Does the speed of sternal retraction during coronary artery bypass graft surgery affect postoperative pain outcomes? A randomized controlled trial protocol

Background and rationale

Coronary artery bypass surgery and chronic post-sternotomy pain. All patients experience pain following coronary artery bypass graft (CABG) surgery both within the early and intermediate postoperative periods. Severe pain may compromise the patients’ recovery by affecting breathing, mobility, and sleep. Inadequately controlled postoperative pain has been associated with increased cardiovascular complications, pneumonia, hyper-coagulability, delirium and wound infection¹. Of the patients readmitted following CABG, many report recurrent ischemic cardiac chest pain while others suffer from non-cardiac chest pain. Pain is the fifth most common reason for readmission within 4 weeks of CABG². Severe, inadequately controlled postoperative pain may also be a predisposing factor for developing chronic post-sternotomy pain (CPSP)³. Although CPSP is now becoming recognized as a serious health issue with a major impact on quality of life and productivity, this complication has traditionally been overlooked and/or dismissed as an unavoidable consequence of surgery. CPSP is characterized by numbness, severe tenderness on palpation, allodynia (pain response to normally non-painful stimuli), as well as constant pain across the anterior chest wall⁴, and this pain can persist for up to 16 months⁵. Inter-scapular and shoulder girdle pain may also be present.

Estimates of the incidence of CPSP vary widely depending upon the population, the pain measures used and the time-point under consideration. Although the prevalence of CPSP has been reported as high as 52% 6 months following CABG⁶, most report an incidence of approximately 30–40% between 6 and 16 months postoperatively^5–7. Given that almost 500,000 CABG procedures were performed within North America during 2009^8,9, this translates to a significant number of patients adversely affected by CPSP. Despite the major impact of chronic post-surgical pain on quality of life, productivity and associated medical expenses, it is still an area of research that receives relatively little attention¹⁰ and the actual process by which acute postsurgical pain transitions into chronic pain receives even less attention¹¹.

The etiology of CPSP is complex and not well understood. As mentioned previously, the development of CPSP is positively correlated with severe and inadequately controlled acute post-operative pain. However, the fact that not all who experience severe post-operative pain go on to develop CPSP, suggests that other factors such as the genetic variation in the underlying pain mechanisms and/or prior experiences may alter one’s response to painful stimuli both in the short and long term. It has also been suggested that techniques associated with internal mammary artery (IMA) harvesting increase the likelihood of CPSP^12,13 but even patients who do not undergo IMA harvesting may report an equally high incidence of CPSP¹⁴. The high incidence of CPSP associated with cardiac surgery can likely be attributed largely to the extensive nerve and tissue damage¹⁵ from the shear forces applied during rapid sternal retraction. Shear forces are not only applied in the lateral-dorsal-ventral directions but also on the rostral-caudal plane.

To our knowledge, no clinical investigations have examined the sternal retraction maneuver as a causal determinant in the severity of postoperative pain or the subsequent development of CPSP. However, Bolotin et al. (2007)¹⁶ did use anesthetized sheep to demonstrate that controlled retraction forces (and hence increased time) to sternal retraction, resulted in significantly lower maximal and average applied forces. In addition, using controlled force to allow equivalent exposure resulted in significantly reduced alterations in blood pressure and heart rate thought to be indicative of reduced pain and/or stress compared to standard sternal retraction forces. A similar study with lateral open thoracotomies in sheep with standard versus slower retraction, observed significant reductions in applied forces and this was associated with reduced animal stress and tissue damage¹⁷. Several other investigations have explored the use of mini-sternotomies for aortic valve surgery^18–20 with mixed results on pain, length of hospital stay, blood loss and/or pulmonary function. The one study which compared mini vs. standard sternotomy for CABG examined only postoperative pulmonary function and observed no difference²¹.

Acute post-sternotomy pain occurs as a result of tissue and nerve damage (intercostal nerves and thoracic nerves (T2-T6) which innervate the sternum and/or ribs) which provokes direct nociceptive input. However, with the physical trauma, numerous inflammatory mediators (i.e., bradykinin, substance P, histamine, 5-Hydroxytryptamine, adenosine triphosphate, nitric oxide, prostanoids and leukotrines) are released and these induce pain and inflammation at more remote sites²². Furthermore, these inflammatory mediators induce sensitization of both peripheral and central neural pathways. It is the sensitization of central pain-signalling neurons from intense and prolonged nociceptive activity which is thought to result in the transition from acute to chronic pain^22–24. The prolonged sensory input provokes abnormal responses to low-threshold mechanoreceptor activity (allodynia and hyperalgesia) and central nervous system remodelling that contributes to this persistent pain state.

Trial design and setting

This is a prospective, double-blind, randomized controlled superiority trial. It will take place at Kingston General Hospital site, Kingston Health Sciences Centre, Ontario, Canada which is a medium size (~ 470 beds), academic, tertiary care centre.

Eligibility criteria

Inclusion criteria

Exclusion criteria

Coronary artery bypass surgeries for participants in the study will be conducted by cardiac surgeon Dr. Dimitri Petsikas (MD, FRCSC) and colleagues at Kingston Health Sciences Centre.

Ethical approval

The Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board approved this study (ANAE-233-13, May 21, 2013). Written, informed consent for participation will be obtained from all participants²⁵.

Explanation for the choice of comparators

To our knowledge, no clinical investigations have examined the sternal retraction maneuver as a causal determinant in the severity of postoperative pain or the subsequent development of CPSP. However, Bolotin et al. (2007)¹⁶ did use anesthetized sheep to demonstrate that controlled retraction forces (and hence increased time) to sternal retraction, resulted in significantly lower maximal and average applied forces. In addition, using controlled force to allow equivalent exposure resulted in significantly reduced alterations in blood pressure and heart rate thought to be indicative of reduced pain and/or stress compared to standard sternal retraction forces. A similar study with lateral open thoracotomies in sheep with standard versus slower retraction, observed significant reductions in applied forces and this was associated with reduced animal stress and tissue damage¹⁷. Several other investigations have explored the use of mini-sternotomies for aortic valve surgery^18–20 with mixed results on pain, length of hospital stay, blood loss and/or pulmonary function. The one study which compared mini vs. standard sternotomy for CABG examined only postoperative pulmonary function and observed no difference²¹.

Thus, the overall objective of the current investigation is to determine whether increasing the time to achieve sternal retraction to 15 minutes (from the standard ~30 seconds), will result in reduced acute and chronic post-sternotomy pain and an improved quality of life.

Intervention

Anesthesia. Patients will receive general anesthesia with endotracheal intubation, using moderate dose opioid (fentanyl 10–20 mcg/kg or sufentanil 1–2 mcg/kg), inhalational anesthesia (isoflurane or sevoflurane up to 1.5 MAC), propofol, midazolam and succinylcholine and/or rocuronium. Monitoring will include standard Canadian Anesthesia Society (CAS) monitors, an invasive arterial line, a central venous line and a Foley catheter. In preparation for cardiopulmonary bypass, all patients will receive intravenous unfractionated heparin to achieve an activated clotting time (ACT) > 480 seconds. The ACT will be maintained at this level with additional heparin as necessary. Following separation from cardiopulmonary bypass, the heparin effects will be reversed with protamine administration to achieve an ACT within 10% of baseline. On admission to the intensive care unit, patients will remain sedated using a propofol infusion 25–75 mcg/kg/min until extubation; and patients will receive protamine 50 mg/hr for 3 consecutive hours.

Surgery. Participants will then receive one of two surgical conditions:

Standard “normal speed” sternal retraction (approximately 30 seconds)

Slow sternal retraction (approximately 15 minutes)

All cases will be performed via median sternotomy with cardiopulmonary bypass support, using standard aortic and single two-stage right atrial venous cannulation. Intermittent antegrade blood cardioplegia will be utilized. All bypasses will be performed under a single cross-clamp. All patients will have a single 32 French anterior mediastinal drain. A 28 French chest tube will be placed in either or both of the pleural spaces should they be opened at any point during the surgery. All chest drains will be placed to suction at -20 cmH₂O.

Criteria for discontinuing or modifying allocated interventions. At any time, either prior to anaesthetic induction or afterward, should the patient become electrocardiographically or hemodynamically unstable, he/she will be withdrawn from the intervention and the operation will proceed as per standard of care for optimal patient safety. Participants will be withdrawn from the study if there is a change in planned surgical procedure.

Strategies to improve adherence to interventions

Study staff, who otherwise have no involvement in the study in terms of patient enrolment or assessment, will be in the operating room (OR) to facilitate protocol compliance with the intervention and measure the time to achieve sternal retraction.

Provisions for post-trial care

Postoperative care for study participants is standard of care. Additionally, as stated in the informed consent form, if participants become ill or injured as a direct result of participating in this study, necessary medical treatment will be available to them at no cost to them²⁵.

Outcomes

The primary outcome measure will be the incidence of chronic post-sternotomy chest pain at 6 months following CABG with median sternotomy. However, we will also measure the incidence of CPSP at 3 and 12 months to determine the trajectory.

Secondary outcomes (in addition to CPSP at 3 and 12 months) will include: Pain intensity (NRS scale) of sternal incision pain at rest and while coughing daily while in hospital until discharge and then at 1 week postoperatively (via telephone call). Analgesic consumption (morphine equivalents) daily while in hospital until discharge, and then at 1 week post-operatively and 3, 6, and 12 months post-operatively. Intra-operative data will include time from initiation to full retraction, latency from full retraction to sternal closure, width of sternal opening at full retraction. Pain quality (McGill Pain Questionnaire short form (MPQ-SF)), quality of life (SF-36 questionnaire), and pain interference with daily function (Brief Pain Inventory (BPI)) at 3, 6 and 12 months post-operatively. All assessments following discharge from the hospital will be via telephone calls from a research nurse blinded to randomization assignment. In-hospital assessments will also be done by a research nurse blinded to group assignment (Table 1). All data collection forms can be found as extended data²⁵.

Sample size

We consider a 40% reduction in the incidence of CPSP at 6 months to be clinically significant. Since the prevalence of CPSP varies between 14–52% using current surgical methods and pain control strategies, and based on the work of Van Gulik et al. (2011)⁷ which observed a 35% incidence of CPSP at 12 months, we expect to see an incidence of 40% CPSP at 6 months, and expect to observe a 40% reduction (i.e., from 40% to 24%) with SLOW sternal retraction. Under these assumptions, we will require 132 patients per group to achieve 80% power at a two-sided alpha=0.05. We will conservatively increase our sample size to 158 per group to allow for up to 20% loss to follow-up (N=316) given the long duration of the follow-up period (i.e. 6 for the primary outcome and 12 months for secondary outcomes). A total of 10 additional patients will also be randomized to account for participants who may not receive the intervention (i.e., protocol non-compliance) or may be lost post-randomization due to surgical complications.

Recruitment

Patients will be approached in the Pre-Anesthesia clinic by the research nurse prior to their surgery date. Eligible patients will be informed about the study and their eligibility to participate assessed. Informed consent will be obtained for all eligible and interested participants. If potential participants require more time to make a decision or would prefer to talk to others before making a decision, they can also take the forms home and if they do decide to participate, written informed consent will be obtained by research personnel on the day of surgery.

Scoring & description assessment tools

The Brief Pain Inventory-short form (BPI-SF) is a validated and reliable tool for measuring pain intensity and interference with daily activities. Scoring 1–10, where 1–4 = mild pain, 5–6 =moderate pain and 7–10= severe pain. Developed by the Pain Research Group of the WHO Collaborating Centre for Symptom Evaluation in Cancer Care²⁶.

The 36-Item Short Form Health Survey (SF-36) is a validated and well-established tool which measures overall mental & physical health as a measure of Quality of life. Scores range from 0-100 where 0 is the lowest quality of life and 100 is the highest²⁷.

The Short form-McGill pain questionnaire (SF-MPQ) will be used to evaluate the intensity & properties of the pain experience. The main component of the SF-MPQ consists of 15 descriptors (11 sensory; 4 affective) which are rated on an intensity scale as 0 = none, 1 = mild, 2 = moderate or 3 = severe. Three pain scores are derived from the sum of the intensity rank values of the words chosen for sensory, affective and total descriptors. The SF-MPQ also includes the Present Pain Intensity (PPI) index of the standard MPQ and a visual analogue scale (VAS)²⁸.

The Douleur Neuropathique 4 (DN4) is a validated clinician-administered tool used to screen for patients experiencing neuropathic pain. The DN4 consists of 10 items split between 4 questions, where yes = 1, and no = 0. A score of 4 or greater indicates a patient likely experiencing neuropathic pain, with a sensitivity of 83% and a specificity of 90%²⁹.

The Numeric Rating Scale (NRS) for pain is commonly used and validated tool used to measure pain intensity in adults. The NRS for pain uses an 11-point numeric scale (0–10) to represent a patient’s pain, where 0 represents one pain extreme (e.g., “no pain”) and 10 representing the other pain extreme (e.g., “worst pain imaginable”)³⁰.

Plans to promote participant retention and complete follow-up

At the time of enrolment and randomization, participant contact information will be confirmed to ensure successful follow up. Permission to contact alternate contacts, family members, and/or the patients family physician will also be sought at the time of enrolment, to promote follow up if we are unable to contact the patient.

Data management

Data will be entered, verified, and stored in a password protected Excel spreadsheet. The study data will be identified only by a study ID number which will be linked to the patient’s identity only on a master (password-protected) spreadsheet stored separately from the data on a secure server. The de-identified data will be exported to SPSS for analysis purposes.

Confidentiality

A unique study ID number will be assigned to each participant. This study ID will be used on all data collection forms and will be linked with the true identity only on a master sheet which will be kept separate from the data in a locked cabinet. Data will be entered into electronic data spreadsheets and stored securely as described above. Only information directly surrounding the surgical procedure and/or relevant to this investigation will be collected. This will either come directly from the patient or from the medical record. Health information will only be used by the study investigators and will not be linked to any other sources. As stated above the information will be identified only by a study ID number. This data may be used for presentation or publication, but no identifiable information will be used. Only principal investigators or their delegates at KHSC will have access to this information. Delegates will include the research nurses who will collect and compile the data, the KHSC biostatisticians who will complete the majority of the data analysis, a research assistant who will assist with the data cleaning and verification. Data will be stored securely for 25 years as required, following which it will permanently destroyed.

Underlying data

No data are associated with this article.

Extended data

Queen’s University Dataverse: Does the Speed of Sternal Retraction during Coronary Artery Bypass Graft Surgery affect Postoperative Pain Outcomes? A Randomized Controlled Trial Protocol https://doi.org/10.5683/SP2/LQC1JH²⁵

This project contains the following extended data:

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).