Abstract
Background
Preoperative anaemia is associated with adverse outcomes after surgery but outcomes after liver surgery specifically are not well established. We aimed to analyze the incidence of and effects of preoperative anemia on morbidity and mortality in patients undergoing liver resection.
Methods
All elective hepatectomies performed for the period 2005–2012 recorded in the American College of Surgeons' National Surgical Quality Improvement Program (ACS-NSQIP) database were evaluated. We obtained anonymized data for 30-day mortality and major morbidity (one or more major complication), demographics, and preoperative and perioperative risk factors. We used multivariable logistic regression models to assess the adjusted effect of anemia, which was defined as (hematocrit <39% in men, <36% in women), on postoperative outcomes.
Results
We obtained data for 12,987 patients, of whom 4260 (32.8%) had preoperative anemia. Patients with preoperative anemia experienced higher postoperative major morbidity and mortality rates compared to those without anemia. After adjustment for predefined variables, preoperative anemia was an independent risk factor for postoperative major morbidity (adjusted OR 1.21, 1.09–1.33). After adjustment, there was no significant difference in postoperative mortality for patients with or without preoperative anemia (adjusted OR 0.88, 0.66–1.16).
Conclusion
Preoperative anemia is independently associated with an increased risk of major morbidity in patients undergoing hepatectomy. Therefore, it is crucial to readdress preoperative blood management in anemic patients prior to hepatectomy.
Introduction
Anemia is commonly encountered in the preoperative setting when patients are being evaluated for surgery. Preoperative anemia has been shown to be an independent risk factor for increased morbidity and mortality in patients undergoing cardiac surgery.
1
, 2
, 3
In non-cardiac surgery, the prevalence of anemia in the preoperative setting varies widely from as low as 5% in geriatric women having hip surgery to as high as 76% in patients with advanced colorectal cancer undergoing colectomy.4
, 5
However, the effect of preoperative anemia on outcomes in non-cardiac surgery has not been firmly established since previous studies had limited sample sizes and lacked a uniform definition of anemia.6
In addition, preoperative anemia is generally viewed as a surrogate marker for overall poorer health of the patient or as a risk factor for postoperative outcomes only due to its association with the higher need for perioperative transfusions.With the development and increased utilization of large national databases such as the American College of Surgeons' National Surgical Quality Improvement Program (ACS-NSQIP) database, the role of preoperative anemia could be better delineated using a large sample of patients with a unified definition of anemia and ability to adjust for several confounders. Indeed, Musallam et al. studied the role of preoperative anemia in 227,425 patients from the ACS-NSQIP database undergoing major non-cardiac surgery in 2008, of whom 30.4% had preoperative anemia. In their analysis, they showed that preoperative anemia was associated with increased morbidity and mortality at 30 days after adjustment of several known risk factors including transfusions.
7
However, the same results may not be valid for the subgroup of patients undergoing liver surgery as they constituted <1% of the total sample. In addition, liver surgery is a more complex procedure with more anticipated blood loss when compared to laparoscopic appendectomy or cholecystectomy which were the top procedures in the above analysis.Only a few studies have explored the implications of preoperative anemia and post-operative outcomes specifically in the post-liver resection patients. However, such studies have been only undertaken in specific subgroups of patients such as the elderly and have not adjusted for the major known confounders, especially the use of perioperative transfusions.
8
, 9
Therefore, in this study, we aimed to identify the prevalence of preoperative anemia in a cohort of patients from the ACS-NSQIP database who underwent liver resection. In addition, we examined whether preoperative anemia is independently associated with higher rates of 30 days morbidity and mortality as this information may trigger changes in the preoperative blood management of patients undergoing liver resection.Methods
Data acquisition and patients
We analyzed data from the American College of Surgeons' National Surgical Quality Improvement program (ACS NSQIP) participant use files for the years 2005–2012. We queried hepatectomy procedures by CPT codes and included partial (CPT 47120), right (47130), left (47125) and extended (47122) hepatectomies performed as a primary procedure. Patients undergoing emergency procedures were excluded (n = 143). We also excluded patients with missing data regarding height, weight and gender (n = 90) or preoperative hematocrit (n = 346).
Variables
Our main independent variable of interest was preoperative anemia, defined as a hematocrit concentration of less than 36% for women and less than 39% for men according to the WHO's criteria.
10
Postoperative outcomes included mortality and morbidity at 30 days. We defined major morbidity as the occurrence of one or more of these serious complications affecting the heart (acute myocardial infarction or cardiac arrest necessitating cardiopulmonary resuscitation), respiratory system (unplanned intubation, ventilator support for >48 h, or pneumonia), central nervous system (cerebrovascular accident with deficits or coma lasting >24 h), kidneys (progressive renal insufficiency requiring replacement therapy), wound (deep incisional surgical site infection, organ or space surgical site infection or wound dehiscence), sepsis or septic shock, pulmonary embolism, or postoperative bleeding as defined by the ACS-NSQIP variable “bleeding transfusion,” which included any postoperative transfusion given on postoperative day (POD) 1 and beyond.11
Of note, we defined perioperative transfusion as any transfusion given intraoperatively, in the postoperative recovery room, blood finishing from the operating room, or any blood given on POD 0.Missing data
Missing data was almost exclusively limited to preoperative laboratory data, and the proportion of missing data for each variable is listed in Table 1 and Supplementary Table 2. Multiple imputation was performed using predictive mean matching and 5 imputation sets to address this deficiency.
12
, 13
Summary statistics for the complete cases as well as each imputation set are presented in Supplementary Table 1.Table 1Baseline characteristics of patients
| No anemia (n = 8727) | Anemia (n = 4260) | p-Value | |
|---|---|---|---|
| General variables | |||
| Age (Mean SD) | 58.1 (13.3) | 60.4 (13.4) | <0.001 |
| Sex (Male) | 4002 (45.9%) | 2288 (53.7%) | <0.001 |
| Race | <0.001 | ||
| White | 6651 (76.1%) | 3069 (72.0%) | |
| Black | 650 (7.4%) | 483 (11.3%) | |
| Other | 1426 (16.3%) | 708 (16.6%) | |
| Functional status prior | <0.001 | ||
| Independent | 8656 (99.2%) | 4130 (96.9%) | |
| Partially dependent | 62 (0.7%) | 104 (2.4%) | |
| Totally dependent | 6 (0.1%) | 15 (0.4%) | |
| Unknown | 3 (<0.1%) | 11 (0.3%) | |
| BMI (Mean SD) | 28.3 (6.3) | 27.5 (6.4) | <0.001 |
| Alcohol>2 drinks/day within 2 weeks | 189 (2.2%) | 70 (1.6%) | 0.046 |
| Chronic steroid use | 185 (2.1%) | 106 (2.5%) | 0.18 |
| Extent of resection | <0.001 | ||
| Partial lobectomy | 5626 (64.5%) | 2514 (59.0%) | |
| Extended lobectomy | 727 (8.3%) | 497 (11.7%) | |
| Left lobectomy | 838 (9.6%) | 454 (10.7%) | |
| Right lobectomy | 1536 (17.6%) | 795 (18.7%) | |
| ASA class | <0.001 | ||
| I–II | 3037 (34.8%) | 1023 (24.0%) | |
| III | 5388 (61.7%) | 2929 (68.8%) | |
| IV–V | 302 (3.5%) | 308 (7.2%) | |
| Operation time (Median, IQR minutes) | 214 (152,296) | 235 (164,323) | <0.001 |
| Perioperative transfusion | 1417 (16.2%) | 1405 (33.0%) | <0.001 |
| Length of stay (Median IQR) | 6 (4,8) | 7 (5,10) | <0.001 |
| Cardiovascular/Pulmonary variables | |||
| Smoker within 1 year | 1449 (16.6%) | 624 (14.6%) | 0.004 |
| Dyspnea at rest or moderate exertion | 646 (7.4%) | 438 (10.2%) | <0.001 |
| Diabetic on oral or insulin | 1178 (13.5%) | 882 (20.7%) | <0.001 |
| Coronary Revascularization (PCI/CABG) | 392 (4.5%) | 283 (6.6%) | <0.001 |
| Severe COPD | 235 (2.7%) | 156 (3.7%) | 0.002 |
| Hypertension requiring medication | 3920 (44.9%) | 2244 (52.7%) | <0.001 |
| History of revascularization/amputation for PVD | 51 (0.6%) | 38 (0.9%) | 0.046 |
| CHF (new diagnosis or symptoms within 30 days) | 9 (0.1%) | 19 (0.4%) | <0.001 |
| Recent Angina or Myocardial infarction | 28 (0.3%) | 24 (0.6%) | 0.040 |
| Currently on dialysis (preoperative) | 19 (0.2%) | 34 (0.8%) | <0.001 |
| Hematological/Oncological variables | |||
| Preop hematocrit (Mean SD) | 41.3 (3.1) | 33.8 (3.6) | <0.001 |
| Transfusion ≥ 1u pRBC within 72h (pre-op) | 12 (0.1%) | 53 (1.2%) | <0.001 |
| Malignancy | 7239 (82.9%) | 3673 (86.2%) | <0.001 |
| >10% Weight loss within 6 months | 294 (3.4%) | 349 (8.2%) | <0.001 |
| Chemotherapy within 30 days of Surgery | 578 (6.6%) | 382 (9.0%) | <0.001 |
| Radiotherapy for malignancy within 90 days | 61 (0.7%) | 57 (1.3%) | <0.001 |
| Disseminated cancer | 3275 (37.5%) | 1736 (40.8%) | <0.001 |
| Hepatobiliary variables | |||
| Ascites in previous 30 days | 54 (0.6%) | 99 (2.3%) | <0.001 |
| Esophageal varices in previous 6 months | 26 (0.3%) | 12 (0.3%) | 0.87 |
| Neurological variables | |||
| History of TIA/CVA | 202 (2.3%) | 133 (3.1%) | 0.006 |
| Preoperative laboratory variables | |||
| Creatinine >1.2 mg/dL | 772 (8.8%) | 719 (16.9%) | <0.001 |
| Total bilirubin >1.0 mg/dL | 929 (11.6%) | 616 (14.5%) | <0.001 |
| AST >40U/L | 1860 (21.3%) | 1158 (27.2%) | <0.001 |
| Alkaline phosphatase >125U/L | 1700 (19.5%) | 1334 (31.3%) | <0.001 |
| Albumin <3 g/dL | 112 (1.3%) | 501 (11.8%) | <0.001 |
| Platelets <150k | 1106 (12.7%) | 643 (15.1%) | <0.001 |
| INR >1.3 | 115 (1.3%) | 174 (4.1%) | <0.001 |
Abbreviations: SD, standard deviation; ASA, American Society of Anesthesiologists; IQR, interquartile range; COPD, chronic obstructive pulmonary disease; PVD, peripheral vascular disease; CHF, congestive heart failure; TIA, transient ischemic attack; CVA, cerebrovascular accident; AST, aspartate aminotransferase, INR, international normalized ratio.
a Any transfusion given intraoperatively, in the postoperative recovery room, blood finishing from the operating room, or any blood given on POD 0.
b Complete laboratory data including missing presented in Supplementary Table 2.
Statistical analysis
We analyzed several preoperative and perioperative variables between patients with or without anemia with the chi-squared test for categorical variables and the independent samples t-test or Mann–Whitney U-test for normal and non-normal continuous variables. The primary outcomes were death or major morbidity at 30 days from the index surgery in the preoperative anemia group compared with the no anemia group.
We created separate univariable and multivariable logistic regression models for 30-day mortality and major morbidity. To accommodate model selection within the multiple imputation framework automated stepwise selection procedures (entry threshold ≤ 0.15, removal threshold > 0.25) were applied individually to the complete case data as well as each imputation set to generate candidate models. The final multivariable models were constructed by including any predictor exhibiting significant association with the outcome (p < 0.05) in any of the candidate models. Final model estimates were then generated by estimating the final multivariable model in the imputed dataset. We completed all statistical analyses using Stata 13.1 (StataCorp, College Station, TX), and considered two-sided p-values < 0.05 to be statistically significant.
Results
Of the 13,562 patients who underwent the hepatic procedures of interest, 575 patients met exclusion criteria and 12,987 were included in the analysis. The mean patient age was 59 and 48.4% were male. A total of 4260 (32.8%) patients met criteria for anemia. Of these, 3868 (29.8%) experienced mild anemia (hematocrit >29–<36% for women and >29–<39% in men), while 392 (2%) experienced moderate-severe anemia (hematocrit ≤29% for both women and men). Both the mild and moderate-severe anemia groups had increased rates of major morbidity and mortality compared to patients without anemia, but since there were relatively few patients with moderate-severe anemia we have decided to combine both groups as one group of patients having anemia in all further analyses.
Compared to patients without anemia, those with anemia were more likely to have other associated risk factors including increased age, lower performance status, higher prevalence of cardiovascular, pulmonary, renal, oncological and neurological disorders, higher American Society of Anesthesia (ASA) score, and abnormal preoperative laboratory studies (Table 1 and Supplementary Table 2). Furthermore, patients with anemia were more likely to have a more complex liver resection, longer operative times, longer hospital stay and more likely to receive perioperative transfusion (Table 1). On the other hand, patients with anemia had a lower prevalence of obesity, smoking and recent alcohol intake (Table 1).
Major morbidity
Of the 12,987 patients in the study, 3390 (26.1%) experienced major morbidity. Major morbidity was significantly higher for patients with anemia (25.6%) than for patients without anemia (17.1%, unadjusted odds ratio [ORunadjusted] 2.17, 95% CI 1.90–2.49). Moreover, compared with patients without anemia, patients with anemia had higher rates of almost all complications with organ space infection and postoperative sepsis the most common serious complication in both the no anemia and anemia groups (10.5% vs. 14.4%, p < 0.001; Table 2).
Table 2Postoperative complications in patients with and without preoperative anemia
| No anemia (n = 8727) | Anemia (n = 4260) | p-Value | |
|---|---|---|---|
| Any complication | 2375 (27.2%) | 1756 (41.2%) | <0.001 |
| Serious complications | 1489 (17.1%) | 1091 (25.6%) | <0.001 |
| Organ space infection | 500 (5.7%) | 310 (7.3%) | <0.001 |
| Postop sepsis | 419 (4.8%) | 304 (7.1%) | <0.001 |
| Postoperative bleeding | 259 (3.0%) | 255 (6.0%) | <0.001 |
| On ventilator >48h | 251 (2.9%) | 217 (5.1%) | <0.001 |
| Unplanned re-intubation | 253 (2.9%) | 185 (4.3%) | <0.001 |
| Pneumonia | 237 (2.7%) | 178 (4.2%) | <0.001 |
| Postop septic shock | 172 (2.0%) | 162 (3.8%) | <0.001 |
| Renal failure requiring dialysis | 77 (0.9%) | 77 (1.8%) | <0.001 |
| Deep surgical site infection | 76 (0.9%) | 60 (1.4%) | 0.005 |
| Pulmonary emboli | 101 (1.2%) | 49 (1.2%) | 0.97 |
| Cardiac arrest | 60 (0.7%) | 48 (1.1%) | 0.010 |
| Wound disruption | 62 (0.7%) | 40 (0.9%) | 0.17 |
| Myocardial infarction | 38 (0.4%) | 23 (0.5%) | 0.41 |
| Cerebrovascular accident with deficit | 30 (0.3%) | 16 (0.4%) | 0.77 |
| Coma >24h | 12 (0.1%) | 10 (0.2%) | 0.21 |
After adjustment for all potential confounders, patients with preoperative anemia were 21% more likely to develop major morbidity within 30 days than those without preoperative anemia (ORadjusted 1.21, 95% CI: 1.09–1.33) (Table 3). Anemia was associated with increased risk of major morbidity in patients who did not receive a perioperative transfusion, while anemic patients who did receive a perioperative transfusion were not subject to increased major morbidity. Anemia was significantly associated with an increased risk of major morbidity at 30 days in all age groups, for all surgical procedures, and in patients with and without malignancy (Table 3). Additional factors associated with major morbidity included perioperative transfusion, age and right or extended lobectomy were all also independently associated with an increased risk of major morbidity (p < 0.01, Supplementary Table 3).
Table 3Effect of preoperative anemia on 30 day mortality and major morbidity
| No anemia (n = 8727) | Anemia (n = 4260) | |
|---|---|---|
| Mortality | ||
| N | 143 (1.6%) | 136 (3.2%) |
| ORunadjusted | Reference | 1.98 (1.56–2.51) |
| ORadjusted | Reference | 0.88 (0.66–1.16) |
| Major morbidity | ||
| N | 1489 (17.1%) | 1091 (25.6%) |
| ORunadjusted | Reference | 1.67 (1.53–1.82) |
| ORadjusted | Reference | 1.21 (1.09–1.33) |
| Strata ORadjusted major morbidity | ||
| Age | ||
| <65 | Reference | 1.18 (1.03–1.34) |
| ≥65 | Reference | 1.26 (1.08–1.47) |
| Perioperative transfusion | ||
| Yes | Reference | 0.99 (0.83–1.18) |
| No | Reference | 1.32 (1.17–1.48) |
| Extent of resection | ||
| Partial lobectomy | Reference | 1.19 (1.04–1.36) |
| Right/Left/Extended | Reference | 1.21 (1.04–1.41) |
| Malignancy | ||
| No | Reference | 1.37 (1.00–1.85) |
| Yes | Reference | 1.18 (1.06–1.32) |
Thirty-day mortality
A total of 279 patients (2.1%) died within 30 days of surgery. Thirty-day mortality was significantly higher for patients with preoperative anemia (3.2%) compared to those without preoperative anemia (1.6%, ORunadjusted 1.98, 95% CI 1.56–2.51, p < 0.001). However, after adjustment for other risk factors, preoperative anemia was not an independent risk factor for 30-day mortality (Table 3, Supplementary Table 4). The c-statistics for multivariable models ranged from 0.70 to 0.87.
Of note, in our analysis we excluded those patients who were missing preoperative hematocrit levels and gender data. To assess the effect of the patients excluded due to missing data, we evaluated our multivariable models with anemia coded as present or absent for all missing values as a form of sensitivity analysis. We found no significant changes regarding the effect of preoperative anemia on major morbidity and mortality the results when we included the excluded patients in either group for analysis.
Discussion
In this large multicenter retrospective cohort study, we demonstrate that preoperative anemia is independently associated with an increased risk of 30-day major morbidity in patients undergoing hepatectomy, after adjusting for a number of known confounders. However, preoperative anemia was not independently associated with increased 30-day mortality in our model.
Our findings build upon the results of previous studies investigating the role of preoperative anemia on postoperative outcomes. For example, in the largest study to date, Tzeng et al. suggested that anemia (defined as hematocrit <39%) was associated with an increased risk of serious complications in patients undergoing hepatectomies, but their study was limited to elderly patients.
9
Our results build upon these findings and suggest that the negative effects of preoperative anemia persist regardless of age or type of liver surgery.We also found an interesting relationship between preoperative anemia and perioperative transfusion. Blood transfusions can be important in maintaining hemodynamic stability and end organ perfusion during complex surgeries. However, several studies in the different surgical specialties, including hepatopancreaticobiliary surgery, have shown that there may be negative effects of transfusion, including increased length of stay, surgical complications and mortality.
6
, 14
, 15
, 16
Though anemia and transfusion were independent risk factors for major morbidity in this study, there was no significant additive or multiplicative effect of having preoperative anemia and receiving a transfusion. This is likely because perioperative transfusion restores hematocrit and reduces the risk of complications due to anemia,7
, 16
, 17
but because there are risks inherently associated with transfusion, the overall rate of complications remains the same.The cause of anemia in the general population can be either due to nutritional deficiencies including iron deficiency, chronic disease or of unknown origin.
18
Patients with nutritional and iron deficiency can be easily evaluated and managed preoperatively if encountered. Iron deficiency anemia has been shown to predict worse outcomes after cardiac surgery and treatment of patients with congestive heart failure with parenteral iron improves their cardiac function.1
, 19
Several small studies have examined the role of parenteral iron prior to orthopedic surgery and currently a large multicenter randomized controlled trial is currently enrolling in the United Kingdom to assess the role of preoperative intravenous iron to treat anemia in major surgery (PREVENTT).20
, - Gonzalez-Porras J.R.
- Colado E.
- Conde M.P.
- Lopez T.
- Nieto M.J.
- Corral M.
An individualized pre-operative blood saving protocol can increase pre-operative haemoglobin levels and reduce the need for transfusion in elective total hip or knee arthroplasty.
Transfus Med. 2009 Feb; 19 (PubMed PMID: 19302453): 35-42
21
Furthermore, iron deficiency anemia is common in patients with malignancies22
and this warrants special attention as >80% of all patients in our study underwent liver resection for oncological reasons. Treatment of preoperative iron deficiency anemia may be important in this population to avoid perioperative transfusions as blood transfusions may have a detrimental effect on cancer specific outcomes after surgery.15
, 23
Morbidity and mortality rates after liver surgery have been improving steadily as surgeons have been able to improve modifiable factors that contribute to the development of complication after liver surgery. Tzeng et al. identified four categories of risk factors for complication after liver resection: surgical experience and volume, the culture of safety at a given hospital, extent of resection, and patient factors.
9
In recent years, centralization of major liver resections to high volume and teaching centers have contributed to improved patient outcomes.24
, 25
, 26
Meanwhile, there may be opportunities for the surgeon to carefully consider he last two categories during preoperative planning. For instance, the surgeon's judgment in using the appropriate extent of resection is important because larger resections are associated with higher rates of postoperative complications. However,with the improvements in surgical technique such as minimally invasive options and advances in anesthetic and postoperative care have allowed for complex procedures to be conducted without increased morbidity. In addition to choosing the least invasive procedure appropriate for the patient's condition, surgeons have the option to optimize preoperative risk factors to reduce the incidence of complications. Our results strongly suggest that more emphasis may need to be placed on identifying and managing anemia preoperatively to improve outcomes and reduce requirements for perioperative transfusion. However, managing anemia may be more successful for some etiologies than for others. For example, in many patients, iron-deficiency anemia can be treated via supplementation in the outpatient setting, while anemia associated with an underlying malignancy may be markedly more difficult to treat before surgery. In patients who can be treated, complete resolution of anemia may not occur before the desired date of surgical intervention. However, there is a lower risk of complications in patients with mild vs. moderate-severe anemia,7
so initiation of treatment before surgery may be beneficial.This study has some limitations. First, the NSQIP database only includes deaths and complications that occur within 30 days of surgical intervention, so we could not determine the effects of anemia on long-term complications. Second, few data are available for complications specific to hepatectomy, which may underestimate postoperative morbidity in this population. Third, it is not possible to identify patients who received less than four units of blood preoperatively using NSQIP data. Consequently, our analysis may have included a small number of patients who received less than 4 units of blood preoperatively although our intent was to exclude all preoperative transfusions. In addition, information about the etiology and time course of anemia was not available, though this information may be relevant to postoperative outcomes. Despite these limitations, the NSQIP database is a large and comprehensive sample of surgical experience across the United States and, because it includes so many perioperative variables, is an excellent tool for assessing the effects of preoperative factors on short-term outcomes.
In conclusion, our findings suggest that anemia is a serious condition that negatively impacts outcomes after liver resection. Whenever possible, efforts to identify and treat anemia prior to elective liver resection may be useful in maintaining physiological hemoglobin levels throughout the perioperative period. In addition to reducing the cost of care, successful management of preoperative anemia may ultimately result in better patient outcomes and improved quality of life.
ACS-NSQIP disclaimer
The American College of Surgeons National Quality Improvement Program and the hospitals participating in the ACS NSQIP represent the source of the data used herein; these institutions have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors.
Funding sources
Samer Tohme ST is funded by Americas Hepato-Pancreato-Biliary Association Research Award (S.T.), the National Cancer Institute Grant Number T32CA113263.
Conflicts of interest
None to declare.
Appendix A. Supplementary data
The following are the supplementary data related to this article:
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Article info
Publication history
Published online: November 13, 2015
Accepted:
September 22,
2015
Received:
September 21,
2015
Footnotes
This study was presented at the Annual Meeting of the AHPBA, 11–15 March 2015, Miami, Florida.
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© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Inc.
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