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1 Higher Rates of Packed Red Blood Cell and Fresh Frozen Plasma Transfusion are Associated with Increased Death and Complication in Non-Massively Transfused Patients: An Explanation for the Increased Burden of Morbidity and Mortality in Emergency General Surgery Patients The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters. Citation Accessed Citable Link Terms of Use Do, Woo Song Higher Rates of Packed Red Blood Cell and Fresh Frozen Plasma Transfusion are Associated with Increased Death and Complication in Non-Massively Transfused Patients: An Explanation for the Increased Burden of Morbidity and Mortality in Emergency General Surgery Patients. Doctoral dissertation, Harvard Medical School. July 21, :31:51 PM EDT This article was downloaded from Harvard University's DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at (Article begins on next page)

2 ABSTRACT Introduction: Morbidity and mortality (M&M) rates are exceedingly high among emergency general surgery (EGS) patients but the exact scope of the problem is unknown and the underlying cause is unclear. Objective: (1) To define the excess M&M attributable to EGS. (2) To identify modifiable risk factors that contribute to the excess M&M of EGS. Methods: (1) Using the American College of Surgery National Surgical Quality Improvement Program (ACS NSQIP) database, we identified 66,665 patients who underwent one of fourteen procedures common to EGS and NEGS from Demographics and post-operative complications were obtained for this nationally representative sample. The primary outcome was 30-day mortality. Secondary outcomes included post-operative complications. (2) Intra-operative data unavailable in ACS NSQIP were collected by chart review on all patients from two academic medical centers who underwent the same fourteen procedures from (n=1,073). Patients receiving massive transfusion were excluded (n=6). Intra-operative vital signs, packed red blood cell (prbc) use, fresh frozen plasma (FFP) use, and estimated blood loss (EBL) were collected. The primary outcome was 30-day mortality. Secondary outcomes included post-operative complications and blood product use. High FFP use was defined as FFP:pRBC >1:1.5. High prbc use was defined as EBL:pRBC <350. Results: (1) Of 66,665 patients, 36% underwent EGS. Unadjusted complication rate was 48.2% for EGS vs. 27.5% for NEGS (p<0.0001). Unadjusted mortality was 12.5% for EGS vs. 2.7% for NEGS (p<0.0001). After adjusting for pre-operative patient characteristics, EGS was an independent risk factor for death (OR 1.39, p=0.029). (2) Of 1,067 patients, 32% underwent EGS. Unadjusted mortality was 17.5% for EGS vs. 2.1% for NEGS (p<0.0001). EGS patients were more likely than NEGS patients to be exposed to high intra-operative prbc use (OR 4.9, p<0.0001) and high intra-operative FFP use (OR 8.4, 1

3 p<0.0001). After propensity scoring to adjust for differences in pre-operative and intra-operative patient characteristics, those exposed to high prbc use were more likely to experience major post-operative complications (OR 18.1, p<0.0001) and death (OR 4.7, p<0.0001). Those exposed to high FFP use were also more likely to experience major complications (OR 5.0, p<0.0001) and death (OR 2.5, p=0.0141). Conclusion: M&M may be higher in EGS because EGS is an independent risk factor for death. Non-massively transfused EGS patients had greater exposure to intra-operative blood product transfusion for the same blood loss, and this exposure was independently associated with death. This discrepancy in transfusion practices may explain the increased M&M of EGS. 2

4 TABLE OF CONTENTS ABSTRACT... 1 TABLE OF CONTENTS... 3 GLOSSARY AND ABBREVIATIONS... 4 INTRODUCTION Background... 6 Literature Review... 6 State of the Field... 9 Purpose of Inquiry Phase A Phase B METHODS Phase A Phase B RESULTS Phase A Phase B DISCUSSIONS, CONCLUSIONS, AND SUGGESTIONS FOR FUTURE WORK Discussions Conclusions and Suggestions for Future Work SUMMARY REFERENCES TABLES AND FIGURES ACKNOWLEDGEMENTS

5 GLOSSARY Emergency General Surgery (EGS): the field of surgery that cares for any patient (inpatient or emergency department) requiring an emergency surgical evaluation (operative or non-operative) for diseases within the realm of general surgery as defined by the American Board of Surgery. [1] Excess M&M of EGS: the quantity of morbidity and mortality (M&M) that is attributable to EGS. Equivalent to the rates of complication and death in EGS patients compared to non-egs (NEGS) patients who undergo the same operations electively, after controlling for all patient characteristics that predispose EGS patients to an elevated risk of M&M. Massive Transfusion: transfusion of ten or more units of packed red blood cells within a 24-hour period High fresh frozen plasma (FFP) use: transfusion of FFP at a ratio of FFP:pRBC >1:1.5 High packed red blood cell (prbc) use: transfusion of prbcs at a ratio of EBL:pRBC <350 ABBREVIATIONS ACS: American College of Surgeons ACS NSQIP: American College of Surgeons National Surgical Quality Improvement Program CI: Confidence Interval CPT: Current Procedural Terminology EGS: Emergency General Surgery EBL: Estimated Blood Loss 4

6 FFP: Fresh Frozen Plasma ICD-9: International Classification of Diseases, 9th Revision INR: International Normalized Ratio M&M: Morbidity and Mortality NEGS: Non-Emergency General Surgery NSQIP: National Surgical Quality Improvement Program OR: Odds Ratio PRBC: Packed Red Blood Cells 5

7 I. INTRODUCTION Background Morbidity and mortality (M&M) rates are exceedingly high among emergency general surgery (EGS) patients but the exact scope of the problem is unknown and the underlying cause is unclear. What is known is that the patients who undergo EGS represent a unique population of the most at-risk surgical patients. EGS patients can present with a wide range of clinical conditions that warrant any number of operations spanning across the 11 major surgical areas described in Table I-1. EGS patients undergoing these operations are 5-8 times more likely to die than non-emergency general surgery (NEGS) patients receiving the same operations electively.[2 6] In addition to facing an excess risk of death, EGS patients suffer from postoperative complication rates as high as 58%.[6] When the broad scope of EGS is taken into account, over 4 million inpatient admissions in a given year fall into the 95 International Classification of Diseases (ICD-9) diagnosis codes unique to EGS practice.[1] EGS encompasses one of the surgical community s highest risk populations, and yet, the number of projects aimed at reducing M&M in the EGS population remains limited. As the following literature review will reveal, the true burden and causes of these exceedingly high rates of death and complication in EGS are unknown. Without these data, quality improvement measures specific to EGS cannot be implemented, leaving this most vulnerable population at risk of dying at persistently elevated rates. Literature Review Emergency General Surgery Patients Experience High Rates of Morbidity and Mortality Several studies have previously demonstrated exceedingly high M&M rates within the field of EGS, but none have identified modifiable risk factors. First, a 2008 study of 864 6

8 emergency colorectal surgery patients revealed complication rates as high as 53.4% and mortality as high as 16.4%.[7] M&M was non-specifically attributed to the fact that all the operations were performed in emergency settings in which patients conditions would be unfit. Intra-operative risk factors for M&M were not studied. Second, a 2011 study of 819 EGS patients within the ACS NSQIP database at a single academic institution demonstrated a complication rate of 24.7% and a mortality rate of 8.9%.[8] Of note, these M&M rates may have been underestimated because this study excluded patients with a prior operation within 30 days. M&M was attributed to pre-operative patient characteristics (age, male gender, current smoker), pre-operative physiologic derangements (serum glucose, albumin, creatinine), and intra-operative characteristics (duration of surgery). Only a limited number of intra-operative risk factors for M&M were studied. Third, a 2013 retrospective cohort study of 562 EGS patients demonstrated a complication rate of 13.9% and a mortality rate of 3.9%.[9] Of note, these M&M rates may have been uncharacteristically low because a significant number (20%) of cases were described as minor (i.e., varicose vein, minor perianal, scrotal, transurethral resection of prostate, and excision of large subcutaneous lesion). M&M was attributed to pre-operative patient characteristics (age, shock, deteriorated conscious level, COPD, ischemic heart disease) and intra-operative characteristics (CV surgery, blood transfusion, nighttime surgery, and duration of surgery). This study was the first to demonstrate that intra-operative blood transfusion was independently associated with a 5.5 times greater odds of M&M (see Table I-2). Table I-2 summarizes the significant results of the three aforementioned studies. The independent risk factors for M&M identified in these studies (along with their odds ratios) are also provided. These studies shared two key limitations: first, their lack of an NEGS control arm prevented them from demonstrating that EGS patients were at any greater risk of exposure to these independent risk factors for M&M compared to NEGS patients; and second, none of the 7

9 risk factors identified were modifiable, meaning these studies left little opportunity for subsequent quality improvement interventions. Comparing Morbidity and Mortality in Emergency versus Non-Emergency General Surgery The lack of an NEGS control arm was a significant limitation in the previously described studies. Several studies containing both EGS and NEGS arms were also published between 2003 and the present. First, a 2003 study investigating medical errors revealed that surgeons are nine times more likely to leave a foreign object (i.e., sponge, instrument, or needle) in the patient under emergency conditions.[10] Second, a 2007 study of 1,867 EGS patients and 3,388 NEGS patients showed that major complication rates (30.1% vs. 11.5%) and mortality rates (13.8% vs. 2.8%) were significantly greater in EGS vs. NEGS.[2] M&M was attributed to pre-operative factors (patient characteristics, comorbidities, and physiologic derangements) and intra-operative factors (blood loss). The number of intra-operative factors examined was limited. Third, a 2010 study of 5,083 EGS patients and 25,710 NEGS patients showed that complication rates (48.2% vs. 24.0%) and mortality rates (15.4% vs. 1.9%) were significantly greater in EGS vs. NEGS.[3] Fourth, a 2013 study of 298 EGS patients and 4,664 NEGS patients showed that complication rates (57.7% vs. 27.3%) and mortality rates (13.1% vs. 0.6%) were significantly greater in EGS vs. NEGS.[6] As in prior studies, M&M was attributed to pre-operative factors (sepsis, pulmonary comorbidities, age). Unlike prior studies, however, this was the first study to suggest EGS was an independent risk factor for M&M (by an odds ratio of 2.6). This finding was limited to surgery performed in the context of patients with ulcerative colitis. Because this was a retrospective review of only patients with ulcerative colitis, the generalizability of these results to the broader scope of EGS was unclear. In summary, a number of studies consistently found that the complication rate (24.0% to 57.7%, depending on whether the study counted all complications or only major 8

10 complications ) and mortality rate (13.1% to 16.4%) for EGS is exceedingly high. Most studies comparing EGS vs. NEGS have found that mortality rates are greater in EGS by a factor of 4.9 to 8.1. These findings are characterized in Table I-3. State of the Field Explanation for Excess Morbidity and Mortality of Emergency General Surgery is Unknown While it has been previously established that emergency status confers an additional risk of M&M, [6,11,12] the true reason why EGS patients are roughly 5-8 times more likely to die than NEGS patients remains unknown. Recent studies have proposed that a combination of pre-operative patient characteristics (e.g., age, gender, smoking history, dependent functional status, and chronic comorbid conditions like chronic obstructive pulmonary disease and ischemic heart disease), pre-operative physiologic derangements (e.g., shock, impaired sensorium, peritonitis, bradycardia, tachycardia, hyponatremia, hyperglycemia, hypoalbuminemia, and hypercreatinemia), and a limited number of intra-operative characteristics (e.g., nighttime surgery, duration of surgery, blood loss, blood transfusion, cardiovascular surgery, and colorectal surgery) may account for this difference in post-operative outcomes (Tables I-2 and I-3). However, none of the previously identified risk factors are modifiable. In the current state of the field, no quality measures can be instituted that would reduce M&M in the EGS population, leaving this most vulnerable population at risk of dying at persistently elevated rates. We therefore set out to identify modifiable risk factors with the goal of changing the practice of surgery in an evidence-based way to reduce the amount of death and complications in EGS. 9

11 Purpose of Inquiry Phase A: Specific Aim The first specific aim of this study is to quantify the excess M&M associated with EGS. Phase A: Hypothesis EGS is an independent risk factor for death. Phase B: Specific Aim The second specific aim of this study is to identify modifiable differences in intraoperative management between EGS and NEGS patients that are independently associated with excess M&M in EGS patients. Phase B: Hypothesis Differences in intra-operative management, specifically transfusion practices, between EGS and NEGS contribute to the increased M&M of EGS. 10

12 II. METHODS Phase A 1 Study Design To define the excess M&M associated with EGS, we conducted a retrospective cohort study of adult patients (age 18) in the ACS NSQIP database who underwent one of fourteen procedures common to both EGS and NEGS from January 1, 2008 to December 31, These procedures (outlined in Table II-1) were selected based on a summary of clinical conditions encompassing EGS as defined by the American Association for the Surgery of Trauma.[1] Patients were stratified based on emergency status (EGS vs. NEGS). As has been done in prior studies, all ACS NSQIP data on pre-operative patient characteristics and postoperative occurrences, to include death and complications, were obtained for analysis.[3,4] These pre-operative and post-operative variables are listed in Table II-2. Outcome Measures The primary outcome was death within 30 days of the initial operation (30-day mortality). Secondary outcomes included length of stay and the following subtypes of post-operative complications: wound (superficial surgical site infection (SSI), deep SSI, organ/space SSI, wound disruption), central nervous system (stroke or cerebrovascular accident), urinary tract (progressive renal insufficiency, acute renal failure, urinary tract infection), cardiac (myocardial infarction, cardiac arrest requiring cardiopulmonary resuscitation), respiratory (pneumonia, unplanned intubation, ventilator dependence within 48 hours, pulmonary embolism), hematologic (deep vein thrombosis requiring therapy, bleeding requiring transfusion), and septic (sepsis, septic shock). Major complications were defined as any ACS NSQIP post-operative 1 The methods of Phase A have been published: Havens JM, Peetz AB, Do WS, Cooper Z, Kelly E, Askari R, Reznor G, Salim A. The excess morbidity and mortality of emergency general surgery. Journal of Trauma and Acute Care Surgery. Feb 2015;78(2):

13 complication excluding superficial SSI, deep SSI, urinary tract infection, deep venous thrombosis and peripheral nerve injury. Statistical Analysis Patient pre-operative characteristics and outcomes were compared between EGS and NEGS using Chi Square tests for categorical variables and Wilcoxon rank sum tests for continuous variables. In order to use all the observations in our statistical model, we imputed the missing data using previously described methods.[13 15] Multi-colinearity diagnostics were performed on continuous variables such as age, BMI and lab values using variance inflation factor (VIF) with a 2.50 cut off. Interaction between EGS and other variables was assessed by including interaction terms in multivariate regression models. After univariate analysis, all variables with a p-value <0.1 were included in the multivariate analysis, except for lab values which were excluded due large numbers of missing data. To adjust our regression model for the large sample size and toughen the hypothesis testing, we multiplied the standard errors of all the covariables by a factor of three as previously described.[16] Alpha level was set at All the computations were made with SAS 9.3 by SAS Institute Inc., Cary, NC, USA. Phase B Study Design To identify modifiable differences in intra-operative management between EGS and NEGS patients that can explain the excess M&M of EGS, we performed a retrospective cohort study of adult patients (age 18) in the ACS NSQIP database who underwent one of fourteen procedures common to both EGS and NEGS from January 1, 2008 to December 31, 2012 at two academic medical centers (Brigham and Women s Hospital and Massachusetts General Hospital). 12

14 The pre-operative patient characteristics and post-operative complications were obtained from the ACS NSQIP data utilized in Phase A for 1,073 of the 66,665 total patients. The pre-operative variables obtained are listed in Tables III-B-1 and III-B-2. The pre-operative variables of bleeding disorder, prbc transfusion within 72 hours, hematocrit (HCT), partial thromboplastin time (PTT), and international normalized ratio (INR) were specifically selected for their clinical relevance to transfusion. To obtain intra-operative data unavailable in ACS NSQIP, a single evaluator reviewed the intra-operative anesthesia record, the intra-operative nursing record, the surgeon s operative note, and any laboratory tests drawn between incision time and surgery end time for 1,073 patients. The following intra-operative variables were collected: length of operation, start time classification (day vs. night), estimated blood loss (EBL), units of prbcs transfused, units of FFP transfused, volume of crystalloid administered, volume of albumin administered, units of cell-saver used for autologous transfusion, number of vasopressor medications administered, vital signs (lowest mean arterial pressure (MAP), lowest heart rate (HR), and lowest temperature), and laboratory measurements (lowest ph and lowest blood glucose). These intraoperative variables were selected based on their previously demonstrated association with postoperative M&M or their clinical relevance to transfusion.[17 20] For all measurements obtained during chart review, all values were considered true values unless they were incompatible with physiology (e.g., temperature of 0 C) or specific note was mentioned in the record that the value was falsely captured (e.g., probe fell off when HR was recorded as abnormally low). For estimated values such as blood loss that could potentially differ among records, the order of precedence was as follows: (1) the surgical resident s operative note, (2) the attending surgeon s operative note, and (3) the intra-operative anesthesia record. For intra-operative hemodynamics, recordings on an invasive arterial line took precedence over non-invasive blood pressure cuff measurements. For the administration of vasopressors (to include ephedrine, phenylephrine, epinephrine, norepinephrine, vasopressin, 13

15 dopamine, and dobutamine), the anesthesia record was reviewed for all medications administered and the number of different vasopressors used was noted; the distinction of whether each vasopressor was administered in the form of a drip or a bolus was not made. All patients (n=6) who met criteria for massive transfusion were excluded. Massive transfusion was defined as the administration of ten or more units of prbcs within any contiguous 24-hour period around the operation. Outcome Measures The primary outcome was death within 30 days of operation (30-day mortality). Secondary outcomes included intra-operative transfusion practices (i.e., high prbc use and high FFP use). High prbc use was defined as intra-operative transfusion of prbcs at an EBL:pRBC ratio <350. High FFP use was defined as intra-operative transfusion of FFP at an FFP:pRBC ratio >1:1.5. Any patient that received FFP but zero units of prbcs was placed in the high FFP use group. Additional secondary outcomes included major complications and thromboembolic complications. Major complications were defined as organ/space SSI, wound disruption, stroke, cerebrovascular accident, progressive renal insufficiency, acute renal failure, myocardial infarction, cardiac arrest requiring cardiopulmonary resuscitation, pneumonia, unplanned intubation, ventilator dependence within 48 hours, pulmonary embolism, bleeding requiring transfusion, sepsis, and septic shock. Major complications excluded superficial SSI, deep SSI, urinary tract infection, deep venous thrombosis and peripheral nerve injury. Thromboembolic complications were defined as deep venous thrombosis and pulmonary embolism. Statistical Analysis Patient pre-operative characteristics and intra-operative characteristics were compared between EGS and NEGS using Chi Square tests for categorical variables and Wilcoxon rank 14

16 sum tests for continuous variables. In order to use all the observations in our statistical model we imputed the missing data using previously described methods.[13 15] Analysis for the relationship between emergency status (EGS vs. NEGS) and intraoperative management variables (high prbc use and high FFP use) was conducted using propensity scores for high prbc use and high FFP use. The propensity scores reflected the predicted probability of exposure to high prbc use or to high FFP use based on all preoperative and intra-operative variables listed in Tables III-B-1, III-B2, and III-B-3, as has been described in previous methods.[21,22] The correlation of each propensity score with EGS was tested by logistic regression. Analysis for the correlation between the intra-operative management variables (high FFP use and high prbc use) in the entire cohort and post-operative outcomes was conducted using the propensity score for high prbc use and the propensity score for high FFP. The propensity scores reflected the predicted probability of exposure to high prbc use or to high FFP use based on all pre-operative and intra-operative variables listed in Tables III-B-1, III-B2, and III-B- 3, as has been described in previous methods.[21,22] The correlation of each propensity score with outcome was tested by logistic regression. Alpha level was set at All the computations were made with SAS 9.3 by SAS Institute Inc., Cary, NC, USA. 15

17 III. RESULTS Phase A 2 Over the 5-year period from 2008 to 2012, a total of 66,665 patients in the ACS NSQIP database were identified who underwent one of fourteen procedures common to EGS and NEGS. Of these, 36% underwent EGS and 64% underwent NEGS. Tables III-A-1 and III-A-2 illustrate the demographics and pre-operative variable comparisons between EGS and NEGS patients. Patients who underwent EGS were notably older (64 years vs. 59 years, p<0.0001) and had more chronic illness and comorbid conditions (Table III-A-1). EGS patients had higher rates of diabetes mellitus (18.1% vs. 16.8% NEGS, p<0.0001), dyspnea at rest (7.0% vs. 1.4% NEGS, p<0.0001), partially/totally dependent functional status (24.0% vs. 8.4% NEGS, p<0.0001), chronic obstructive pulmonary disease (11.6% vs. 7.9% NEGS, p<0.0001), hypertension requiring medications (57.7% vs. 54.1% NEGS, p<0.0001), open wound (6.3% vs. 5.8%, p<0.0001), and steroid use (10.0% vs. 6.0%, p<0.0001). Additionally, the clinical and physiologic characteristics suggested that the EGS patients were significantly more acutely ill upon admission compared to NEGS patients (Table III-A-2). EGS patients had higher rates of ascites within 30 days (7.4% vs. 1.9% NEGS, p<0.0001) congestive heart failure within 30 days (3.6% vs. 1.1% NEGS, p<0.0001), ventilator dependence within 48 hours (8.0% vs. 0.9% NEGS, p<0.0001), acute renal failure within 24 hours (4.4% vs. 0.6% NEGS, p<0.0001), pneumonia (3.9% vs. 0.8% NEGS, p<0.0001), dialysis within 2 weeks (4.3% vs. 1.3% NEGS, p<0.0001), impaired sensorium (6.6% vs. 0.7% NEGS, p<0.0001), systemic inflammatory response syndrome (22.0% vs. 6.0% NEGS, p<0.0001), septic shock (12.4% vs. 0.8% NEGS, p<0.0001), sepsis within 48 hours (18.4% vs. 3.4% 2 The results of Phase A have been published: Havens JM, Peetz AB, Do WS, Cooper Z, Kelly E, Askari R, Reznor G, Salim A. The excess morbidity and mortality of emergency general surgery. Journal of Trauma and Acute Care Surgery. Feb 2015;78(2):

18 NEGS, p<0.0001), bleeding disorders (15.3% vs. 6.8% NEGS, p<0.0001), prbc transfusion within 72 hours (4.2% vs. 1.5% NEGS, p<0.0001), and American Society of Anesthesia (ASA) class of 4 or 5 to indicate severity of disease ranging from severe systemic disease that is a constant threat to life to not expected to survive without the operation (32.7% vs. 9.0%, p<0.0001). The comparison of mean laboratory values (Table III-A-2) further corroborated the acute physiologic derangements of presenting EGS patients. Of note, EGS patients had lower mean sodium (137.4 vs NEGS, p<0.0001), higher mean creatinine (1.4 vs. 1.0 NEGS, p<0.0001), higher mean white blood cell count (12.8 vs. 8.5 NEGS, p<0.0001), and higher mean INR (1.3 vs. 1.1, p<0.0001). The only pre-operative variables that did not reveal a significant difference were a history of disseminated cancer (4.7% EGS vs. 4.4% NEGS, p=0.0785) and a history of >10% loss of body weight in the past 6 months (4.7% EGS vs. 4.8% NEGS, p=0.5971). Post-operative Outcomes Table III-A-3 demonstrates the unadjusted post-operative outcomes for both EGS and NEGS patients. The complication rates were higher in EGS than in NEGS for every category of complication. The wound complication rate was (vs. 12.4% NEGS, p<0.0001), central nervous system complication rate was 0.8% (vs. 0.3% NEGS, p<0.0001), urinary tract complication rate was 8.4% (vs. 4.8% NEGS, p<0.0001), cardiac complication rate was 4.0% (vs. 1.4% NEGS, p<0.0001), hematologic complication rate was 15.6% (vs. 9.1% NEGS, p<0.0001), and septic complication rate was 16.3% (vs. 7.4% NEGS, p<0.0001). The respiratory complication rate was most pronounced at 25.6% (vs. 8.3% NEGS, p<0.0001). Nearly half (48.2%) of all EGS patients had a post-operative complication (vs. 27.5% NEGS, p<0.0001). 17

19 p<0.0001). Major post-operative complications occurred in 32.8% of EGS (vs. 12.4% NEGS, The mortality rate was 12.5% for EGS vs. 2.7% for NEGS (p<0.0001). Predictors of Mortality and Post-operative Complications Table III-A-4 demonstrates the multivariate logistic regression analysis for the relationship between EGS and negative outcomes. EGS was an independent risk factor for death within 30 days after index operation (OR 1.39, CI , p=0.029). The odds of developing a major post-operative complication were 31% higher in EGS than in NEGS (p=0.001). If all (both major and minor) post-operative complications were considered, the odds were still higher in the EGS group (OR 1.20, CI , p=0.005). When each of the categories of post-operative complications was examined individually, only the respiratory complications subtype was independently associated with EGS (OR 1.46, CI , p<0.0001). The EGS post-operative outcomes model demonstrated good discrimination for death within 30 days (AUROC 0.938, CI ) and major complications (AUROC 0.821, CI ). Phase B Over the 5-year period from 2008 to 2012, a total of 1,067 non-massively transfused patients underwent one of fourteen procedures common to both EGS and NEGS. Of these, 32% underwent EGS and 68% underwent NEGS. Tables III-B-1 and III-B-2 illustrate the demographics and pre-operative variable comparisons between EGS and NEGS patients. Similar to the findings from Phase A, patients who underwent EGS were notably older (64 years vs. 59 years, p<0.0001) and had more chronic illness and comorbid conditions (Table III-B-1). EGS patients had higher rates of diabetes mellitus (15.4% vs. 11.5% NEGS, p<0.0001), partially/totally dependent functional status (32.0% vs. 8.0% NEGS, p<0.0001), chronic 18

20 obstructive pulmonary disease (11.6% vs. 4.1% NEGS, p<0.0001), and steroid use (14.8% vs. 10.0%, p<0.0001). Also similar to the findings from Phase A, there was no significant difference in the history of disseminated cancer or the history of weight loss in EGS vs. NEGS. Unlike the findings from Phase A, a number of other pre-operative variables were not significantly different between EGS and NEGS in this smaller patient sample. This included gender, body mass index, dyspnea at rest, hypertension requiring medication, and smoking history. The clinical and physiologic characteristics suggested that EGS patients were significantly more acutely ill upon admission compared to NEGS patients (Table III-B-2). These differences were significant for every variable related to the clinical indications for transfusion, including bleeding disorder (22.9% EGS vs. 7.5% NEGS, p<0.0001), prbc transfusion within 72 hours (5.6% EGS vs. 1.9% NEGS, p=0.001), pre-operative HCT (35.4 ± 6.7 EGS vs ± 5.7 NEGS, p=0.01) (mean ± standard deviation), pre-operative PTT (32.0 ± 10.9 EGS vs ± 9.0 NEGS, p=0.002), and pre-operative INR (1.3 ± 0.4 EGS vs. 1.1 ± 0.2 NEGS, p<0.0001). Additionally, EGS patients had higher rates of ascites within 30 days (7.4% vs. 2.4% NEGS, p<0.0001), congestive heart failure within 30 days (5.0% vs. 0.4% NEGS, p<0.0001), ventilator dependence within 48 hours (16.0% vs. 1.0 % NEGS, p<0.0001), acute renal failure within 24 hours (6.5% vs. 0.7% NEGS, p<0.0001), pneumonia (8.3% vs. 1.5% NEGS, p<0.0001), dialysis within 2 weeks (4.8% vs. 0.8% NEGS, p<0.0001), impaired sensorium (17.1% vs. 0.6% NEGS, p<0.0001), systemic inflammatory response syndrome (15.2% vs. 4.9% NEGS, p<0.0001), septic shock (25.6% vs. 1.0% NEGS, p<0.0001), sepsis within 48 hours (24.1% vs. 4.7% NEGS, p<0.0001), and American Society of Anesthesia (ASA) class of 4 or 5 to indicate severity of disease ranging from severe systemic disease that is a constant threat to life to not expected to survive without the operation (29.4% vs. 3.0%, p<0.0001). 19

21 Intra-operative Characteristics Table III-B-3 demonstrates the intra-operative characteristics for EGS vs. NEGS. EGS operations were more likely to take place at night (44.5% vs. 5.5% in NEGS, p<0.0001). EGS cases were notably shorter in duration (2 hours 26 minutes ± 1 hour 16 minutes vs. 2 hours 52 minutes ± 1 hour 52 minutes NEGS, p<0.0001) (mean ± standard deviation). However, these data regarding length of operation were greatly skewed by lengthy vascular NEGS cases. When only non-vascular cases were analyzed, there was no significant difference in length of operation in EGS vs. NEGS (2 hours 24 minutes ± 1 hour 14 minutes vs. 2 hours 29 minutes ± 1 hour 34 minutes, p=0.388). Vascular cases comprised 2.1% of EGS vs. 13.2% of NEGS (p<0.0001). Estimated blood loss was not significantly different in EGS vs. NEGS (306 cc ± cc vs. 354 cc ± cc, p=0.213). Although the estimated blood loss was similar between NEGS and EGS, the number of units of prbcs and FFP transfused were significantly greater in EGS. The number of prbc units transfused in EGS vs. NEGS was 0.6 units ± 1.2 units vs. 0.4 units ± 0.9 units (p<0.0001). The number of FFP units transfused in EGS vs. NEGS was 0.6 units ± 1.4 units vs. 0.1 units ± 0.7 units (p<0.0001). High intra-operative prbc use occurred in a total of 108 patients; the rate of high prbc use was 18.7% (63 of 337 patients) for EGS vs. 6.2% (45 of 730 patients) for NEGS (p<0.0001). High intra-operative FFP use occurred in a total of 73 patients; the rate of high FFP use was 15.7% (53 of 337 patients) for EGS vs. 2.7% (20 of 730 patients) for NEGS (p<0.0001). The remainder of the differences in intra-operative characteristics between NEGS and EGS are provided in Table III-B-3. Of the intra-operative vital signs and laboratory markers, statistically significant differences were noted in lowest HR (73.77 ± EGS vs ± NEGS, p<0.0001) (mean ± standard deviation), lowest temperature (35.90 C ± 1.66 C EGS vs C ± 2.15 C NEGS, p<0.0001), lowest ph (7.28 ± 0.12 EGS vs ±

22 NEGS, p<0.0001), and lowest blood glucose ( ± EGS vs ± NEGS, p=0.010). Relationship between EGS and Intra-operative Transfusion Practices Table III-B-4 demonstrates the relationship between EGS and intra-operative transfusion practices. On propensity score analysis, patients who underwent EGS had 4.9 times greater odds of being exposed to high intra-operative prbc use (OR 4.9, CI , p<0.0001). Likewise, patients who underwent EGS had 8.4 times greater odds of being exposed to high intra-operative FFP use (OR 8.4, CI , p<0.0001). Relationship between Intra-operative Transfusion Practices and Outcomes Table III-B-5 demonstrates the relationship between high intra-operative prbc use in the entire cohort and post-operative outcomes. On univariate analysis, patients who were exposed to high intra-operative prbc use had 26.6 times greater odds of experiencing a major complication (OR 26.6, CI , p<0.0001) and 7.6 times greater odds of death (OR 7.6, CI , p<0.0001). After multivariate analysis, patients who were exposed to high intraoperative prbc use had 18.1 times greater odds of experiencing a major complication (OR 18.1, CI , p<0.0001) and 4.7 times greater odds of death (OR 4.7, CI , p<0.0001). High intra-operative prbc use was not independently associated with thromboembolic complications (OR 0.6, CI , p=0.4381). Table III-B-6 demonstrates the relationship between high intra-operative FFP use in the entire cohort and post-operative outcomes. On univariate analysis, patients who were exposed to high intra-operative FFP use had 7.3 times greater odds of experiencing a major complication (OR 7.3, CI , p<0.0001) and 6.2 times greater odds of death (OR 6.2, CI , p<0.0001). After multivariate analysis, patients who were exposed to high intra-operative FFP use had 5.0 times greater odds of experiencing a major complication (OR 5.0, CI , 21

23 p<0.0001) and 2.5 times greater odds of death (OR 2.5, CI , p=0.0141). High intraoperative FFP use was not independently associated with thromboembolic complications (OR 0.4, CI , p=0.3184). 22

24 IV. DISCUSSIONS, CONCLUSIONS, AND SUGGESTIONS FOR FUTURE WORK Discussions In a nationally representative sample containing 66,665 patients undergoing one of fourteen procedures common to both NEGS and EGS, we demonstrated that, after adjusting for the significant differences in NEGS and EGS patients pre-operative risk factors, EGS is independently associated with death and major complications. Emergency surgery itself, after accounting for all the accepted reasons that a patient might have poor surgical outcomes, is still a significant risk factor for death. This finding suggests that something inherent in the process of EGS beyond the patient or the procedure is contributing to the excess M&M of EGS. In a subset of the national sample containing 1,067 non-massively transfused nontrauma patients undergoing the same fourteen procedures at two academic medical centers, we demonstrated that EGS is independently associated with differences in intra-operative blood product transfusion practices, and those intra-operative transfusion practices are independently associated with M&M. Despite similar blood loss in EGS vs. NEGS, EGS patients were three times more likely to be exposed to high intra-operative prbc use and six times more likely to be exposed to high intra-operative FFP use. Those who were exposed to high intra-operative prbc use (regardless of emergency status) had an 18-fold increased risk of major complication and a 5-fold increased risk of death. Those who were exposed to high intra-operative FFP use (regardless of emergency status) had a 5-fold increased risk of major complication and a 2.5- fold increased risk of death. This is the first study to demonstrate that in the non-massively transfused patient, high prbc use and high FFP use are independently associated with death and major complications. This is also the first study to demonstrate that EGS patients are at increased risk of exposure to those intra-operative transfusion practices (i.e., high prbc use and high FFP use), independent of pre-operative risk factors and clinical factors related to transfusion. 23

25 Discussion of Phase A 3 We found that after controlling for all factors previously described to be associated with M&M, EGS patients are still 39% more likely to die and 31% more likely to experience major complications compared to their NEGS counterparts who undergo the same procedures electively. This finding suggests that something intrinsic to the process of EGS beyond the patient or the procedure is contributing to the excess M&M of EGS. While prior studies had shown an association between EGS and negative outcomes, those studies had attributed the M&M of EGS to pre-operative patient characteristics (such as chronic comorbidities like diabetes mellitus, chronic obstructive pulmonary disease, ischemic heart disease, and dependent functional status), pre-operative physiologic derangements (such as impaired sensorium, sepsis, shock, lower sodium measurements, higher blood glucose measurements, higher serum creatinine measurements, and lower serum albumin measurements), and a limited number of intra-operative characteristics, none of which were modifiable risk factors (Table I-2 and I-3). Furthermore, these prior studies had been limited by a host of factors, such as: small sample size;[23] narrow scope of procedures or diseases examined;[6,24] narrow scope of intra-operative factors examined;[6 9,3,4] absence of a control NEGS group;[3,25 27] or comparisons of dissimilar EGS and NEGS operations.[28] By addressing these limitations and by accounting for previously defined reasons EGS patients might be predisposed to a higher M&M than NEGS patients, we have quantified the excess M&M associated with EGS. Our 30-day mortality rate of 12.5%, major complication rate of 32.8%, and complication rate of 48.2% are consistent with established results. Prior studies of the EGS population have demonstrated 30-day mortality rates around 8.9% to 16.4% and complication rates around 24.0% to 53.4% (Table I-2 and I-3). 3 The discussion of Phase A has been published: Havens JM, Peetz AB, Do WS, Cooper Z, Kelly E, Askari R, Reznor G, Salim A. The excess morbidity and mortality of emergency general surgery. Journal of Trauma and Acute Care Surgery. Feb 2015;78(2):

26 Our finding that respiratory complications are associated with EGS also builds upon existing literature. Prior studies have demonstrated that post-operative respiratory complications are common after EGS.[8,26] To our knowledge, however, our analysis is the first to provide evidence of the independent association between EGS and respiratory complications. We defined respiratory complications in a manner that was consistent with ACS NSQIP nomenclature (to include pneumonia, unplanned intubation, ventilator dependence for greater than 48 hours, and pulmonary embolism), but we acknowledge that variations in grouping and defining types of complications exist throughout studies of surgical outcomes. Under our definition, every respiratory complication also counted as a major complication, and it appears that the effect size of the association between EGS and respiratory complications was driving the association between EGS and major complications. When we performed a separate multivariate analysis to determine the association between EGS and major complications excluding respiratory complications, the risk of developing a major complication after EGS became statistically insignificant, suggesting that respiratory complications are a major source of the excess complication burden of EGS. This is consistent with reports that medical complications (which include pneumonia and ventilator dependence) have a far stronger association with negative outcomes after EGS than surgical complications like hemorrhage or wound dehiscence.[26] Taken together with such prior reports, our evidence further reinforces the role of peri-operative respiratory care as a priority for quality measures that may reduce the M&M of EGS in the future. Limitations for Phase A 4 There are several important limitations to Phase A of this study. First, our study is limited to ACS NSQIP participating hospitals. Roughly 525 hospitals in the United States currently 4 The limitations of Phase A have been published: Havens JM, Peetz AB, Do WS, Cooper Z, Kelly E, Askari R, Reznor G, Salim A. The excess morbidity and mortality of emergency general surgery. Journal of Trauma and Acute Care Surgery. Feb 2015;78(2):

27 participate in this quality improvement program, comprising a significant but imperfect representation of the entire nation. Second, our study is limited to only fourteen procedures. In designing this study, we opted to limit the procedures to those that were representative of procedures performed by an Acute Care Surgeon, as well as procedures that were common to both EGS and NEGS. While we believe this constraint improved the rigor of the comparison between EGS and NEGS, this constraint also reduces the generalizability of our results beyond visceral resections, hernia repairs, mesenteric revascularization, and aortic reconstruction. Third, emergency status was determined by the ACS NSQIP definition, which is subject to documentation error. However, reports of inter-rater reliability suggest that the data are of sufficient quality.[29] Fourth, because of the large sample size, small clinically insignificant differences in patient factors and outcomes achieved statistical significance. We addressed this limitation by increasing our standard error rate by a factor of three, a previously described technique to strengthen hypothesis testing.[16] Fifth, as comprehensive as the ACS NSQIP database is, we were not able to comment on the intra-operative conditions or the hospitalspecific factors that may have contributed to negative outcomes, as the database is limited to pre-operative and post-operative variables. Discussion of Phase B We have demonstrated that in the non-massively transfused patient, high prbc use and high FFP use are independently associated with death and major complications. We have further demonstrated that EGS patients are at increased risk of exposure to those intraoperative transfusion practices (i.e., high prbc use and high FFP use), independent of preoperative risk factors and clinical factors related to transfusion. Regarding the first of the key findings (that high prbc use in non-massively transfused patients is independently associated with M&M), recent studies of different NEGS populations have demonstrated similar associations. First, one study of 8,519 patients within ACS NSQIP 26

28 undergoing gynecologic cancer surgery (13.8% of whom required peri-operative blood transfusion) demonstrated that peri-operative blood transfusion is independently associated with increased peri-operative morbidity (OR 1.85), surgical site infection (OR 1.80), and mortality (OR 3.38).[30] This study had no findings concerning FFP transfusion and was limited in generalizability to gynecologic oncology patients. Another key distinction is that this study did not distinguish whether a patient experienced high prbc use or appropriate prbc use but instead focused on whether the patient received any transfusion. A second study of 27,120 colorectal cancer patients (14.1% of whom required blood transfusion) also demonstrated that blood transfusions are associated with increased mortality (OR 1.78), morbidity (OR 2.38), pneumonia (OR 2.70), and surgical-site infection (OR 1.45).[31] This study further expanded upon the state of the field by demonstrating that this effect is dose dependent, meaning patients who receive 3 or more units of blood have increased morbidity (OR 1.53) and pneumonia (OR 2.52). While this dose response was a novel observation, the estimated blood loss was not divided by the units of blood administered to generate a ratio, as was performed in our study. Because of this, a comparison of the patients in this study s high dose group and our study s high prbc use group is imperfect. This study was further revealing in that it showed emergency status was one of the predictive factors in the multivariate logistic regression model, but again, the lack of a EBL:pRBC ratio makes it difficult to draw a conclusion that emergent colorectal surgery patients are exposed to a modifiable difference in transfusion practices when compared to non-emergent patients having similar risk factors for transfusion. This study had no findings concerning FFP transfusion, and was limited in generalizability to colorectal cancer patients. Finally, in the vascular surgery population, a recent study of 2,946 patients (25% of whom required blood transfusion) demonstrated an association between emergency status and blood transfusion (OR 1.40) as well as the association between blood transfusion and death (OR 6.9), myocardial infarction (OR 8.0), and pneumonia (OR 7.4).[32] This study did not make 27

29 the distinction of whether a patient received transfusion at a high ratio or at an appropriate ratio. Furthermore, this study had no findings concerning FFP transfusion, and was limited in generalizability to vascular patients. While these studies of the gynecologic cancer, colorectal cancer, and vascular populations demonstrate an association between blood transfusion and M&M, they do not demonstrate that blood transfusion is a modifiable variable. By contrast, our study was able to demonstrate that blood transfusion practices differ between EGS and NEGS and it is this very difference in transfusion practices that contributes to M&M. Furthermore, our study was able to demonstrate the same finding for FFP transfusion. By defining high prbc use as a ratio of EBL:pRBC and by defining high FFP use as a ratio of FFP:pRBC, we were able to demonstrate that the rates at which EGS patients are transfused at the high (inappropriate) ratio exceed the rates at which NEGS patients are transfused at the same ratio, independent of risk factors that raise the propensity for transfusion. It is this finding that suggests a need for a targeted quality improvement intervention. We found that although the estimated blood loss did not significantly differ between EGS and NEGS, EGS patients received more units of prbcs and FFP. We anticipated that this tendency for EGS patients to be transfused at higher rates despite similar blood loss might be attributable to a number of pre-operative conditions related to clinical indications for transfusion. In fact, we found that EGS patients were more likely to have a history of a bleeding disorder, a history of prbc transfusion within 72 hours of their operation, a lower pre-operative HCT, a higher pre-operative PTT, and a higher pre-operative INR. Each of these variables falls in accord with appropriate reasons a patient might be transfused. For this reason, we had significant concern that these and other pre-operative and intra-operative variables might vary systematically and substantially across the treatment groups so that we could not obtain an unbiased estimate of the effect of high intra-operative prbc transfusion and high intra-operative FFP transfusion on post-operative outcomes; this concern has been described in the literature 28

30 as an appropriate indication for, and an advantage of, propensity score analysis.[21,22] Using propensity scoring to account for all of the differences that might clinically warrant transfusion, we found that EGS patients were still more likely to be exposed to high intra-operative prbc use as well as to high intra-operative FFP use. The propensity scoring technique we utilized allowed us to account for the significant differences between EGS and NEGS populations. As in Phase A, the clinical and physiologic characteristics suggested that EGS patients were significantly more acutely ill upon admission compared to NEGS patients. The intra-operative vital signs we examined showed that EGS patients had a higher lowest HR than NEGS patients. Prior research has shown that intraoperative EBL (which was not significantly different between EGS and NEGS in our study), lowest MAP (which was not significantly different between EGS and NEGS in our study), and lowest HR can be combined to produce a score that predicts risk of death or complication.[17 20] According to this research, if a patient had a lowest HR greater than 85 (with no abnormalities in EBL or MAP), that alone contributed to a relative risk of complication/death of 4.5. Congruent with this prior research, univariate analysis revealed that these intra-operative variables were significantly associated with death. We expand upon this prior research, which was limited to the NEGS population, by demonstrating that EGS patients were more likely to experience a higher lowest HR but not a higher EBL or a lower lowest MAP. Intra-operative analysis also showed that EGS patients had a higher lowest temperature than NEGS patients. While hypothermia has been associated with M&M,[46] sepsis (which was colinear with a high lowest temperature) has also been associated with M&M.[6,9] The EGS patients in our study had significantly high rates of systemic inflammatory response syndrome (15.2% vs. 4.9% NEGS, p<0.0001), septic shock (25.6% vs. 1.0% NEGS, p<0.0001), and sepsis (24.1 vs. 4.7% NEGS, p<0.0001) on presentation. The other intra-operative variables we examined showed that EGS patients had a lowest blood glucose that was more hyperglycemic than NEGS patients, and a lowest ph that was more acidotic than NEGS patients. This is congruent with an 29