An Anesthesia-Centered Bundle to Reduce Postoperative Pulmonary Complications: The PRIME-AIR Study

Study Overview
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Brief Summary
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Postoperative pulmonary complications (PPCs) are a major cause of morbidity and mortality in surgical patients. National estimates suggest 1,062,000 PPCs per year, with 46,200 deaths, and 4.8 million additional days of hospitalization. The objective of the study is to develop and implement perioperative strategies to eliminate PPCs in abdominal surgery, the field with the largest absolute number of PPCs. We will conduct a randomized controlled pragmatic trial in 750 studied participants. The effectiveness of an individualized perioperative anesthesia-centered bundle will be compared to the usual anesthetic care in patients receiving open abdominal surgery. At the end of this project, the investigators expect to change clinical practice by establishing a new and clinically feasible anesthesia-centered strategy to reduce perioperative lung morbidity. The research will be conducted across 14 US academic centers, and will be funded by the National Institute of Health.

Detailed Description
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Postoperative pulmonary complications (PPCs) are a major cause of morbidity and mortality in surgical patients. National estimates suggest 1,062,000 PPCs per year, with 46,200 deaths, and 4.8 million additional days of hospitalization. Abdominal surgery is the field with the largest absolute number of PPCs. The long-term goal is to develop and implement perioperative strategies to eliminate PPCs. Whereas PPCs are as significant and lethal as cardiac complications, research in the field has received much less attention, and strategies to minimize PPCs are regrettably limited. Recently, the investigators and others have suggested a crucial role of anesthesia related interventions such as ventilatory strategies, and administration and reversal of neuromuscular blocking agents in reducing PPCs. These findings are consistent with the beneficial effects of lung protective ventilation during the adult respiratory distress syndrome (ARDS). While surgical patients differ substantially from ARDS patients as most have no or limited lung injury at the start of surgery, intraoperative anesthetic and abdominal surgery interventions result in lung derecruitment and predispose to or produce direct and indirect, potentially multiple-hit, lung injury. Thus, effective anesthetic strategies aiming at early lung protection in this group of patients are greatly needed. Indeed, the current lack of evidence results in wide and unexplained variability in anesthetic practices creating a major public health issue as some practices within usual care appear to be suboptimal and even potentially injurious. The investigators hypothesize that an anesthesia-centered bundle, based on recent findings and focused on perioperative lung protection, will minimize multiple and synergistic factors responsible for the multiple-hit perioperative pulmonary dysfunction and result in decreased incidence and severity of PPCs. Founded on strong preliminary data, we will leverage a network of US academic centers to study this hypothesis in two aims: Aim 1. To compare the number and severity of PPCs in participants receiving an individualized perioperative anesthesia-centered bundle to those in participants receiving usual anesthetic care during open abdominal surgery. For this, the investigators propose to conduct a prospective multicenter randomized controlled pragmatic trial with a blinded assessor in a total of 750 studied participants. The bundle will consist of optimal mechanical ventilation comprising individualized positive end-expiratory pressure to maximize respiratory system compliance and minimize driving pressures, individualized use of neuromuscular blocking agents and their reversal, and postoperative lung expansion and early mobilization; Aim 2. To assess the effect of the proposed bundle on plasma levels of lung injury biomarkers. The investigators theorize that our intervention will minimize overinflation and atelectasis reducing plasma levels of biomarkers of lung inflammatory, epithelial, and endothelial injury. Such mechanistic insights will facilitate bundle dissemination and support adoption as it has for lung protective ventilation for ARDS. At the end of this project, the investigators expect to change clinical practice by establishing a new and clinically feasible anesthesia-centered strategy to reduce perioperative lung morbidity.

Official Title
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An Anesthesia-Centered Bundle to Reduce Postoperative Pulmonary Complications: The PRIME-AIR Study

Conditions
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Postoperative Pulmonary Complications

Intervention / Treatment
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* Other: Preoperative Education
* Procedure: Intraoperative PEEP (Positive End-Expiratory Pressure) Individualization
* Other: Individualization of Neuromuscular Blockade
* Procedure: Postoperative Incentive Spirometry
* Behavioral: Postoperative Ambulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (>=18 years) scheduled for elective surgery with expected duration >=2 hours Open abdominal surgery including: gastric, biliary, pancreatic, hepatic, major bowel, ovarian, renal tract, bladder, prostatic, radical hysterectomy, and pelvic exenteration Intermediate or high risk of PPCs defined by an ARISCAT (Assess Respiratory Risk in Surgical Patients in Catalonia Score) risk score>=26 Exclusion Criteria: Inability or refusal to provide consent Inability or significant difficulty to perform any study interventions, including incentive spirometry, ambulation and/or maintaining follow-up contact with study personnel for up to 90 days after the date of surgery. Participation in any interventional research study within 30 days of the time of the study. Previous surgery within 30 days prior to this study. Pregnancy Emergency surgery Severe obesity (above Class I, BMI>=35 kg/m2) Significant lung disease: any diagnosed or treated respiratory condition that (a) requires home oxygen therapy or non-invasive ventilation (except nocturnal treatment of sleep apnea without supplemental oxygen), (b) severely limits exercise tolerance to <4 metabolic equivalents (METs) (e.g., patients unable to do light housework, walk flat at 4 miles/h or climb one flight of stairs), (c) required previous lung surgery, or (d) includes presence of severe pulmonary emphysema or bullae Significant heart disease: cardiac conditions that limit exercise tolerance to <4 METs Renal failure: peritoneal or hemodialysis requirement or preoperative creatinine >=2 mg/dL Neuromuscular disease that impairs ability to ventilate without assistance Severe chronic liver disease (Child-Turcotte-Pugh Score >9, Appendix I) Sepsis Malignancy or other irreversible condition for which 6-month mortality is estimated >=20% Bone marrow transplant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Usual Care<br>Participants in this arm will receive usual anesthetic and postoperative care as provided in each site. | |
| Experimental: Intervention<br>This arm will receive the bundle of interventions. | Other: Preoperative Education<br>* Brochure and video about relevance of postoperative pulmonary complications, postoperative mobilization and use of incentive spirometry.<br>Procedure: Intraoperative PEEP (Positive End-Expiratory Pressure) Individualization<br>* PEEP will be set by maximizing respiratory system compliance along a decremental PEEP titration following an incremental recruitment maneuver.<br>Other: Individualization of Neuromuscular Blockade<br>* Administration of neuromuscular blocking agents and their reversal will be done based on established protocol.<br>Procedure: Postoperative Incentive Spirometry<br>* Participants will be encouraged to adhere to incentive spirometry to be started 2 hours after surgery and maintained until participant freely ambulates. Supervision will be provided 3 times/day for continuous education and management of barriers to optimal performance.<br>Behavioral: Postoperative Ambulation<br>* Participants will be encouraged to adhere to prescription of early ambulation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Severity of Postoperative Pulmonary Complications between Participant Groups | The distribution of the number and severity of post-operative pulmonary complications (PPCs) between the control and intervention groups during the first 7 days after surgery. | Postoperative Days 0 through 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-Cause Postoperative Mortality | Mortality for any cause within 7, 30, and 90 days after the day of surgery. | Postoperative Days 0 through 7, 30, and 90 | 
| Grade 3 and 4 Postoperative Pulmonary Complications | Individual grade 3 and 4 postoperative pulmonary complications within 30 and 90 days after the day of the surgery. | Postoperative Days 30 and 90 | 
| Presence of Individual Components of Postoperative Pulmonary Complications in the Primary Endpoint | Presence of each of the individual components of the list of pulmonary complications in the primary endpoint within 7, 30, and 90 days after the day of the surgery. | Postoperative Days 0 through 7, 30, and 90 | 
| Rate of Intraoperative Adverse Events | Rate of intraoperative adverse events (hypoxemia, hypotension during lung recruitment, need for vasoactive medications and volume replacement, muscle weakness. This will be assessed as Train Of Four scores less than 0.9 after extubation, or, in the absence of quantitative assessment, clinical assessments such as inability to generate a tidal volume above 4 mili-Liters per kilogram of predicted body weight, Predicted Body Weight (PBW), at time of extubation or to maintain sustained hand grip or 5-s head lift, presence of diplopia or ventilatory failure after extubation). | Days 0 through 7, 30, and 90 | 
| Rate of Major Extrapulmonary Complications | Rate of extrapulmonary complications defined based on existing diagnosis in the medical chart. | Days 0, 7, 30, and 90 | 
| Length of Stay in Post-Anesthesia Care | Length of stay in post-anesthesia care after the day of surgery until discharge. | Days 0 through 7, 30, and 90 | 
| Length of Postoperative Oxygen Support | Number of time (hours or days) spent in the postoperative oxygen therapy or other respiratory support | Day 0 | 
| Unexpected Readmission to ICU | The incidence of an unexpected admission to the Intensive Care Unit after the day of discharge from the surgery. | After date of discharge to day 90 | 
| Length of ICU stay | The number of days in the Intensive Care Unit, if admitted. | After date of discharge to day 90 | 
| Length of Hospital Stay | Number of days the participant has spent in the hospital since the day of the surgery. | Days 0 through 7, 30, and 90 | 
| Incidence of Other Hospital Readmission(s) After Initial Discharge | The incidence of hospital readmission(s), other than to the Intensive Care Unit, if admitted. | After the date of discharge to day 90 | 
| Difference in Fatigue Participant-Reported Outcomes Measurements Information System (PROMIS) scores | PROMIS is system of individual scales (e.g., Fatigue PROMIS measure, Dyspnea PROMIS measure) to quantify the physical, mental, and social health outcomes of a participant surrounding a particular health issue. The short form for both the Fatigue PROMIS measure will be used for the current study. Items on the Fatigue PROMIS measure are rated on a 5-point Likert-type scale (1-5), where 1 most often means not at all and 5 most often means very much. Some items are reverse-coded. Total T-scores will be used in the analysis of the current study. T-scores are derived from the total raw scale scores (sum of each item on the scale). Lower values represent a better outcome and higher values represent a worse outcome. Fatigue PROMIS T-scores will be compared at 4 time-points. | Baseline (pre-Day 0), Days 7, 30, and 90 | 
| Difference in Dyspnea Participant-Reported Outcomes Measurements Information System (PROMIS) scores | PROMIS is system of individual scales (e.g., Fatigue PROMIS measure, Dyspnea PROMIS measure) to quantify the physical, mental, and social health outcomes of a participant surrounding a particular health issue. The short form for both the Dyspnea PROMIS measure will be used for the current study. Items on the Dyspnea PROMIS measure are rated on a 4-point Likert-type scale (0-3), were 0 means no difficulty and 3 means much difficulty. Each item also allows the participant to enter a missing value (X). Total T-scores will be used in the analysis of the current study. T-scores are derived from the total raw scale scores (sum of each item on the scale). Lower values represent a better outcome and higher values represent a worse outcome. Dyspnea PROMIS T-scores will be compared at 4 time-points. | Baseline (pre-Day 0), Days 7, 30, and 90 |