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The Association Between Beta-Blockade and Clinical Outcomes in the Context of Surgical and Traumatic Stress
Örebro University, School of Medical Sciences.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic injury and major abdominal surgery are areas in general surgery associated with high rates of morbidity and mortality. The overall colorectal cancer surgery mortality rate is around 4%, with that for emergency surgery more than twice as high as for planned. Surgical morbidity varies between 25% and 45%. Around half of trauma patients develop low mood. In one quarter of patients this becomes permanent. Depression is known to impede physical rehabilitation and recovery. The onset of physiological stress, driven by adrenergic hyperactivity following traumatic and surgical injury is hypothesized to contribute to these adverse outcomes. Interest has therefore been sparked into blocking adrenergic receptor activation.

Papers I and II investigated the role of beta-blocker therapy in preventing post-traumatic depression following severe traumatic brain injury (Paper I) and severe extracranial injury (Paper II). The Karolinska University Hospital Trauma Registry was used to identify patients admitted between 2007 and 2011. In Paper I (n = 545), patients on pre-injury beta-blocker therapy were matched to beta-blocker naïve patients with equivalent injury burden. Results revealed that beta-blocked patients exhibited a 60% reduced risk of needing antidepressant therapy within one year of trauma. In Paper II (n = 596), the lack of beta-blocker use before extracranial trauma was linked to a three-fold increase in the risk of antidepressant initiation.

Papers III-V explored the role of pre-operative beta-blocker therapy in patients undergoing surgery for colorectal cancer between 2007 and 2016, identified using the nationwide Swedish Colorectal Cancer Registry. Paper III (n = 3,187) identified a 69% reduction in the risk of 30-day mortality in beta-blocked patients. Paper IV (n = 22,337) outlined long-term survival benefits for patients on beta-blocker therapy prior to undergoing elective surgery for colon cancer. Beta-blocked patients showed a risk reduction of 42% for 1-year all-cause mortality and 18% for 5-year cancerspecific mortality. Similarly, patients on beta-blocker therapy who underwent surgery for rectal cancer demonstrated improved survival up to one year after surgery with a risk reduction of 57% and a reduction in anastomotic failure and infectious complications in Paper V (n = 11,966).

Place, publisher, year, edition, pages
Örebro: Örebro University , 2019. , p. 96
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 194
Keywords [en]
Beta-blocker therapy, adrenergic hyperactivity, physiological stress, trauma, depression, colorectal cancer, complications, mortality
National Category
Surgery
Identifiers
URN: urn:nbn:se:oru:diva-73256ISBN: 978-91-7529-277-9 (print)OAI: oai:DiVA.org:oru-73256DiVA, id: diva2:1297762
Public defence
2019-06-05, Örebro universitet, Campus USÖ, hörsal C2, Södra Grev Rosengatan 32, Örebro, 10:00 (English)
Opponent
Supervisors
Available from: 2019-03-21 Created: 2019-03-21 Last updated: 2019-08-07Bibliographically approved
List of papers
1. Does early beta-blockade in isolated severe traumatic brain injury reduce the risk of post traumatic depression?
Open this publication in new window or tab >>Does early beta-blockade in isolated severe traumatic brain injury reduce the risk of post traumatic depression?
2017 (English)In: Injury, ISSN 0020-1383, E-ISSN 1879-0267, Vol. 48, no 1, p. 101-105Article in journal (Refereed) Published
Abstract [en]

Introduction: Depressive symptoms occur in approximately half of trauma patients, negatively impacting on functional outcome and quality of life following severe head injury. Pontine noradrenaline has been shown to increase upon trauma and associated beta-adrenergic receptor activation appears to consolidate memory formation of traumatic events. Blocking adrenergic activity reduces physiological stress responses during recall of traumatic memories and impairs memory, implying a potential therapeutic role of beta-blockers. This study examines the effect of pre-admission beta-blockade on post-traumatic depression.

Methods: All adult trauma patients (>= 18 years) with severe, isolated traumatic brain injury (intracranial Abbreviated Injury Scale score (AIS) >= 3 and extracranial AIS <3) were recruited from the trauma registry of an urban university hospital between 2007 and 2011. Exclusion criteria were in-hospital deaths and prescription of antidepressants up to one year prior to admission. Pre- and post-admission beta-blocker and antidepressant therapy data was requested from the national drugs registry. Post-traumatic depression was defined as the prescription of antidepressants within one year of trauma. Patients with and without pre-admission beta-blockers were matched 1: 1 by age, gender, Glasgow Coma Scale, Injury Severity Score and head AIS. Analysis was carried out using McNemar's and Student's t-test for categorical and continuous data, respectively.

Results: A total of 545 patients met the study criteria. Of these, 15% (n = 80) were prescribed beta-blockers. After propensity matching, 80 matched pairs were analyzed. 33% (n = 26) of non beta-blocked patients developed post-traumatic depression, compared to only 18% (n = 14) in the beta-blocked group (p = 0.04). There were no significant differences in ICU (mean days: 5.8 (SD 10.5) vs. 5.6 (SD 7.2), p = 0.85) or hospital length of stay (mean days: 21 (SD 21) vs. 21 (SD 20), p = 0.94) between cohorts.

Conclusion: beta-blockade appears to act prophylactically and significantly reduces the risk of posttraumatic depression in patients suffering from isolated severe traumatic brain injuries. Further prospective randomized studies are warranted to validate this finding.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Traumatic brain injury, Beta-blockade, Depression
National Category
Orthopaedics Surgery
Identifiers
urn:nbn:se:oru:diva-54816 (URN)10.1016/j.injury.2016.10.041 (DOI)000390544600018 ()2-s2.0-85005893752 (Scopus ID)
Available from: 2017-01-19 Created: 2017-01-19 Last updated: 2019-05-15Bibliographically approved
2. Corrigendum to "Does early beta-blockade in isolated severe traumatic brain injury reduce the risk of post traumatic depression?": [Injury 48 (2017) 101–105]
Open this publication in new window or tab >>Corrigendum to "Does early beta-blockade in isolated severe traumatic brain injury reduce the risk of post traumatic depression?": [Injury 48 (2017) 101–105]
2017 (English)In: Injury, ISSN 0020-1383, E-ISSN 1879-0267, Vol. 48, no 11, p. 2612-2612Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Elsevier, 2017
National Category
Orthopaedics Surgery
Identifiers
urn:nbn:se:oru:diva-62779 (URN)10.1016/j.injury.2017.09.017 (DOI)000414228200042 ()28965685 (PubMedID)2-s2.0-85030663249 (Scopus ID)
Available from: 2017-11-24 Created: 2017-11-24 Last updated: 2019-05-13Bibliographically approved
3. Does beta-blockade reduce the risk of depression in patients with isolated severe extracranial injuries?
Open this publication in new window or tab >>Does beta-blockade reduce the risk of depression in patients with isolated severe extracranial injuries?
Show others...
2017 (English)In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 41, no 7, p. 1801-1806Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Approximately half of trauma patients develop post-traumatic depression. It is suggested that beta-blockade impairs trauma memory recollection, reducing depressive symptoms. This study investigates the effect of early beta-blockade on depression following severe traumatic injuries in patients without significant brain injury.

METHODS: Patients were identified by retrospectively reviewing the trauma registry at an urban university hospital between 2007 and 2011. Severe extracranial injuries were defined as extracranial injuries with Abbreviated Injury Scale score ≥3, intracranial Abbreviated Injury Scale score <3 and an Injury Severity Score ≥16. In-hospital deaths and patients prescribed antidepressant therapy ≤1 year prior to admission were excluded. Patients were stratified into groups based on pre-admission beta-blocker status. The primary outcome was post-traumatic depression, defined as receiving antidepressants ≤1 year following trauma.

RESULTS: Five hundred and ninety-six patients met the inclusion criteria with 11.4% prescribed pre-admission beta-blockade. Patients receiving beta-blockers were significantly older (57 ± 18 vs. 42 ± 17 years, p < 0.001) with lower Glasgow Coma Scale score (12 ± 3 vs. 14 ± 2, p < 0.001). The beta-blocked cohort spent significantly longer in hospital (21 ± 20 vs. 15 ± 17 days, p < 0.01) and intensive care (4 ± 7 vs. 3 ± 5 days, p = 0.01). A forward logistic regression model was applied and predicted lack of beta-blockade to be associated with increased risk of depression (OR 2.7, 95% CI 1.1-7.2, p = 0.04). After adjusting for group differences, patients lacking beta-blockers demonstrated an increased risk of depression (AOR 3.3, 95% CI 1.2-8.6, p = 0.02).

CONCLUSIONS: Pre-admission beta-blockade is associated with a significantly reduced risk of depression following severe traumatic injury. Further investigation is needed to determine the beneficial effects of beta-blockade in these instances.

Place, publisher, year, edition, pages
New York: Springer, 2017
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:oru:diva-57385 (URN)10.1007/s00268-017-3935-5 (DOI)000403056400020 ()28265730 (PubMedID)2-s2.0-85014574094 (Scopus ID)
Available from: 2017-05-08 Created: 2017-05-08 Last updated: 2019-05-13Bibliographically approved
4. Effect of beta-blocker therapy on early mortality after emergency colonic cancer surgery
Open this publication in new window or tab >>Effect of beta-blocker therapy on early mortality after emergency colonic cancer surgery
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2019 (English)In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 106, no 4, p. 477-483Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Emergency colorectal cancer surgery is associated with significant mortality. Induced adrenergic hyperactivity is thought to be an important contributor. Downregulating the effects of circulating catecholamines may reduce the risk of adverse outcomes. This study assessed whether regular preoperative beta-blockade reduced mortality after emergency colonic cancer surgery.

METHODS: This cohort study used the prospectively collected Swedish Colorectal Cancer Registry to recruit all adult patients requiring emergency colonic cancer surgery between 2011 and 2016. Patients were subdivided into those receiving regular beta-blocker therapy before surgery and those who were not (control). Demographics and clinical outcomes were compared. Risk factors for 30-day mortality were evaluated using Poisson regression analysis.

RESULTS: A total of 3187 patients were included, of whom 685 (21·5 per cent) used regular beta-blocker therapy before surgery. The overall 30-day mortality rate was significantly reduced in the beta-blocker group compared with controls: 3·1 (95 per cent c.i. 1·9 to 4·7) versus 8·6 (7·6 to 9·8) per cent respectively (P < 0·001). Beta-blocker therapy was the only modifiable protective factor identified in multivariable analysis of 30-day all-cause mortality (incidence rate ratio 0·31, 95 per cent c.i. 0·20 to 0·47; P < 0·001) and was associated with a significant reduction in death of cardiovascular, respiratory, sepsis and multiple organ failure origin.

CONCLUSION: Preoperative beta-blocker therapy may be associated with a reduction in 30-day mortality following emergency colonic cancer surgery.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-69119 (URN)10.1002/bjs.10988 (DOI)000459801800023 ()30259967 (PubMedID)
Available from: 2018-10-01 Created: 2018-10-01 Last updated: 2019-05-13Bibliographically approved
5. The Effects of Beta-Blocker Therapy on Mortality After Elective Colon Cancer Surgery
Open this publication in new window or tab >>The Effects of Beta-Blocker Therapy on Mortality After Elective Colon Cancer Surgery
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Surgery
Identifiers
urn:nbn:se:oru:diva-74247 (URN)
Available from: 2019-05-13 Created: 2019-05-13 Last updated: 2019-05-13Bibliographically approved
6. β-Blockade in Rectal Cancer Surgery: A Simple Measure of Improving Outcomes
Open this publication in new window or tab >>β-Blockade in Rectal Cancer Surgery: A Simple Measure of Improving Outcomes
Show others...
2020 (English)In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140, Vol. 271, no 1, p. 140-146Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To ascertain whether regular β-blocker exposure can improve short- and long-term outcomes after rectal cancer surgery.

BACKGROUND: Surgery for rectal cancer is associated with substantial morbidity and mortality. There is increasing evidence to suggest that there is a survival benefit in patients exposed to β-blockers undergoing non-cardiac surgery. Studies investigating the effects on outcomes in patients subjected to surgery for rectal cancer are lacking.

METHODS: All adult patients undergoing elective abdominal resection for rectal cancer over a 10-year period were recruited from the prospectively collected Swedish Colorectal Cancer Registry. Patients were subdivided according to preoperative β-blocker exposure status. Outcomes of interest were 30-day complications, 30-day cause-specific mortality, and 1-year all-cause mortality. The association between β-blocker use and outcomes were analyzed using Poisson regression model with robust standard errors for 30-day complications and cause-specific mortality. One-year survival was assessed using Cox proportional hazards regression model.

RESULTS: A total of 11,966 patients were included in the current study, of whom 3513 (29.36%) were exposed to regular preoperative β-blockers. A significant decrease in 30-day mortality was detected (incidence rate ratio = 0.06, 95% confidence interval: 0.03-0.13, P < 0.001). Deaths of cardiovascular nature, respiratory origin, sepsis, and multiorgan failure were significantly lower in β-blocker users, as were the incidences in postoperative infection and anastomotic failure. The β-blocker positive group had significantly better survival up to 1 year postoperatively with a risk reduction of 57% (hazard ratio = 0.43, 95% confidence interval: 0.37-0.52, P < 0.001).

CONCLUSIONS: Preoperative β-blocker use is strongly associated with improved survival and morbidity after abdominal resection for rectal cancer.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2020
Keywords
beta-blocker, mortality, rectal cancer, surgery
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-74248 (URN)10.1097/SLA.0000000000002970 (DOI)000525016300026 ()30048321 (PubMedID)2-s2.0-85077036188 (Scopus ID)
Available from: 2019-05-13 Created: 2019-05-13 Last updated: 2020-04-30Bibliographically approved

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