Risk Factors for Adverse Outcomes After the Surgical Treatment of Appendicitis in Adults

Abstract

Objective:

To define risk factors that predict adverse outcomes after the surgical treatment of appendicitis in Department of Veterans Affairs Medical Centers.

Summary Background Data:

Risk factors for adverse outcomes after the surgical treatment of appendicitis in adults are poorly defined. Accurate presurgical assessment of the risk of perioperative complications and death is important in planning surgical therapy.

Methods:

The VA National Surgical Quality Improvement Program contains prospectively collected and extensively validated data on ∼1,000,000 major surgical operations. All patients undergoing surgical intervention for appendicitis from 1991 to 1999 registered in this database were selected for study. Independent variables examined included 68 putative preoperative risk factors and 12 intraoperative process measures. Dependent variables were 21 specific adverse outcomes, including death. Stepwise logistic regression analysis was used to construct models predicting 30-day morbidity rate and the 30-day postoperative mortality rate.

Results:

There were 4163 patients identified. The mean age was 50 years; 96% were male. Sixteen percent of patients had 1 or more complications after surgical intervention. Prolonged ileus, failure to wean from the ventilator, pneumonia, and both superficial and deep wound infection were the most frequently reported complications, accounting for the majority of the morbidity. The 30-day mortality rate was 1.8% (74 deaths). For >50% of the complications reported, the 30-day mortality rates were significantly higher (P < 0.01) for patients with complications than for those without. Thirty-day mortality rates for several complications exceeded 30%, including cardiac arrest, coma >24 hours, myocardial infarction, acute renal failure, bleeding requiring >4 units of red cells, and systemic sepsis. Four preoperative factors predicted a high risk of 30-day mortality in the logistic regression analysis: “completely dependent” functional status, bleeding disorder, steroid usage, and current pneumonia. “Threat to life” or “moribund” American Society of Anesthesiologists classification and more than a 10% weight loss in the 6 months before surgery were associated with a high risk of complications.

Conclusions:

Morbidity and mortality rates after the surgical treatment of appendicitis in VA hospitals are comparable with those reported in other large series. Most postsurgical complications are associated with an increased 30-day mortality rate. The models presented here are the most robust available in predicting 30-day morbidity and mortality for VA patients with appendicitis. Furthermore, they provide a starting point for the design of similar models to evaluate non-VA patients with appendicitis using the data the National Surgical Quality Improvement Program is currently gathering from private hospitals.

Appendicitis is the most common cause of the acute abdomen in the United States, with an estimated lifetime risk between 5 and 20%.¹ In fact, appendectomy is the most common nonelective operation performed by general surgeons.^2–4 Although it has been over 115 years since Reginald Heber Fitz first demonstrated the natural history and pathophysiology of appendicitis and advocated early appendectomy in his landmark article,⁵ appendicitis continues to present challenges for the surgeon today.

There has been a dramatic reduction in the mortality rate attributed to acute appendicitis over the past 50 years from nearly 26% to less than 1%.⁶ However, the morbidity rate, which has heavily impacted health care costs, has not experienced a similar drop.^7,8 Identifying risk factors that predict the likelihood of complications associated with appendicitis is a crucial step in managing these patients.^9–16 This has traditionally been accomplished through retrospective reviews, which are often flawed. Limitations of retrospective reviews include inconsistent data gathering techniques and nonuniform definitions for the complications under investigation. Also, such reviews often represent the experience of a limited number of specialists at a single institution.

The Department of Veterans Affairs (VA) National Surgical Quality Improvement Program (NSQIP) was designed to obviate some of the limitations of retrospective analyses by prospectively gathering reliable, valid data about patient risk and outcomes of surgery in the VA health care system. These data are then used to construct mathematical models that report comparative risk-adjusted surgical morbidity and mortality rates. The initial National Veterans Affairs Surgical Risk Study that was conducted from October 1, 1991, through December 31, 1993, included 44 Veterans Affairs Medical Centers (VAMCs). The program was expanded on January 1, 1994, and now prospectively gathers data on surgical procedures performed at 123 VAMCs, numbering >1,000,000 entries to date. Each of these cases was selected according to defined criteria, assessed for 68 putative presurgical and 12 intraoperative variables judged likely to be predictors of complications and death and monitored after surgery for 30-day mortality and for 21 specific and well-defined adverse outcomes. The reproducibility and accuracy of data collection have been demonstrated elsewhere.^17–19 These data permit the construction of risk–prediction models using well-accepted statistical techniques.²⁰ The present study uses these techniques to assess risk factors for morbidity and mortality after surgical treatment of appendicitis in Department of Veterans Affairs patients.

PATIENTS AND METHODS

Details of the NSQIP have been described previously.¹⁷ It is an ongoing observational study in which trained, dedicated nurses prospectively collect preoperative, intraoperative, and postoperative information on patients undergoing major cardiac and noncardiac surgery under general, spinal, or epidural anesthesia for operations known to have significant complication rates at 123 participating VAMCs. In the 119 VAMCs that perform fewer than 140 eligible surgical procedures per month, all operations are entered into the study. In the 4 VAMCs that perform more than 140 eligible surgical procedures each month, the first 36 eligible operations are entered into the study in each consecutive 8-day period, beginning with a different day each period.

In the present study, all patients diagnosed with appendicitis (identified by ICD-9-CM codes 540–542) from October 1991 through September 1999 were selected from the NSQIP database for analysis. Several different surgical procedures were used to treat patients with appendicitis, including 44950 (appendectomy), 44960 (appendectomy for ruptured appendicitis with generalized peritonitis), 44900 (drainage of periappendiceal abscess), and 44140 through 44144 (right colectomy and cecectomy). CPT code 44955 (incidental appendectomy) was excluded. Vital status was determined by the NSQIP study nurses and validated by matching social security numbers from the NSQIP data sets with records in the VA Beneficiary Identification and Records Locator Subsystem. This system has a sensitivity greater than 94% for identification of death in veterans who have ever been treated at a VAMC.^21,22

A χ² analysis was used to compare 30-day mortality rates between patients with and without complications. Stepwise logistic regression analysis was used to construct models predicting 30-day morbidity (defined as 1 or more complications) and 30-day mortality. Independent variables examined included 68 presurgical clinical parameters (including demographics, comorbid conditions, and laboratory test values) and 12 intraoperative process-of-care variables, including emergency versus elective designation, anesthesia technique, American Society of Anesthesiologists (ASA) classification, wound classification, primary surgeon, first assistant, operation time, intraoperative blood loss, intraoperative blood transfusion, CPT code for the index procedure, CPT codes for other procedures performed by the same surgical team, and CPT codes for concomitant procedures performed by a different surgical team previously used by the NSQIP.¹⁷ The dependent variables were 21 specific adverse outcomes and 30-day mortality. Data regarding “redo” operations were excluded from the regression analyses as there are concerns regarding the reliability of this particular measure in the database.

The bivariate relationship between morbidity and mortality and each of the 78 candidate variables for entry into the logistic regression models was analyzed using the t test for continuous variables and the χ² test for categorical variables. Those variables that were significant (P < 0.05) were then entered into a stepwise logistic regression procedure. Standard measures of logistic regression model fit, such as the c index, Hosmer–Lemeshow goodness-of-fit measurement, and model χ² determination were calculated.²³

RESULTS

Patient Demographics

From the NSQIP database, 4163 patients with appendicitis were identified from 10/91 to 09/99. The mean age was 50 years (range, 17 to 104), and 4005 (96%) were male.

Patient Preoperative Risk Factors

Of the 4163 patients, 1561 (37%) were smokers, 508 (12%) drank more than 2 alcoholic drinks per day, and 95 (2%) were drug addicts. Comorbid medical conditions included 412 (10%) with diabetes requiring insulin or oral agents, 412 (10%) with hypertension requiring medication, 395 (9%) with dyspnea on minimal exertion or at rest, 374 (9%) with chronic obstructive pulmonary disease, 247 (6%) with a “partially dependent” or “totally dependent” functional health status, 78 (2%) with a history of congestive heart failure, and 57 (1%) with a history of angina. There were also 18 (0.4%) patients with ascites, 15 (0.4%) with hepatomegaly, 15 (0.4%) with active hepatitis, and 4 (0.1%) with esophageal varices at the time of surgery. Thirty-eight (0.9%) patients were being treated for pneumonia and 25 (0.6%) were on dialysis at the time of surgery. A number of patients had a history of neurologic events, including 134 (3%) with cerebrovascular accident and residual deficit, 65 (2%) with cerebrovascular accident and no residual deficit, and 61 (1%) with a history of transient ischemic attacks. There were 66 (2%) patients who were either paraplegic, quadriplegic, or hemiplegic. One hundred twenty (3%) had an open or infected wound at the time of surgery, 73 (2%) were chronic steroid users, 39 (0.9%) had a chronic bleeding disorder, and 5 (0.1%) had received more than 4 units of packed red blood cells before surgery. Finally, 35 (0.8%) had sustained weight loss >10% of body weight in the 6 months before surgery, and 18 (0.4%) had a “do not resuscitate” status before surgery.

Presurgical Laboratory Tests

Several presurgical laboratory values are of interest. The mean serum albumin concentration was 4.0 g/dL (range, 1.2 to 6.7), the mean serum alkaline phosphatase concentration was 86 μg/L (range, 57 to 380), the mean serum total bilirubin concentration was 1.0 mg/dL (range, 0.4 to 6.8), the mean serum blood urea nitrogen level was 15 mg/dL (range, 2 to 133), the mean serum creatinine concentration was 1.2 mg/dL (range, 0.4 to 32), the mean serum aspartate aminotransferase level was 27 μg/L (range, 3 to 1745), the mean serum sodium concentration was 138 mEq/L (range, 119 to 167), the mean serum potassium concentration was 4.1 mEq/L (range, 2.8 to 7.5), the mean serum glucose concentration was 128 mg/dL (range, 47 to 712), the mean white blood cell count concentration was 13.9 thousand/mm³ (range, 1.3 to 129), the mean hematocrit was 43% (range, 19 to 65), the mean platelet count was 238 thousand/mm³ (range, 25 to 906), the mean partial thromboplastin time was 28 seconds (range, 17 to 69), and the mean prothrombin time was 13 seconds (range, 9 to 60).

Operative Variables

Of the 4163 patients, none underwent elective surgery and 3548 (85%) were considered emergency operations. Intraoperative wound classification was as follows: 1801 (43%) clean/contaminated, 983 (24%) contaminated, 750 (18%) clean, and 634 (15%) infected. A general surgeon performed the operation in 4125 (99%) patients and general anesthesia was used in 4018 (97%) of cases. There were 297 (7%) patients with ASA Class IV (threat to life) or Class V (moribund). Surgical time ranged from 0.1 to 23.5 hours (mean 1.4 hours). Blood loss ranged from minimal (scored as 0) to 2800 mL (mean 92 mL). As shown in Table 1, the majority of patients underwent appendectomy, either without generalized peritonitis specified (74.4%) or with generalized peritonitis (21.1%). A small number had either right colectomy or cecectomy (3.2%) or drainage for a periappendiceal abscess (1.3%). The complication rate was 12.7% (393/3095) for appendectomy without peritonitis specified, 24.9% (219/878) for appendectomy with generalized peritonitis, 14.6% (8/55) for drainage of periappendiceal abscess, and 43.7% (59/135) for colectomy/cecectomy. The mortality rate was 0.7% (20/3095) for appendectomy without peritonitis specified, 4.0% (35/878) for appendectomy with generalized peritonitis, 3.6% (2/55) for drainage of periappendiceal abscess, and 12.6% (17/135) for colectomy/cecectomy. Because of the small number of patients in the latter 2 treatment groups (190/4163; 4.6% of total), all patients with appendicitis were grouped together for statistical modeling.

TABLE 1. Morbidity and Mortality Rates for Appendicitis By Procedure Type

Outcomes

The 30-day mortality rate was 1.8% (74 deaths). Overall, 16% (679 patients) had 1 or more complications after surgery. The most frequently reported complications are listed in Table 2, as well as the associated 30-day mortality rate for patients with and without the complication. Prolonged ileus, failure to wean from the ventilator, pneumonia, and both superficial and deep wound infection were the most frequently reported complications, accounting for the majority of the overall morbidity. For patients experiencing pneumonia, reintubation, failure to wean from the ventilator after 48 hours, progressive renal insufficiency, acute renal failure, cerebrovascular accident, coma > 24 hours, cardiac arrest requiring cardiopulmonary resuscitation, myocardial infarction, bleeding requiring > 4 units of blood, and systemic sepsis, 30-day mortality rates were significantly higher (P < 0.001 to P < 0.01) than in patients not experiencing these events. In fact, 30-day mortality rates for several complications exceeded 30%: cardiac arrest, coma > 24 hours, myocardial infarction, acute renal failure, bleeding requiring > 4 units of blood, and systemic sepsis.

TABLE 2. Incidence of Postoperative 30-Day Complications After Appendectomy for Appendicitis and Associated 30-Day Mortality Rate

Logistic Regression Models

Eleven factors were predictive of postoperative 30-day morbidity in the logistic regression analysis (Table 3). ASA Class III (severe), ASA Class IV or V (threat to life or moribund, respectively), “partially dependent” functional health status, history of chronic obstructive pulmonary disease, >10% weight loss within the 6 months before surgery, contaminated/infected wound classification, advanced age (in decades), and increasing operative time were all positively associated with morbidity (defined as 1 or more complications). Likewise, several laboratory values, including preoperative total bilirubin, blood urea nitrogen, and white blood cell count were also positively associated with morbidity, indicating that patients with higher levels at the time of surgery were more likely to experience a postoperative complication. Preoperative albumin, in contrast, was negatively associated with morbidity, indicating that patients with higher albumin levels at the time of surgery were less likely to experience a postoperative complication. Examination of the c index (0.706) and the Hosmer-Lemeshow goodness of fit statistic (3.9904, P = 0.8580) for this model indicates an acceptable model fit.

TABLE 3. 30-Day Morbidity: Logistic Regression Analysis Results

Eleven factors were predictive of 30-day mortality in the logistic regression analysis (Table 4). ASA Class IV/V (threat to life/moribund), “totally dependent” functional health status, diabetes requiring insulin, history of chronic obstructive pulmonary disease, current pneumonia, chronic steroid use, history of a bleeding disorder, advancing age (in decades), elevated preoperative blood urea nitrogen, transfusion of >4 units blood, and elevated preoperative alkaline phosphatase, were all positively associated with a 30-day mortality. The relative impact of preoperative alkaline phosphatase appears to be minimal (odds ratio 1.009) and may represent a statistical aberration. Elevated preoperative albumin and clean/contaminated wound classification were negatively associated with 30-day mortality. Examination of the c index (0.922) and the Hosmer-Lemeshow goodness of fit statistic (5.5087, P = 0.7021) for this model indicates an excellent model fit.

TABLE 4. 30-Day Mortality: Logistic Regression Analysis Results*

DISCUSSION

Appendicitis is one of the most common intra-abdominal diseases encountered, the solution to which is a relatively simple operation. Although mortality rates attributed to appendicitis have been dramatically reduced over the past century, complications are common.^6,24,25 This stems from the fact that perforation rates remain high (17–20%), despite the increased use of imaging modalities such as ultrasound and computed tomography.^2,26 Although the surgeon may not be as involved in the early care of the patient with appendicitis as in years past, there is significant need for the surgeon to influence the observed morbidity of these patients. By using NSQIP data, we investigated the risk factors that contribute to the morbidity and mortality of adults requiring surgical treatment of appendicitis.

One of the obvious uses of the NSQIP data is to compare the experience of the VAMC system with published reports from other institutions and systems. The overall 30-day mortality rate following surgery for appendicitis in our study was 1.8%, which is slightly higher than the published rates of <1% in the literature.^2,27,28 This is likely to be a result of the fact that the VA consists of adults only (mean age 50 years in this study) who are more likely to suffer from medical comorbidities compared with non-VA patients with appendicitis, who are often generally healthy children and adolescents. The mean age of patients in previous large studies in the past 30 years ranged from 21–26.^13–15,27 Blomqvist et al²⁸ found that the mortality rate was strongly related to age, ranging from a minimum of 0.07 per 1000 appendectomies in patients ages 20 to 29 years to a maximum of 164 per 1000 in nonagenarians (≥90 years of age). Likewise, the VAMC experience of 16% overall surgical morbidity is slightly higher than, but comparable to, rates reported in the recent literature when the above age and comorbidity factors are considered.2,13–15,27,28

The morbidity and mortality rates in the present study also represent a composite of patients with simple, acute appendicitis and those with complex, perforated appendicitis treated by a variety of surgical interventions. Clearly, those patients receiving appendectomy for perforated appendicitis have a higher risk of complications (24.9% versus 12.7%) and death (4.0% versus 0.7%) than those undergoing simple appendectomy for appendicitis without peritonitis specified. Further, there is a higher incidence of complications and death in patients with appendicitis undergoing either drainage of periappendiceal abscess (14.6% and 3.6%, respectively) or colectomy/cecectomy (43.7% and 12.6%, respectively) than those undergoing simple appendectomy for appendicitis without peritonitis specified (12.7% and 0.7%, respectively). However, the strength of our models is acceptable with a c index of 0.92 for the mortality model and 0.71 for the morbidity model.

The most common complications observed after surgical treatment of appendicitis were superficial and deep wound infections, prolonged ileus, and pneumonia (together accounting for the majority of the complications). Despite the routine use of prophylactic antibiotics, wound infection is the most common complication resulting from appendectomy.^29–31 Importantly, however, we found that wound infection did not have a significant adverse effect on mortality. Not surprisingly, systemic sepsis, as well as pneumonia, failure to wean from the ventilator at 48 hours, reintubation, progressive renal insufficiency, acute renal failure, cerebrovascular accident, coma >24 hours, cardiac arrest requiring cardiopulmonary resuscitation, myocardial infarction, and bleeding requiring >4 units of blood transfusion did significantly impact the observed mortality.

The generation of 30-day morbidity and mortality risk models by stepwise logistic regression analysis provides information on the relative impact of significant risk factors as measured by the relevant odds ratios. The validity of some putative risk factors incorporated in the NSQIP study design have been confirmed by this study, whereas others failed to predict adverse events. Preoperative factors predictive of postoperative morbidity included ASA class III, IV, or V, “partially dependent” functional health status, history of chronic obstructive pulmonary disease, >10% weight loss 6 months prior to surgery, advancing age (in decades), and preoperative albumin, bilirubin, blood urea nitrogen, and white blood cell count. Intraoperatively, the presence of a contaminated/infected wound classification and prolonged operative time was also predictive of morbidity. It is interesting to note that 18% of the procedures performed were classified as clean. Because even a simple appendectomy requires entering the gastrointestinal tract, these procedures would have been more correctly graded as clean/contaminated. However, despite this, logistic regression analysis did demonstrate that, compared with clean/contaminated wounds, a contaminated or infected wound classification predicted increased morbidity. The odds ratio expressed for interval data (eg, operative time, albumin) represents the increase in the odds of experiencing a complication associated with a 1 unit increase in the independent variable. For example, the odds of a postoperative complication is increased by a factor of 1.070 for each hour increase in operative time and the odds of complication are decreased by a factor of 0.811 for each additional g/dL of serum albumin.

Preoperative factors that clearly impact mortality include ASA class IV or V, diabetes requiring insulin, “totally dependent” functional status, history of chronic obstructive pulmonary disease, current pneumonia, chronic steroid use, history of a bleeding disorder, advancing age (in decades), and preoperative serum albumin and blood urea nitrogen levels. The relationship of preoperative alkaline phosphatase to mortality most likely represents a statistical aberration. Why chronic steroid use was a strong predictive factor of mortality, but not morbidity, cannot be answered with available data. The NSQIP database provides complication data for the 30-day perioperative period only. We are unable to ascertain whether patients using steroids chronically had a higher morbidity at >30 days. Significant intraoperative factors include transfusion > 4 units (which positively predicts mortality) and presence of a clean/contaminated wound (which negatively predicts mortality).

The inability to differentiate traditional open versus laparoscopic techniques, which have been stringently compared in the recent literature,^32–35 is a recognized shortcoming of this study. In the case of open procedures, the database does not provide information on type of incision, primary versus secondary wound closure, or use of drains. In addition, these data also cannot account for the impact of nonoperative approaches, such as intravenous antibiotic therapy, in patients with perforated appendicitis.³⁶ The NSQIP was designed to collect data on a wide variety of major surgical procedures, and it has not been practical to include alternative nonsurgical therapy data in the noncardiac procedure database. The inability to construct separate regression models for each surgical procedure used in the treatment of appendicitis is another recognized shortcoming of this study. The small sample size for drainage of periappendiceal abscess and colectomy/cecectomy precluded such analyses. The sample size, although large, permits only a limited estimation of the actual risk of adverse outcomes for some procedures. The use of extended colonic resection, while extremely rare in the typical healthy adolescent presenting with appendicitis, is necessary in a small number of VA patients with appendicitis. Because of the advanced age and multiple comorbidities that are common in these patients, delayed presentations of appendicitis in our database resulted in cecal rupture in 3.2% of patients, requiring colectomy/ cecectomy.

One of the recognized limitations of doing research in the VA system is that the population is predominantly older males who often have multiple comorbidities and a lower socioeconomic status. However, as the NSQIP database has grown, its statistical power has increased. One of the great strengths of the NSQIP is that it is a current, constantly enlarging database with the ability to keep pace with frequent changes and advancements in surgical technique and patient care. The prospective nature of the data collection and use of sophisticated statistical modeling will allow us to better predict the ability of our patients to tolerate proposed operations and generate new hypotheses for improved preoperative and intraoperative care.

One final criticism of the NSQIP database has been that the 123 VAMCs contributing to the database vary widely in size and in the volume of operations performed annually. For example, only 4 of the VAMCs perform >140 cases per month. There has been an assumption by some that better surgical outcomes are achieved in hospitals with larger surgical volumes.^37–40 However, Khuri et al⁴¹ recently analyzed the relation between surgical volume and outcome in 8 commonly performed operations of intermediate complexity in the VAMCs. They found that there were no statistically significant associations between procedure or specialty volume and 30-day mortality rate for any of the operations analyzed. Although these findings need to be validated by others outside the VAMC system, it provides support for the contention that surgical volume at individual VAMCs should not be considered a measure of the quality of surgery performed.

The morbidity and mortality models presented here provide an insight into the relative significance of various preoperative and intraoperative events. While it is true that some patient risk factors are not modifiable, such as steroid use, health status, diabetes, and chronic obstructive pulmonary disease, many of the preoperative and intraoperative factors identified by the NSQIP may be altered. Preoperative fluid resuscitation in patients with high serum blood urea nitrogen levels, aggressive weaning from the ventilator, cardioprotective measures, and careful hemostasis to prevent bleeding that requires transfusion >4 units are only several of the factors identified as important in preventing morbidity and mortality. We anticipate that analyses such as those performed in the present study will provide hypotheses on which to base future trials designed to decrease the risk of adverse outcomes.

ACKNOWLEDGMENTS

The authors thank Mr Bharat Thakker, MA, for his expert assistance with the statistical analyses.