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Neuroendocrine Stress Response after Burn Trauma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Some aspects of the stress response during acute intensive care for severe burns are described and quantified by measuring hormonal and neuroendocrine patterns and relating these to organ function in the short term. This includes an assessment of whether there are markers for the severity of stress that are better than conventional descriptors of the severity of a burn in predicting failing organ function.

P-CgA after a major burn injury is an independent and better predictor of organ dysfunction assessed as SOFA score than the traditionally used TBSA% burned. The results also suggest that the extent of neuroendocrine activation is related to organ dysfunction, and this motivates a more extensive effort to evaluate P-CgA as a prognostic marker with respect to mortality and long-term outcome.

P-NT-proBNP exhibited a complex pattern with considerable inter-individual and day-to-day variations. Values of P-NT-proBNP were related to size of burn, water accumulation and systemic inflammatory response. A considerable covariation with trauma response and SOFA scores was observed in day by day analyses, but with weight change only on day 2.

Maximum P-NT-proBNP showed a stronger correlation with SOFA score on day 14, with mortality, and with LOS, than did age and TBSA% burned. High values were also independent predictors of all subsequent SOFA scores up to two weeks after injury.

P-NT-proBNP and NT-proANP reflect and predict organ function after burn injury similarly, notwithstanding a significantly larger intra-individual variability for P-NT-proBNP. P-NT-proBNP, but not NT-proANP, reflects the systemic inflammatory trauma response.

Free cortisol concentration was related to the size of burns, as was the circadian cortisol rhythm. This effect of burn size was, at least in part, related to its effect on organ function.

This thesis points to the fact that the stress response is richly interwoven, and cannot be adequately assessed by one biomarker only. All biomarkers studied here can be viewed as representing efferent limbs of the stress reaction, and they would need to be supplemented by biomarkers representing individual physiologic responses that follow the stress signaling.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 908
Keyword [en]
Burn, Injuries, Neuroendocrine, Intensive Care, Cortisol, Chromogranin A, Natriuretic peptides
National Category
Surgery
Research subject
Plastic Surgery
Identifiers
URN: urn:nbn:se:uu:diva-198466ISBN: 978-91-554-8686-0 (print)OAI: oai:DiVA.org:uu-198466DiVA: diva2:618208
Public defence
2013-06-14, Skoogsalen, Entrance 78-79, Akademiska Sjukhuset, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2013-05-24 Created: 2013-04-15 Last updated: 2013-08-30
List of papers
1. Plasma chromogranin A after severe burn trauma
Open this publication in new window or tab >>Plasma chromogranin A after severe burn trauma
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2013 (English)In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 47, no 3, 207-212 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Chromogranin A (CgA) in plasma (P-CgA), a neuroendocrine marker of sympathetic stress, has been shown to predict mortality in medical intensive care. We hypothesized that the magnitude of CgA release would reflect stress load, and thereby injury severity in burn intensive care patients.

METHODS:

Fifty-one consecutive patients with a burn area exceeding 10% were included. P-CgA was measured twice daily for seven days after injury. The point value at 24h, the mean and maximum values and the AUC at days 1-7, were tested as possible predictors. Injury severity in the form of organ dysfunction was measured as SOFA score at day 7.

RESULTS:

P-CgA could be classified into two types with respect to variability over time. Patients with high variability had more deep injuries and were older than those with low variability. All measures of CgA correlated with SOFA score at day 7, but not with total burn size. Univariate regressions showed that age, burn size and three of four measures of P-CgA predicted organ dysfunction. Multiple regressions showed that age, burn size, and either P-CgA at 24h, the mean value up to day 7, or the maximum value up to day 7, were independent predictors for organ dysfunction. Significant organ dysfunction was best predicted by age, burn area and the CgA point value at 24h with an AUC value of 0.91 in a ROC-analysis.

CONCLUSIONS:

The extent of neuroendocrine activation assessed as P-CgA after a major burn injury is independently related to organ dysfunction.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-188785 (URN)10.1016/j.npep.2012.10.004 (DOI)000320751200010 ()23206950 (PubMedID)
Available from: 2012-12-19 Created: 2012-12-19 Last updated: 2017-12-06Bibliographically approved
2. Natriuretic peptide type B in burn intensive care
Open this publication in new window or tab >>Natriuretic peptide type B in burn intensive care
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2013 (English)In: Journal of Trauma and Acute Care Surgery, ISSN 2163-0755, E-ISSN 2163-0763, Vol. 74, no 3, 855-861 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

The plasma concentration of natriuretic peptide type B (BNP) or NT-proBNP (P-BNP or P-NT-proBNP) reflects cardiac load. In intensive care unit settings and in chronic inflammation, it is also affected by non-heart-related mechanisms. It has been suggested to be a marker of hydration after severe burns and to predict outcome in critically ill patients, but results are contradictory. We therefore measured P-NT-proBNP after severe burns and related it to injury related variables and to organ dysfunction.

METHODS:

Fifty consecutive patients with a burn size greater than 10% were studied for the first 2 weeks. P-NT-proBNP changes were analyzed in relation to burn size, age, changes in body weight, C-reactive protein in plasma, and organ function assessed as Sequential Organ Failure Assessment (SOFA) scores

RESULTS:

P-NT-proBNP showed large day-to-day and between patient variations. Daily change in body weight correlated with P-NT-proBNP only on Day 2, when maximum mobilization of edema occurred. Thereafter, P-NT-proBNP correlated with C-reactive protein in plasma as well as with SOFA scores. Burn size correlated with maximal weight change, which in turn correlated with both time for and value of maximum P-NT-proBNP. Maximal P-NT-proBNP was related to mortality and correlated better with SOFA score on Day 14 compared with age and burn size. In linear regressions, together with age at injury and total body surface area, P-NT-proBNP assessed on Days 3 to 8 was an independent predictor for every subsequent SOFA score measured one or more days later up to Day 14.

CONCLUSION:

P-NT-proBNP exhibited considerable interindividual and day-to-day variations. Values were related to mortality, burn size, water accumulation, posttraumatic response, and organ function. Maximum P-NT-proBNP correlated stronger with length of stay and with organ function on Day 14, compared with age and burn size. High values in Days 3 through 8 were also independent predictors of subsequent organ function up to 2 weeks after injury.

LEVEL OF EVIDENCE:

Epidemiologic/prognostic study, level III.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-197866 (URN)10.1097/TA.0b013e31827e154a (DOI)000316321900030 ()23425748 (PubMedID)
Available from: 2013-04-05 Created: 2013-04-05 Last updated: 2017-12-06Bibliographically approved
3. Concentrations of ANP and BNP convey different types of information in Burn Intensive Care
Open this publication in new window or tab >>Concentrations of ANP and BNP convey different types of information in Burn Intensive Care
(English)Manuscript (preprint) (Other academic)
Abstract [en]

ANP and BNP have been thoroughly investigated in patients with critical illness. A direct comparison of their dynamics in severe burn injuries has so far not been undertaken. Their amino-terminal biologically inactive fragments (NT-proANP and NT-proBNP) in serum (S-) or in plasma (P-) were assessed daily for 14 days in 50 patients treated in Burn Intensive Care. Their mean age was 41.0 years (range 19-60) and their mean burn size was 30.5 % (range 10-95.5).

Both analytes showed a time dependent pattern with an increase followed by a plateau phase. S-NT-proANP exhibited less variability and reached its maximum days later than  P-NT-proBNP. The absolute values and the day-to-day changes for the two NPs correlated only moderately well, suggesting that they are controlled and expressed differently. There was a temporary decrease in the S-NT-proANP/P-NT-proBNP ratio that was most pronounced at days 4 and 5, a considerable inter- and intra-individual variability, and substantial day-to-day fluctuations.  P-CRP was a better predictor for P-NT-proBNP than for S-NT-proANP. Both NPs were predicted by Cardiovascular, Respiratory and Renal SOFA scores, although with some differences.

In conclusion, S-NT-proANP and P-NT-proBNP reflect severity of illness similarly in terms of Cardiovascular, Respiratory and Renal SOFA scores, notwithstanding a significantly larger intra-individual variability for P-NT-proBNP. An important difference between the two analytes is that P-NT-proBNP also reflects the systemic trauma response per se.

National Category
Medical and Health Sciences
Research subject
Plastic Surgery
Identifiers
urn:nbn:se:uu:diva-198460 (URN)
Available from: 2013-04-26 Created: 2013-04-15 Last updated: 2013-08-30
4. Circadian Cortisol Rhythm after Burn Injury
Open this publication in new window or tab >>Circadian Cortisol Rhythm after Burn Injury
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: The stress response to critical illness includes activation of the hypothalamic-pituitary-adrenal (HPA) axis, and increased release of cortisol and diminished or lost physiological diurnal variation. Details of this response were analyzed in consecutive burn patients.

Methods: Forty-nine patients, 15 women and 34 men, median age 41(range 19-60), median burn size 31 % (range 10-96)n and treated at Uppsala Burn Center were investigated during their first week after injury. Clinical parameters were registered daily, serum cortisol concentrations were analyzed four times daily for seven days, and the daily diurnal slope starting from the daily maximum was calculated. Relevant confounding variables were identified by means of a directed acyclic graph (DAG).

Results: The circadian zenith for free cortisol frequently occurred at noon rather that in early morning, it was not related to burn size, ventilator care, or surgery, but was weakly related to the SOFA score. Multilevel modeling revealed that burn size explained cortisol slope. After adjustments for covariates, including the SOFA score, the only significant covariate was the SOFA score itself. Ventilator care explained cortisol slope, but surgery the preceding day did not. Differences between large and small burns were only noticed for the free cortisol concentration at 6pm, suggesting that the flattening of the slope was primarily due to a slower decline in free cortisol from morning to evening.  When adjusting for all covariates, slope at 6pm was explained by burn size and P-CgA as well as SOFA score. Both burn size and SOFA score explained the daily coefficient of variability (CV) in free cortisol concentration. Similarly, burn size, P-CgA and SOFA explained AUC.

Conclusions: Free cortisol concentration was related to the size of burns, as was the circadian cortisol rhythm. This effect of burn size was related at least in part to its effect on organ function.

National Category
Medical and Health Sciences Surgery
Research subject
Plastic Surgery
Identifiers
urn:nbn:se:uu:diva-198463 (URN)
Available from: 2013-04-26 Created: 2013-04-15 Last updated: 2017-01-25

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