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Mayo Clin Proc Innov Qual Outcomes
Mayo Clin Proc Innov Qual Outcomes
Mayo Clinic Proceedings: Innovations, Quality & Outcomes
2542-4548
Elsevier

S2542-4548(24)00043-2
10.1016/j.mayocpiqo.2024.07.002
Original Article
Perioperative Mortality: A Retrospective Cohort Study of 75,446 Noncardiac Surgery Patients
Nuttall Gregory A. MD gnuttall@mayo.edu
a∗
Merren Michael P. MD, MS a
Naranjo Julian DO a
Portner Erica R. RRT, LRT a
Ambrose Amanda R. MD a
Rihal Charanjit S. MD b
a Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN
b Department of Cardiovascular Disease, Mayo Clinic, Rochester, MN
∗ Correspondence: Address to Gregory A. Nuttall, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. gnuttall@mayo.edu
21 8 2024
10 2024
21 8 2024
8 5 435442
23 5 2024
20 6 2024
1 7 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Objective

To evaluate whether major adverse cardiac events (MACE) continue to be a major causative factor for mortality after noncardiac surgery.

Patients and Methods

We performed retrospective study of 75,410 adult noncardiac surgery patients at Mayo Clinic Rochester, between January 1, 2016, and May 4, 2018. Electronic medical records were reviewed and data collected on all deaths within 30 days (n=692 patients) of surgery. The incidence of death due to MACE was calculated.

Results

Postoperative MACE occurred in 150 patients (21.4 events per 10,000 patients; 95% CI, 18.2-25.2 events per 10,000 patients) with most occurring within 3 days of surgery (n=113). Postoperative MACE events were associated with atrial fibrillation with rapid rate response in 25 patients (16.7%), sepsis in 15 patients (10%), and bleeding in 15 patients (10%). There were 12 intraoperative deaths of which 9 were due to exsanguination (75%) and the remaining 3 (25%) due to cardiac arrest. Of the 56 deaths on the first 24 hours after surgery, 7 were due to hemorrhage, 17 due to cardiovascular causes, 20 due to sepsis, and 7 due to neurologic disease. The leading cause of total death over 30 days postoperatively was sepsis (28%), followed by malignancy (27%), cardiovascular disease (12%) neurologic disease (12%), and hemorrhage (5%).

Conclusion

MACE was not the leading cause of death both intraoperatively and postoperatively.

Abbreviations and Acronyms

cTnT cardiac troponin concentration

MACE major adverse cardiac events

MI myocardial infarction
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pmcAnnually, over 310 million surgical procedures are performed worldwide.1 Mortality and morbidity estimates for surgery vary. A mortality rate of 0.5% worldwide is the most recent estimate but can range up to 12.3% depending on the definition of mortality period, surgery type, urgency, and risk profile.2, 3, 4, 5, 6 Perioperative risk of mortality depends on the interaction between the patient’s pathology, and specific aspects of anesthesia, and surgery.7 Perioperative mortality can be assessed at different time points in the transoperative period including intraoperatively, in 48 hours, at 30 days, and even 1 year after surgery. It is known that a small group of high-risk patient account for increased mortality and hospital length of stay.5,8, 9, 10, 11, 12, 13

Many studies have identified risk factors for surgical mortality such as age, sex, urgency and type of surgery, American Society of Anesthesiologists physical status, and patient comorbidities.14, 15, 16, 17, 18, 19, 20, 21 Efforts have been made to predict mortality with most studies focusing on perioperative major adverse cardiac events (MACEs) as a cause of mortality.8 Patients who develop MACE including myocardial infarction (MI) and cerebral vascular accident have a mortality rate upward of 25%.22 There are multiple risk scoring and calculators that have been developed for MACE.23, 24, 25, 26, 27, 28 In a large observational multicenter cohort study in the United States from 2005 to 2013 with just over 9.5 million patients undergoing noncardiac surgery, the incidence of perioperative MI was observed to be 88 events per 10,000 patients.29 The authors of this study also noted the incidence of perioperative MI was dropping over that study period. A study from our institution and a large longitudinal study also showed a similar reduction in MACE.6,30 We hypothesized that MACE continues to be a major causative factor for perioperative mortality.

Materials and Methods

After institutional review board approval, a retrospective study of adult patients who underwent noncardiac surgery at Mayo Clinic Rochester, between January 1, 2016, and May 4, 2018, was performed. All patients included in the study granted permission to use their medical records for research (consistent with Minnesota Statute 144.295). The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were used in the design and conduct of this investigation.31

Patients and Data Collection

The electronic medical record “EPIC” was implemented at Mayo on May 5, 2018. The information from the electronic medical records (intraoperative anesthesia medical record and postoperative data recorded in the medical record) were reviewed and collected for all patients who underwent both elective and emergent noncardiac surgical procedures during the study period. For patients who underwent multiple surgeries during the study period, the first surgery was included.

All deaths within 30 days of surgery were reviewed. The cause of death was determined. Further, to identify all patients who had a possible MACE event, the charts of all patients who had a 12-lead electrocardiogram (ECG) or troponin level drawn plus a cardiology consult, MI diagnosis, cardiac catheterization with or without coronary intervention, coronary artery bypass grafting within 1 week after noncardiac surgery, and their associated International Classification of Disease (ICD)-10 care management codes I21.9, I24.9, I49.9, R79.89, R57, and Z95.111 were reviewed (G.A.N., M.P.M.).

Definitions

Cause of Death

The cause of death for each patient was broken up into the following 8 variables: hemorrhage, cardiovascular (CV), sepsis, neurologic, malignancy, respiratory, hepatorenal, and other. The primary or largest contributing etiology of death was used to place patient’s death into each category. All patients’ charts were evaluated by 2 of the researchers and placed into 1 of the 8 categories. If the 2 researchers did not agree, there was a discussion until an agreement was made as to the category in which the cause of death belonged to.

The hemorrhage cause of death included all causes in which patients developed hemorrhagic shock directly leading to death and requiring a transfusion of blood products. The CV cause of death includes cardiogenic shock, aortic dissections, severe peripheral arterial disease, mesenteric ischemia due to peripheral arterial disease, pulmonary embolism, cardiac arrhythmia, acute MI, and cardiac arrest due to a cardiac event; excluded in this was cardiac arrest due to another etiology such as sepsis, hemorrhage, respiratory arrest, and stroke.

The sepsis cause of death included all patients who developed septic shock because of an infectious etiology to include pneumonia, meningitis, intra-abdominal sepsis, neutropenic sepsis, endocarditis, bacteremia, line infection, colitis, perforated viscera, and soft tissue infection. The neurologic cause of death included ischemic and hemorrhagic strokes, seizure, tumor, or lesion leading to herniation and traumatic brain injury.

The malignancy cause of death included patients where the malignancy or spread of malignancy was the sole cause of the patient’s death excluding those that developed sepsis, brain herniation, or hemorrhage because of their malignancy. The respiratory cause of death included those with end-stage chronic obstructive pulmonary disease, ruptured diaphragm, and acute respiratory distress syndrome due to aspiration or pneumonia, excluding those who developed septic shock because of pneumonia, idiopathic pulmonary fibrosis, interstitial lung disease, and aspiration without acute respiratory distress syndrome.

The hepatorenal cause of death included those with decompensated liver failure and end-stage cirrhosis without any of the other categories as the primary contributor to death. The other causes of death were those without any explanation of the cause of death because these patients were discharged from the hospital and died while at home or nursing facility without any other explanation or documentation in the chart.

Major Adverse Cardiac Events

MACE was defined as a rising and/or falling cardiac troponin measurement greater than the 99th percentile and clinical evidence of acute myocardial ischemia. The cardiac troponin concentration (cTnT) was measured using the contemporary fourth-generation cTnT assay (Roche Diagnostics) on the Cobas e 601 until March 5, 2018. Both the lowest reportable concentrations and 99th percentile upper reference limit (URL) are <0.01 ng/mL. A concentration of 0.01 ng/mL or greater is indicative of myocardial injury. Results were reported in decimals in nanograms per milliliter. Institutional guidelines recommend 0-, 3-, and 6-hour protocol to rule-in and rule-out acute MACE, with a 99th percentile URL used to determine the presence of myocardial injury and support the diagnosis of acute MACE

After March 5, 2018, cTnT was measured using the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics) on the Cobas e 601. Troponin concentrations were reported down to the limit of quantitation of <6 ng/L. Sex-specific 99th percentile URL of 10 ng/L for women and 15 ng/L for men. Concentrations of >10 ng/L for woman and >15 ng/L for men were considered indicative of myocardial injury. Results were reported in whole nanograms per liter. Institutional guidelines recommend 0- and 6-hours protocol to rule-in and rule-out acute MACE, with a sex-specific 99th percentile URL used to determine the presence of myocardial injury and support the diagnosis of acute MACE.32

Statistical Analysis

The occurrences of perioperative death and MACE were categorized as intraoperative and postoperative in the first 7 and 30 days based on chart review. The frequency of intraoperative and postoperative death and MACE was quantified as the number of events per 10,000 patients and summarized using point estimates and 95% CIs.

Results

Complete data were collected on 75,410 noncardiac surgery patients (Figure). The demographic and surgical characteristics of patients are summarized in Table 1. The records of 1317 patients were reviewed in detail, of which all deaths within 30 days (n=692 patients) were reviewed. The indications for the chart review were a 12-lead ECG and/or troponin level drawn plus either cardiac consult within 1 week of surgery, diagnosis acute MACE within 1 week of surgery, or cardiac catheterization with/or without coronary intervention with 1 week of surgery, coronary artery bypass grafting surgery within 1 week after noncardiac surgery, and their associated ICD-10 care management codes I21.9, I24.9, I49.9, R79.89, R57, and Z95.1,11 with some patients having more than 1 indication for review.Figure Consolidated Standards of Reporting Trials (CONSORT) diagram describing the flow of patients through the study.

Table 1 Patient Characteristics

Characteristic	Overall (N=75,410a)	Perioperative deaths (n=692b)	
Age (y)			
 Mean ± SD	56.7±17.1	69.5±14.5	
 Median (25th, 75th)	59 (45, 69)	71 (60, 79)	
Sex (%)			
 Female	51.4	45.7	
 Male	48.6	54.3	
ASA status (%)			
 I	7.8	0.2	
 II	46.7	5.8	
 III	40.9	49.4	
 IV/V	4.7	44.6	
Emergency (%)			
 No	94.6	45.2	
 Yes	5.4	54.8	
ASA, American Society of Anesthesiologists.

a Sex data were missing for 315 (0.4%) patients; ASA status was missing for 4397 (5.8%) patients, and emergency data were missing for 4322 (5.7%) patients.

b ASA status was missing for 75 (10.8%) patients.

The frequency and timing of perioperative death are tabulated in Table 2. The death rate increased from 2 per 10,000 patients intraoperatively to 9 per 10,000 patients in the first 24 hours postoperatively. It increased again to 31 per 10,000 patients from postoperative day 2 to 7 and 92 per 10,000 patients from postoperative day 8 to 30.Table 2 Frequency and Timing of Perioperative Deaths (N=75,410 Surgeries)

Timing	No. of deaths in interval	Cumulative No. of deaths	Rate per 10,000, estimate (95% CI)	
Intraoperative	12	12	2 (1, 3)	
Postop day 0, 1	56	68	9 (7, 11)	
Postop day 2-7	169	237	31 (28, 36)	
Postop day 8-30	455	692	92 (85, 99)	
Postop, postoperative.

The causes of perioperative deaths are summarized on Table 3. There were 12 intraoperative deaths of which 9 were due to exsanguination (75%) and the remaining 3 (25%) due to cardiac arrest (Table 3). Intraoperative MACE occurred in 7 patients (1.0 events per 10,000 patients); for a more detailed description of the intraoperative deaths, see Supplemental Data (available online at http://www.mcpiqojournal.org) case descriptions of intraoperative deaths.Table 3 Causes of Perioperative Deaths

Cause	Time interval, n (%)	Overall (n=692), n (%)	
Intraop (n=12)	Day 0, 1 (n=56)	Day 2-7 (n=169)	Day 8-30 (n=455)	
Hemorrhage	9 (75)	7 (13)	9 (5)	13 (3)	38 (5)	
CV	3 (25)	17 (30)	23 (14)	43 (9)	86 (12)	
Sepsis	0 (0)	20 (36)	48 (28)	126 (28)	194 (28)	
Neurologic	0 (0)	7 (13)	34 (20)	44 (10)	85 (12)	
Malignancy	0 (0)	4 (7)	27 (16)	158 (35)	189 (27)	
Respiratory	0 (0)	0 (0)	10 (6)	12 (3)	22 (3)	
Hepatorenal	0 (0)	0 (0)	1 (1)	4 (1)	5 (1)	
Unknown	0 (0)	1 (2)	17 (10)	55 (12)	73 (11)	
CV, cardiovascular; intraop, intraoperative; unknown, death after discharge from the hospital.

No patients with perioperative MACE died in the operating room. The overall leading cause of death from surgery to 30 days was sepsis (28%), followed by malignancy (27%), CV disease (12%) neurologic disease (12%), and hemorrhage (5%). Postoperative MACE occurred in 150 patients (21.4 events per 10,000 patients; 95% CI, 18.2-25.2 events per 10,000 patients). Most of the postoperative MACE occurred within 3 days of surgery (n=113), and many were type 2 MIs (n=55). The postoperative MACE were associated with new onset of atrial fibrillation with rapid rate response in 25 patients (16.7%), sepsis in 15 patients (10%), and bleeding in 15 patients (10%).

Discussion

In a large observational multicenter cohort study in the United States from 2005 through 2013 with just over 9.5 million surgical patients undergoing noncardiac surgery, the incidence of perioperative MI was observed to be 88 events per 10,000 patients.29 The authors noted the incidence of perioperative MI was dropping over the time of the study. Our data demonstrated a similar but lower incidence of perioperative MACE of 30.6 events per 10,000 patients. None of the intraoperative patients with MACE were undergoing vascular, transplant, or thoracic surgeries. Of the 150 postoperative patients with MACE, 33 (22%) patients underwent vascular surgery, 8 (5.3%) patients underwent thoracic surgery, and 7 (4.7%) underwent transplant surgery. As with other studies, we found a higher incidence of perioperative MACE in patients undergoing vascular, transplant, and thoracic surgeries compared with that in those undergoing other surgeries.

Perioperative myocardial ischemia continues to be a mortality problem.33,34 We found no intraoperative deaths due to MACE. We did find that perioperative MACE was associated with increased incidence of death 7 and 30 days after surgery. Our results are consistent with previous studies that have demonstrated perioperative MACE with elevated serum troponin being associated with increase mortality 7 and 30 days after noncardiac surgery such as in the VISION trial.35 This resulted in a new diagnosis called myocardial injury after noncardiac surgery.36, 37, 38, 39 Van Waes et al40 performed a prospective study of 3224 noncardiac surgery patients who had serial serum troponin measurements over 3 days postoperatively. They detected 715 patients (22%) who had postoperative myocardial injury with varying levels elevated serum troponin levels. Elevated levels of serum troponin were associated with increased 1-year all-cause mortality.

Postoperative mortality is an objective end point that can evaluate anesthesia and surgical safety both within and between institutions. Further, it is an end point that can be used to track practice changes.41 Our rate of intraoperative death of 0.02% (2/10,000 patients), first 24 hours postoperatively of 0.1% (10/10,000 patients) and 30 postoperative days 1.0% (96/10000 patients) is very low compared with the literature.2, 3, 4, 5,14 It should be noted there were no intraoperative deaths due to loss of airway, pulmonary aspiration, drug errors, or anesthesia machine failures. A common reference death rate is the annual mortality rate for motor vehicle accidents. Our intraoperative death rate of 2/10,000 is comparable with the annual mortality rate of automobile travel.42

The cause of perioperative mortality in our data changed over the course of the 30-day perioperative period with hemorrhage being the major cause of intraoperative death and sepsis and malignancy disease progression becoming the major cause of death over the next 30 days. Our result of sepsis being the major cause of death 30 days after surgery is similar to those of Gabriel et al who had a 30 day mortality rate of 2.1%.14,43

The median world population is aging. As the population ages, frailty will be increasingly seen in surgical patients. Frailty status has recently been found to be a predictive tool to postoperative morbidity and mortality.44,45 Frailty can be defined biologically as a decrease reserve and resistance to stress. This results from the cumulative decline of multiple physiologic systems causing vulnerability to adverse outcomes.46 There are more than 60 assessment tools of frailty available. Many assessment tools use data, such as grip strength and walking speed, which is not easily available for this retrospective study. Enhanced recovery after surgery (ERAS) is another system that has been recently implemented.47 ERAS is a constantly evolving program based on the best evidence currently available in perioperative care. Management of the metabolic stress response to surgery is a critical feature of ERAS protocols such as optimizing nutrition, prehabilitation, antibiotic use, and correction of preoperative anemia.

The Institute of Medicine (IOM) and the Joint Commission on the Accreditation of Health Organizations, and the Institute of Healthcare Improvement have made improvements in medication safety and adverse event tracking a top priority in the United States. The IOM in 1999 presented statistics suggesting that medical error accounts for nearly 100,000 American patient deaths.48 This resulted in a greater interest in developing systems to improve patient safety. As an example of these efforts, hospital acquired conditions such as patient falls, adverse drug events, and patient infections have steadily declined, although our results suggest that sepsis continues to be major cause of patient mortality.49

Much effort has been made to develop risk models to predict mortality and CV outcomes after surgery.8,24 Predictors of disability after surgery have also been developed.50, 51, 52 The most effort until recently has been developing risk scores and calculators to predict the risk of MACE.23, 24, 25, 26, 27, 28,53 MACE occurs in up to 20% of noncardiac surgery patients.29,54 The prevention and treatment of perioperative MACE have been developed.12,36

Study Limitations

Our study has limitations secondary to retrospective design. The designation of the cause of death may not be correct especially when the patient had multiple comorbidities. Further, the primary cause of death may be difficult to assign because bleeding or sepsis can cause CV collapse and MACE. For most patient who died outside the hospital, it was difficult to determine the cause of death. It is possible that patients had myocardial ischemia with or without MACE and were not identified to have serum troponins or 12-lead ECG performed. Further, perioperative MACE events are frequently asymptomatic. Finally, one of the highest risk groups for perioperative MACE is the vascular surgery population. We found no intraoperative MACE events in this group, although 21.8% of postoperative patients with MACE were vascular surgery patients.

Conclusions

In this retrospective single-academic center study, hemorrhage was the leading cause of intraoperative death. Sepsis and malignant disease progression became the leading cause of death over the next 30 days. Postoperative MACE occurred in 150 patients (21.4 events per 10,000 patients; 95% CI, 18.2-25.2 events per 10,000 patients). Most of the postoperative MACE occurred within 3 days of surgery (n=113), and many were type 2 MIs. The postoperative MACE were associated with new onset of atrial fibrillation with rapid rate response in 25 patients (16.7%), sepsis in 15 patients (10%), and bleeding in 15 patients (10%).

Potential Competing Interests

The authors report no competing interests.

Supplemental Online Material

Supplementary Data

Grant Support: This study was supported by the Mayo clinic department of anesthesia and critical care medicine.

Supplemental material can be found online at http://www.mcpiqojournal.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.
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