We compared outcomes for patients who developed L-PRF to patients who did not develop PRF (No-PRF) and to patients who developed E-PRF. L-PRF was associated with increased morbidity, mortality, hospital and ICU length of stay, and total costs when compared to both No-PRF and E-PRF. While the impact of PRF (e.g., length of stay and cost) have been detailed in two large, multisite studies set in Academic Medical Centers and the Veteran’s Administration,  we have quantified, using newer data, the significantly worse outcomes associated with L-PRF when compared to E-PRF and No-PRF. We also assessed for risk factors associated with L-PRF, when compared to a matched cohort of patients with No-PRF, and identified pre-existing neurologic disease, increased anesthesia duration, and increased maximum peak inspiratory pressure as significant and potentially modifiable risk factors. These findings add to a growing body of critical care and surgical literature examining factors associated with PRF.
Intraoperative Peak Inspiratory Pressure
A key finding from our study is that a higher maximum intraoperative peak inspiratory pressure (PIP) was associated with increased odds of developing L-PRF. It has long been accepted that changes in the respiratory system occur as soon as general anesthesia and MV are initiated[39, 40]; it has more recently been postulated that these changes can last several days to several weeks.[42-45] Less clear is which components of MV are most harmful or protective in existing ARDS as well as in healthy lungs when the intent is to reduce the risk of ventilator induced lung injury.
In a 29-center study of 2,466 moderate and severe ARDS patients, there was substantial center-to-center variability in early adherence to lung protective ventilation (LPV) (0-65%) and mortality (16.7 – 73.3%). Center standardized mortality rates (SMRs), which calculated the ratio between observed and expected mortality, ranged from 0.33 – 1.98 and, of the treatment-level factors explored, only early LPV was associated with lower SMR. The authors concluded that early adherence to LPV was associated with lower center mortality and postulated LPV to be a surrogate for overall quality of care processes. The authors defined LPV as tidal volume <6.5 ml/kg of predicted body weight (PBW) and plateau pressure and/or peak inspiratory pressure (PIP) < 30 cmH2O. In a case-control study of 50,367 surgical hospitalizations, with 93 (0.2%) cases of postoperative ARDS, the authors found higher median PIP in ARDS patients (27 versus 21, p<0.001) and stated their data suggest intraoperative exposure to elevated PIP with a lack of positive end expiratory pressure (PEEP) was associated with the development of postoperative ARDS, possibly due to barotrauma and atelectrauma produced by these ventilator settings. While they recommended further investigation, the authors concluded their findings potentially offered clinicians opportunities to reduce postoperative ARDS. These two studies by Qadir et al. and Blum et al. are relevant to our work as the authors deemed low PIP to be an acceptable surrogate of LPV in the absence of information about plateau pressures, which they found to be measured only 49.6% of the time on day one in the ICU and not collected at all in the intraoperative environment. While we would have liked to evaluate plateau pressures, these data were not documented in the operating suite for adults undergoing elective surgical procedures during the timeframe for our study. Because, in many intraoperative situations, LPV is not always verified with a plateau pressure, we felt our use of PIP was a reasonable surrogate measure of adherence to an LPV approach.
While plateau or driving pressures may best correlate with lung injury, evidence of an association between PIP and hospital mortality from ARDS and acute hypoxic respiratory failure is also provided by the international, multi-site LUNG SAFE study. In 2,377 patients enrolled in LUNG SAFE, potentially modifiable factors associated with increased hospital mortality on multivariable analyses included lower PEEP; higher PIP, plateau pressure, and driving pressure; and increased respiratory rate. In an invited editorial of the LUNG SAFE study, the authors further reinforced the conclusion that PIP was higher in non-survivors. They concluded that PIP is a potential target for improvement of outcomes in ARDS patients.
The Qadir et al. findings of low adherence to LPV in known ARDS patients is interesting considering decades of evidence that LPV improves survival in ARDS, but perhaps makes more sense when we consider the evolution of LPV from an initial focus on lower tidal volume and higher PEEP with or without lung recruitment measures, [50-52] to the addition of lower plateau pressures, to a more recent focus on lower driving pressure (the difference between plateau pressure and PEEP). More recently, literature has emerged on dynamic, rather than static, indicators of energy load (e.g., flow amplitude and the clinician-selected flow waveform),[55-57] Future research to evaluate applicability in the operating suite ventilator management of adult elective surgery patients and possible associations between these modifiable determinants of ventilator induced lung injury (VILI) and PRF may be warranted.
Our finding of an association between increased intraoperative PIP and L-PRF suggests more research is needed to assess the long-term effects of anesthesia and intraoperative LPV on PRF. Specifically, future research to assess possible associations between measures of mechanical power delivered to healthy lungs and development of PRF are needed. Several publications describe the physiologic changes to the respiratory system (e.g., alteration in respiratory muscle function, modification in respiratory mechanics, and reduction in lung volumes, factors which lead to increased atelectasis, decreased functional residual capacity, and decreased vital capacity) that occur upon induction of general anesthesia and initiation of mechanical ventilation[39, 40] and that can persist for several days to several weeks.[42-45]. These physiologic changes, combined with the published theory of cascade iatrogenesis in adverse events, to include postoperative respiratory failure, and the known injurious effects of barotrauma and atelectrauma, further highlight the need for future research to explore the association of intraoperative LPV, to include PIP, and the development of L-PRF
Our findings align with prior studies regarding increased risk of L-PRF with increased duration of anesthesia and surgery. While one study identified risk factors for six common procedures (pancreatectomy, hepatectomy, esophagectomy, abdominal aortic aneurysm repair, open aortoiliac repair, and lung resection) and found the risk factors varied by procedure type, the one risk factor that was consistent across all procedures was prolonged procedure time. Aside from consideration of less aggressive operative approaches and optimization of perioperative supplies, team staffing and expertise, there are limited options available to reduce total surgery and anesthesia duration. While we did not find an association between type of anesthesia and L-PRF, very few patients in our cohort received conscious sedation, also known as monitored anesthesia care. In abdominal aortic aneurysm and aortoiliac repair, an endovascular approach using monitored anesthesia care was associated with lower risk of PPCs (OR 0.48, 95% CI 0.24-0.92).
Pre-existing Neurologic Comorbidities
We also found an association between pre-existing neurologic comorbidities and increased odds of L-PRF. While pre-existing neurologic comorbidities are largely non-modifiable, we believe that—given the mortality, morbidity, and costs associated with PRF—more research is needed to determine if some neurologic disorders might be responsive to preoperative optimization. Examples of potential interventions include protocolized swallow evaluation and swallow training to reduce aspiration risk, incentive spirometry to reduce atelectasis, and exercise programs to improve strength in anticipation of early postoperative mobilization. Some studies on colorectal and cardiac surgery patients have demonstrated positive benefits of multimodal “prehabilitation” to optimize such factors as nutrition, exercise, and smoking cessation.[61-63] Delay of elective procedures to better prehabilitate the patient might also be considered in high-risk neurological patient populations. In addition, a better understanding and awareness of which neurologic diseases are at highest risk would allow providers to target these patients for prevention in the perioperative period.
Our results should be interpreted with some caution. These findings are based on retrospective analysis of a rare event in five academic medical centers within one health system, for the years 2012-2015, a timeframe during which the UC systems were in the process of implementing perioperative bundles such as Enhanced Recovery After Surgery (ERAS) . These interventions might account for the limited variability we saw between groups with some variables of interest, such as mechanical ventilation tidal volume. We were unable to analyze some variables of interest, such as operative plateau pressure and minute-to-minute documentation of all ventilator settings due to missing documentation and limited resources for manual data abstraction. Lung protective lung ventilation involves multiple ventilator parameters, their interaction with the patient’s physiology, and surgical factors (e.g., laparoscopic surgery with pneumoperitoneum, Trendelenburg position, body habitus). The rare nature of PRF also makes analysis complex. While the OR and CIs for preexisting neurologic conditions were both high and wide, respectively, due to the low incidence (n=27 in the L-PRF group and n=12 in the No-PRF group), the ORs and CIs for anesthesia duration and PIP were reasonable and plausible. We were also unable to analyze the effect of preoperative frailty, which has been shown to be associated with significant morbidity and mortality, and other comorbidities of interest due to the incidence of PRF as a rare event. The ability to collect these data is crucial for future studies. These study limitations are similar to those described by Blum et al., in their case-control study of 93 surgical patients who developed postoperative ARDS and Chen et al., in their case-control study of 36 patients who required unplanned reintubation following general anesthesia. Despite the limitations associated with studying rare events, early and novel studies on a topic, such as our study of L-PRF, are often hypothesis generating and serve as a good launching point to design higher powered future studies.
Late PRF is associated with significant morbidity, mortality, and increased hospital and intensive care unit length of stay and healthcare costs, making it of interest to health care clinicians, administrators, and consumers/patients. A strength of our study is our database, which included 414 confirmed cases of PRF, 319 E-PRF and 95 L-PRF, among nearly 60,000 elective surgical admissions over four years from five academic medical centers. We believe our analysis is one of the first to describe the different risk factors and outcomes associated with E-PRF versus L-PRF.
While the importance of studying rare adverse events to better understand modifiable risk factors is paramount to improve patient outcomes, this can only be achieved with increased power. Increasing sample size is the most effective way to improve power but is dependent upon funding for multi-center studies in which each center provides complete data for analysis. Larger, multi-center studies also allow for adjustment for other risk factors, therefore reducing variation and increasing power. Machine learning techniques (e.g., Classification and Regression Tree [CART] and random forest models) can help in identifying risk factors and building strong models. Emerging synthetic health data generation methods may also help accelerate rare event outcomes research. The UC3RC is exploring all of these avenues. We continue to add to our database and work to form collaborative relationships with other leading clinical research institutions to increase sample size and statistical power. We are currently transitioning our data abstraction, curation, and validation methods from manual to automated and mapping the data to standardized taxonomies to better facilitate multi-center collaborations. We also continue to seek additional resources to expand our effort.
While manual data abstraction by trained clinicians has many benefits, it is costly and time-consuming and limits the scope of this type of research. As electronic health records continue to evolve and clinician documentation is increasingly mapped to standardized taxonomies (e.g., SNOMED CT, RxNorm, LOINC), the burden of abstraction will become less prohibitive. While automatic data capture from the electronic health record may prove beneficial for future studies, it must be balanced against burden of validation of the documentation and mapping to the existing standardized taxonomies.