Breast reduction with Paravertebral block using local anesthetic.

Breast reduction with Sham paravertebral block using saline.

Breast augmentation with Paravertebral block using local anesthetic.

Breast augmentation with Sham paravertebral block using saline.

Breast reduction with Enhanced recovery after breast surgery (ERABS) strategies.

Breast reduction, standard perioperative management.

Breast augmentation with Enhanced recovery after breast surgery (ERABS) strategies.

Breast augmentation, standard perioperative management.

Pain, Acute

Nausea

Vomiting, Postoperative

Opioid Use

Satisfaction

Paravertebral block (PVB) will be performed in the standard fashion using an out-of-plane ultrasound approach by an anesthesiologist with appropriate training in regional anesthesia. Landmarks on the patient will be identified. The skin will be sterilized. The intended target (paravertebral space) will be located using an ultrasound. A Pajunk UniPlex NanoLine needle will be inserted. A syringe filled with sterile saline (used for hydrodissection) connected to a syringe of 0.25% bupivacaine with 2.5 mcg/mL of epinephrine will be connected to the Pajunk needle and used for injection. The needle will be advanced toward and through the superior costotransverse ligament or internal intercostal membrane. Once through the ligament, the pleura will be seen deflecting anteriorly with the hydrodissection. Negative aspiration will be confirmed, and the local anesthetic will be injected into the paravertebral space.

Paravertebral block procedure using either local anesthetic (0.25% bupivacaine) or sterile saline

For comparing ERABS strategies to our current standard of care, we will utilize the following perioperative strategies [Arsalani]:
Standardized written information given preoperatively.
Allow clear liquids for up to 2 hours prior to arrival at the surgery center.
Use paravertebral block to augment postoperative pain control.
Standardized multimodal analgesic regimen
Antiemetics
Easily accessible call-in or walk-in postop care/support
The proposed strategies differ from standard of care in the following ways:
PVB is less commonly used in elective surgery.
Patients do not eat or drink after midnight.
There is no standardized preoperative information packet.
Anesthetic/intraoperative analgesic and antiemetic regimen varies between providers.

Enhanced recovery after breast surgery (ERABS) strategies

Paravertebral block (PVB) will be performed in the standard fashion using an out-of-plane ultrasound approach by an anesthesiologist with appropriate training in regional anesthesia. Landmarks on the patient will be identified. The skin will be sterilized. The intended target (paravertebral space) will be located using an ultrasound. A Pajunk UniPlex NanoLine needle will be inserted. A syringe filled with sterile saline (used for hydrodissection) connected to a syringe of sterile saline will be connected to the Pajunk needle and used for injection. The needle will be advanced toward and through the superior costotransverse ligament or internal intercostal membrane. Once through the ligament, the pleura will be seen deflecting anteriorly with the hydrodissection. Negative aspiration will be confirmed, and the local anesthetic will be injected into the paravertebral space.

Sham paravertebral block using saline

Use of local anesthetic (0.25% bupivacaine) that is *NOT* an experimental drug but will be used as part of the paravertebral block to provide local anesthetic. This will not be given to those in the sham block groups.

Paravertebral block using local anesthetic

University of Wisconsin Madison

Enhanced Recovery Strategies in Elective Breast Surgery

Evaluating the Use of Enhanced Recovery Strategies and Paravertebral Block in Elective Breast Reduction and Breast Augmentation

Our primary outcome of interest is self-reported pain (0-10 visual analog scale) on post-operative day 1 (POD1).

Time between conclusion of surgery and discharge from the surgery center

Quantity and frequency of pain medication usage

Occurrence of nausea and vomiting after surgery

Use of anti-nausea mediation postoperatively

Patients' assessment of quality of recovery using validated 'quality of recovery 40' survey

University of Wisconsin, Madison

There are four serial aims of this study. The overarching goal is to prospectively assess the use of PVB as an adjunct for postoperative pain control both alone and in the setting of related ERABS strategies in elective breast surgery (both breast reduction and breast augmentation, two of the most common non-oncologic breast operations performed in an ambulatory setting). The methodologies used to assess postoperative pain, the set of collective ERABS strategies, the potential risks and benefits of study participation, and the inclusion/exclusion criteria will be the same in the groups studying breast reduction and those studying breast augmentation. As both operations are performed on a regular basis in the PI's practice, we feel it essential to evaluate both operations.

Participants will be blinded as to which treatment arm within their group that they are allocated. The surgery team including the surgeon (PI) and resident will be blinded as well. Anesthesiologists will not be blinded.

Melatonin

Placebo

Total

Sex: Female, Male

Region of Enrollment

Type of surgery

Surgery duration

Anaesthesia duration

Only registered as which oncological treatment (if any at all) the patients received during their participation in the MELODY trial

Oncological treatment

Only registered as which anti-hormone therapy (if any at all) the patients received during their participation in the MELODY trial

Anti-hormone therapy

The MDI is a self-rating scale including 12 questions and has been validated in a Danish population. The MDI assesses information on depressive symptoms that have been present continuously during the previous 2 weeks. The individual items are measured on a 6-point Likert scale, ranging from 0 to 5, with graduations depending on the extent of the symptom the previous 14 days. Accordingly, the theoretical score ranges from 0 to 50.

MDI - Major Depression Inventory

Menopausal status

MDI is a self-rating depression scale with 12 questions. MDI has previously been investigated in a Danish population. On a six-point Likert scale, the items measure how much time the symptoms have been present during the last 14 days. MDI is scored according to specific guidelines and can be used either as a rating scale or diagnostic instrument.
For inclusion we used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements we used the rating scale.
Diagnostic scale using the ICD-10 algorithm:
Mild depression: 2 core symptoms and 2 other symptoms Moderate depression: 2 core symptoms and 4 other symptoms Severe depression: 3 core symptoms and 5 other symptoms
Rating scale:
No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50

Major Depression Inventory (MDI)- Depression at One Point in the Study

MDI is a self-rating depression scale with 12 questions. MDI has previously been investigated in a Danish population. On a six-point Likert scale, the items measure how much time the symptoms have been present during the last 14 days. MDI is scored according to specific guidelines and can be used either as a rating scale or diagnostic instrument.
For inclusion we used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements we used the rating scale.
Rating scale:
No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50 This analysis includes only patients who have taken study medication as planned.

Per Protocol - Depression at One Point in the Study Period

MDI is a self-rating depression scale with 12 questions. MDI has previously been investigated in a Danish population. On a six-point Likert scale, the items measure how much time the symptoms have been present during the last 14 days. MDI is scored according to specific guidelines and can be used either as a rating scale or diagnostic instrument.
For inclusion we used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements we used the rating scale.
Rating scale:
No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50 For this analysis all missing MDI data have been analyzed as "NO" depression.

Intention to Treat (Underestimate) - Depression at One Point in the Study Period

MDI is a self-rating depression scale with 12 questions. MDI has previously been investigated in a Danish population. On a six-point Likert scale, the items measure how much time the symptoms have been present during the last 14 days. MDI is scored according to specific guidelines and can be used either as a rating scale or diagnostic instrument.
For inclusion we used the diagnostic instrument (depression was an exclusion criteria) and for all other MDI measurements we used the rating scale.
Rating scale:
No depression - score from 0-20 Mild depression - score from 21-25 Moderate depression - score from 26-30 Severe depression - score from 31-50 For this analysis all missing MDI data have been analyzed as "YES" for depression.

Intention to Treat (Overestimate) - Depression at One Point in the Study Period

Anxiety measured by VAS (visual analog scale). A subjective feeling of anxiety was registered on a VAS going from "no anxiety", equivalent to 0mm to "worst possible anxiety", equivalent to 100mm.
Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively.
Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %

Area Under the Curve (AUC) for VAS Data on Anxiety - Immediate Postoperative Period

Anxiety measured by VAS (visual analog scale). Completed every 14th day. A subjective feeling of anxiety was registered on a VAS going from "no anxiety", equivalent to 0mm to "worst possible anxiety", equivalent to 100mm.
Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day).
Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %

Area Under the Curve (AUC) for VAS Data on Anxiety - Long-term Postoperative Period

Sleepiness measured by Karolinska Sleepiness Scale. KSS is a 9-point scale from 1 (very awake) to 9 (very sleepy) where a score of 7 or more reflects pathological sleepiness.
Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively.
Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %

Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Immediate Postoperative Period

Sleepiness measured by Karolinska Sleepiness Scale. KSS is a 9-point scale from 1 (very awake) to 9 (very sleepy) where a score of 7 or more reflects pathological sleepiness.
Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day).
Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %

Area Under the Curve (AUC) for Data on Sleepiness (KSS) - Long-term Postoperative Period

Fatigue on a Visual Analog Scale - filled out daily. A subjective feeling of fatigue was registered on a VAS going from "no fatigue", equivalent to 0mm to "worst possible fatigue", equivalent to 100mm.
Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively.
Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %

Area Under the Curve (AUC) for VAS Data on Fatigue - Immediate Postoperative Period

Fatigue on a Visual Analog Scale - filled out every 14th day. A subjective feeling of fatigue was registered on a VAS going from "no fatigue", equivalent to 0mm to "worst possible fatigue", equivalent to 100mm.
Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day).
Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %

Area Under the Curve (AUC) for VAS Data on Fatigue - Long-term Postoperative Period

General well-being on a Visual Analog Scale - filled out daily. A subjective feeling of general well-being was registered on a VAS going from "very high well-being", equivalent to 0mm to "very low well-being", equivalent to 100mm.
Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively.
Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %

Area Under the Curve (AUC) for Data on General Well-being - Immediate Postoperative Period

General well-being on a Visual Analog Scale - filled out every 14th day. A subjective feeling of general well-being was registered on a VAS going from "very high well-being", equivalent to 0mm to "very low well-being", equivalent to 100mm.
Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day).
Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %

Area Under the Curve (AUC) for VAS Data on General Well-being - Long-term Postoperative Period

Pain on a Visual Analog Scale - filled out daily. A subjective feeling of pain was registered on a VAS going from "no pain", equivalent to 0mm to "worst possible pain", equivalent to 100mm.
Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively.
Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %

Area Under the Curve (AUC) for VAS Data on Pain - Immediate Postoperative Period

Pain on a Visual Analog Scale - filled out every 14th day. A subjective feeling of pain was registered on a VAS going from "no pain", equivalent to 0mm to "worst possible pain", equivalent to 100mm.
Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day).
Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %

Area Under the Curve (AUC) for VAS Data on Pain - Long-term Postoperative Period

Subjective sleep score on Visual Analog Scale. Subjective sleep quality was registered on a VAS going from "best possible sleep", equivalent to 0mm to "worst possible sleep", equivalent to 100mm.
Patients were only included in the analysis if they had completed daily VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness for at least 8 days postoperatively.
Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 2 %

Area Under the Curve (AUC) for VAS Data on Sleep Quality - Immediate Postoperative Period

Subjective sleep on a Visual Analog Scale. Subjective sleep quality was registered on a VAS going from "best possible sleep", equivalent to 0mm to "worst possible sleep", equivalent to 100mm.
Patients were only included in the analysis if they had completed VAS on anxiety, sleep quality, general well-being, fatigue, pain and sleepiness in the long-term postoperative period (every 14th day).
Single missing data were filled out using last observation carried forward (LOCF). % of cases filled out by LOCF < 1 %

Area Under the Curve (AUC) for VAS Data on Sleep Quality - Long-term Postoperative Period

Actigraphy (total minutes asleep, sleep effectiveness, sleep latency, awakenings). A wrist actigraph will be worn from inclusion till 14 days postoperatively.

Sleep Architecture

A blood sample will be taken at inclusion and analysed for HPER3 genotype (4/4, 4/5, 5/5) and this will be investigated for a correlation with sleep, cognitive function and depressive symptoms 7 patients did not give blood samples

HPER3 Genotype

Calculations for POCD were based on normative data from 133 females aged 40-60 years. We evaluated changes from the preoperative baseline to the 2 postoperative test sessions. In controls we calculated mean and standard deviations (SD) of these differences. The mean change in this group may be taken as estimated learning effects. For the individual patients, we compared baseline scores with the 2- and 12-week postoperative test results, subtracted the average learning effect from the changes and divided the result by the SD of the control group to obtain a Z score for the 7 individual test outcomes. A large positive Z score indicated deterioration in cognitive function from baseline in patients. We defined a composite Z score as the sum of the 7 Z scores and normalized this using the SD for that sum in the controls. POCD was defined as a combined Z score >1.96 or a Z score >1.96 in at least 2 of the 7 subtests.
Units of measure = % of patients with YES to POCD

Incidence of Postoperative Cognitive Dysfunction (POCD) App. 2 Weeks Postoperatively.

Incidence of Postoperative Cognitive Dysfunction (POCD) App. 10 Weeks Postoperatively

Overall Study

MD Melissa Voigt Hansen

Breast Cancer

Depression

6 mg oral melatonin daily 1 hour before bedtime

Melatonin (N-acetyl-5-methoxytryptamine)

6 mg oral placebo daily 1 hour before bedtime

Herlev Hospital

The Effect of Melatonin on Depression, Anxiety, Cognitive Function and Sleep Disturbances in Breast Cancer Patients

Melissa Voigt Hansen

M.D., ph-D student

University of Copenhagen

Rigshospitalet, Denmark

Pharma Nord

Peri-operative etodolac and propranolol as described in protocol

peri-operative placebo as described in protocol

Primary Operable Breast Cancer

propranolol 10 mg X 4 /day, starting on day -3 pre-op, for 6 days, till POD 2 Etodolac 400 mg X2/day, starting on day -3 pre-op, for 6 days, till POD 2

Propranolol, etodolac

Rabin Medical Center

Sheba Medical Center

Kaplan Medical Center

Perioperative Administration of COX 2 Inhibitors and Beta Blockers to Women Undergoing Breast Cancer Surgery

Perioperative Administration of COX 2 Inhibitors and Beta Blockers in Women Undergoing Breast Cancer Surgery: an Intervention to Decrease Immune Suppression, Metastatic Potential and Cancer Recurrence

anxiolytic/borstkanker

Enhanced Recovery Strategies in Elective Breast Surgery

The Effect of Melatonin on Depression, Anxiety, Cognitive Function and Sleep Disturbances in Breast Cancer Patients

Perioperative Administration of COX 2 Inhibitors and Beta Blockers to Women Undergoing Breast Cancer Surgery

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