immunosuppressive states.

Conclusions: We concluded that advanced age is one of the strongest non-injury related risk factors for poor outcomes after severe trauma with hemorrhagic shock and is associated with an altered and unique peripheral leukocyte genomic response. As the general population's age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

No MeSH data available.


Related in: MedlinePlus

Calculated difference from reference (DFR) for 51 of the 63 known genes that distinguish clinical trajectory. Using a false discovery adjusted probability <0.001 and a twofold difference in expression, the temporal pattern of expression of the 51 genes that differed between the matched aged (≥55 years old) and young (<55 years old) trauma patients with complicated outcomes, as well as healthy controls, was analyzed and used to calculate a DFR score. The summary of the DFR scores for the patients in each cohort at days 0.5, 1.0 and 4.0 after traumatic injury is presented. Statistical analysis at 0.5, one and four days revealed significant differences in the DFRs between the young and aged. On days 0.5 and 1.0, the expression patterns in the young complicated trauma patients were significantly more aberrant from control to those seen in the advanced age cohort. By day 4, the expression patterns in the aged were found to be significantly more aberrant from controls than those seen in the young (Newman-Keuls multiple comparison test, *P <0.05).
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Fig2: Calculated difference from reference (DFR) for 51 of the 63 known genes that distinguish clinical trajectory. Using a false discovery adjusted probability <0.001 and a twofold difference in expression, the temporal pattern of expression of the 51 genes that differed between the matched aged (≥55 years old) and young (<55 years old) trauma patients with complicated outcomes, as well as healthy controls, was analyzed and used to calculate a DFR score. The summary of the DFR scores for the patients in each cohort at days 0.5, 1.0 and 4.0 after traumatic injury is presented. Statistical analysis at 0.5, one and four days revealed significant differences in the DFRs between the young and aged. On days 0.5 and 1.0, the expression patterns in the young complicated trauma patients were significantly more aberrant from control to those seen in the advanced age cohort. By day 4, the expression patterns in the aged were found to be significantly more aberrant from controls than those seen in the young (Newman-Keuls multiple comparison test, *P <0.05).

Mentions: Subsequently, secondary analysis was conducted on the 63 total leukocyte genes whose dysregulation is known to predict complicated outcomes after severe trauma [8]. This demonstrated that only 51 of the 63 previously identified genes were significantly expressed in the PMNs of both the young and aged trauma cohorts with complicated outcomes. Therefore, only these 51 genes were used for subsequent comparison. Analysis demonstrated differential expression over time between the aged and young complicated trauma patients. The DFRs of these 51 genes in the aged cohort with complicated courses, revealed that their gene expression patterns were significantly less perturbed at 12 hours and 1 day after injury (DFR (×103): 1.031 ± 0.364 versus 0.776 ± 390 and 1.741 ± 0.705 versus 0. 984 ± 0.506; P <0.05). By day four after injury, the aged patients had significantly increased alterations in their gene expression patterns (DFR (×103): 1.549 ± 0.680 versus 1.024 ± 0.673; P <0.05) when compared to controls and their younger counterparts (Figure 2).Figure 2


Advanced age is associated with worsened outcomes and a unique genomic response in severely injured patients with hemorrhagic shock.

Vanzant EL, Hilton RE, Lopez CM, Zhang J, Ungaro RF, Gentile LF, Szpila BE, Maier RV, Cuschieri J, Bihorac A, Leeuwenburgh C, Moore FA, Baker HV, Moldawer LL, Brakenridge SC, Efron PA, Inflammation and Host Response to Injury Investigato - Crit Care (2015)

Calculated difference from reference (DFR) for 51 of the 63 known genes that distinguish clinical trajectory. Using a false discovery adjusted probability <0.001 and a twofold difference in expression, the temporal pattern of expression of the 51 genes that differed between the matched aged (≥55 years old) and young (<55 years old) trauma patients with complicated outcomes, as well as healthy controls, was analyzed and used to calculate a DFR score. The summary of the DFR scores for the patients in each cohort at days 0.5, 1.0 and 4.0 after traumatic injury is presented. Statistical analysis at 0.5, one and four days revealed significant differences in the DFRs between the young and aged. On days 0.5 and 1.0, the expression patterns in the young complicated trauma patients were significantly more aberrant from control to those seen in the advanced age cohort. By day 4, the expression patterns in the aged were found to be significantly more aberrant from controls than those seen in the young (Newman-Keuls multiple comparison test, *P <0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4404112&req=5

Fig2: Calculated difference from reference (DFR) for 51 of the 63 known genes that distinguish clinical trajectory. Using a false discovery adjusted probability <0.001 and a twofold difference in expression, the temporal pattern of expression of the 51 genes that differed between the matched aged (≥55 years old) and young (<55 years old) trauma patients with complicated outcomes, as well as healthy controls, was analyzed and used to calculate a DFR score. The summary of the DFR scores for the patients in each cohort at days 0.5, 1.0 and 4.0 after traumatic injury is presented. Statistical analysis at 0.5, one and four days revealed significant differences in the DFRs between the young and aged. On days 0.5 and 1.0, the expression patterns in the young complicated trauma patients were significantly more aberrant from control to those seen in the advanced age cohort. By day 4, the expression patterns in the aged were found to be significantly more aberrant from controls than those seen in the young (Newman-Keuls multiple comparison test, *P <0.05).
Mentions: Subsequently, secondary analysis was conducted on the 63 total leukocyte genes whose dysregulation is known to predict complicated outcomes after severe trauma [8]. This demonstrated that only 51 of the 63 previously identified genes were significantly expressed in the PMNs of both the young and aged trauma cohorts with complicated outcomes. Therefore, only these 51 genes were used for subsequent comparison. Analysis demonstrated differential expression over time between the aged and young complicated trauma patients. The DFRs of these 51 genes in the aged cohort with complicated courses, revealed that their gene expression patterns were significantly less perturbed at 12 hours and 1 day after injury (DFR (×103): 1.031 ± 0.364 versus 0.776 ± 390 and 1.741 ± 0.705 versus 0. 984 ± 0.506; P <0.05). By day four after injury, the aged patients had significantly increased alterations in their gene expression patterns (DFR (×103): 1.549 ± 0.680 versus 1.024 ± 0.673; P <0.05) when compared to controls and their younger counterparts (Figure 2).Figure 2

Bottom Line: We found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts.Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities.As the general population's age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Molecular Genetics and Microbiology, University of Florida, PO Box 100245, Gainesville, FL, 32610-0245, USA. erin.vanzant@surgery.ufl.edu.

ABSTRACT

Introduction: We wished to characterize the relationship of advanced age to clinical outcomes and to transcriptomic responses after severe blunt traumatic injury with hemorrhagic shock.

Methods: We performed epidemiological, cytokine, and transcriptomic analyses on a prospective, multi-center cohort of 1,928 severely injured patients.

Results: We found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts. However, aged patients had more comorbidities. Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities. Additionally, advanced age was an independent predictor of a complicated recovery and 28-day mortality. Acutely after trauma, blood neutrophil genome-wide expression analysis revealed an attenuated transcriptomic response as compared to the young; this attenuated response was supported by the patients' plasma cytokine and chemokine concentrations. Later, these patients demonstrated gene expression changes consistent with simultaneous, persistent pro-inflammatory and immunosuppressive states.

Conclusions: We concluded that advanced age is one of the strongest non-injury related risk factors for poor outcomes after severe trauma with hemorrhagic shock and is associated with an altered and unique peripheral leukocyte genomic response. As the general population's age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

No MeSH data available.


Related in: MedlinePlus