Malnutrition and the Development of Periprosthetic Joint Infection in Patients Undergoing Primary Elective Total Joint Arthroplasty

Malnutrition and the Development of Periprosthetic Joint Infection in Patients Undergoing Primary Elective Total Joint Arthroplasty

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Accepted Manuscript Malnutrition and the Development of Periprosthetic Joint Infection in Patients Undergoing Primary Elective Total Joint Arthroplasty Kier Blevins, BA, Arash Aalirezaie, MD, Noam Shohat, MD, Javad Parvizi, MD PII:

S0883-5403(18)30388-7

DOI:

10.1016/j.arth.2018.04.027

Reference:

YARTH 56591

To appear in:

The Journal of Arthroplasty

Received Date: 20 March 2018 Revised Date:

11 April 2018

Accepted Date: 12 April 2018

Please cite this article as: Blevins K, Aalirezaie A, Shohat N, Parvizi J, Malnutrition and the Development of Periprosthetic Joint Infection in Patients Undergoing Primary Elective Total Joint Arthroplasty, The Journal of Arthroplasty (2018), doi: 10.1016/j.arth.2018.04.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Malnutrition and the Development of Periprosthetic Joint Infection in Patients Undergoing Primary Elective Total Joint Arthroplasty

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Kier Blevins BA1 Arash Aalirezaie MD1 Noam Shohat MD1,2 Javad Parvizi MD1

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Running Title: Malnutrition in TJA and Risk for PJI

The Rothman Institute at Thomas Jefferson University, Philadelphia, PA

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Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel

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Corresponding Author Javad Parvizi MD, FRCS The Rothman Institute 125 S 9th St. Ste 1000 Philadelphia, PA 19107 P: 267-339-7813 F: 215-503-5651 [email protected]

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Malnutrition and the Development of Periprosthetic Joint Infection in Patients Undergoing

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Primary Elective Total Joint Arthroplasty

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Running Title: Malnutrition in TJA and Risk for PJI

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ABSTRACT

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Background: Although an abundance of literature exists linking malnutrition with infectious

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complications in surgical patients, there is little specifically examining the link between

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malnutrition and periprosthetic joint infection (PJI). This study evaluated the relationship

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between abnormal nutritional parameters and development of PJI in patients undergoing primary

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total joint arthroplasty (TJA).

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Methods: We retrospectively reviewed TJA patients from 2000-2016 with preoperative

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nutritional screening at a single institution. Any development of PJI at two years was assessed as

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the primary outcome. The Musculoskeletal Infection society (MSIS) criteria were used to define

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PJI. The association between the aforementioned nutritional markers and PJI was evaluated in a

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bivariate analysis followed by multivariate logistic regression. Performance for markers were

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assessed using receiver operator characteristic (ROC) curves. Sensitivity and specificity were

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also compared.

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Results: Multivariate analysis demonstrated that low Albumin (adjusted odds ratio (OR) 4.69,

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95% confidence interval (CI) 2.428-9.085, p<0.001) and low hemoglobin (adjusted OR 2.718,

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95% CI 1.100-2.718, p=0.018) to be significantly associated with PJI. Albumin had the highest

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specificity and (95% CI 97.8%-98.4%) and positive predictive value (PPV) compared to all other

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markers. Platelet to WBC ratio had the highest sensitivity (95% CI 29.5%-40.3%). The area

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under curve was greatest for Albumin (0.61, 95% CI 0.55-0.67) followed by Hemoglobin (0.57,

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95% CI 0.51-0.63), Platelets (0.56, 95% CI 0.50-0.62) and Platelets to WBC ratio (0.54, 95% CI

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0.49-0.60).

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Conclusion: The most valuable predictor of PJI following primary TJA, among nutritional

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parameters examined was preoperative albumin with a very high specificity and PPV.

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Keywords: Periprosthetic Joint Infection; Malnutrition; Total Joint Arthroplasty; Risk; Outcomes

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Introduction: Malnutrition has proven to be a critical risk factor for adverse surgical outcomes and increased postoperative mortality in various surgical specialties including orthopedics [1–4] .

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There is an abundance of evidence in the literature showing that malnutrition increases the risk

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of surgical site infection (SSI) in TJA [2,5–8]. Clinical signs and symptoms for malnutrition are

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not often detectable until they have progressed severely. Hence, multiple surrogates including

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laboratory values, anthropometric criteria and scoring systems have been introduced to assess

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malnutrition [9–11]. The primary laboratory values used to indicate a nutritional deficit are

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serum albumin, total lymphocyte count and serum transferrin. These have been used as a means

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of screening for preoperative nutritional status.

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At present time there is no gold standard test or metric for elucidating preoperative nutrition

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status of patients and their association with subsequent periprosthetic joint infection (PJI) in

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patients undergoing total joint arthroplasty. We examined a cohort of patients undergoing TJA

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with preoperative nutritional parameters and evaluated their propensity for developing PJI. The

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primary purpose of our study was to determine the most valuable marker for use as a surrogate

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for nutritional status in patients undergoing TJA.

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Materials and Methods

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Selection criteria and Data Sources

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Following institutional review board approval, we retrospectively reviewed all primary

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TJA procedures between the years 2000 to 2016. All TJA revision cases were excluded from the

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study. We queried all general patient demographics that included age, body mass index (BMI),

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Charlson comorbidity index, sex, type of joint operated (knee vs hip), and length of hospital stay

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(LOS). All preoperative nutrition and laboratory parameters from our primary TJA database

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were queried with 9,001 patients having available preoperative albumin values, 30,352 patients

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with platelet values, 30,367 with white blood cell (WBC) count values, and 30,369 patients with

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hemoglobin values available. Not all patients underwent preoperative nutritional screening for

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albumin, therefore only 9,001 patient records with albumin were ascertained. Patients with the

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available lab parameters of interest in our primary TJA database were then crossed matched to

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our prospectively-maintained institutional PJI database to identify those who developed PJI after

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their index arthroplasty.

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Preoperative Data and Outcomes

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The primary outcome assessed was development of PJI at two years with the diagnosis of

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PJI being established using the Musculoskeletal Infection Society (MSIS) criteria [12]. A manual

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chart review was performed to confirm the diagnosis of PJI. Malnutrition was defined based on

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having at least one of the following serum marker values: albumin <3.5g/dL, WBC count <4

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cells x 103/µL, platelets <150 cells x 103/µL, hemoglobin <12g/dL, platelet to white blood cell

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count ratio of <28.57. These values were selected on the basis of current literature suggesting

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these levels to be associated with poor nutritional [13,14].

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The platelet to white blood cell count ratio of <28.57 was selected because it was the threshold for the lower quartile of our studies values and because recent literature suggested its

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utility as a signal in a patient’s ability to mount an inflammatory response [15–17].

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Statistical Analysis

For each of the nutritional parameters of interest, patients were stratified into two groups with one group considered malnourished based on previous definitions discussed and the other

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group having no nutritional deficits. These groups were further evaluated on the likelihood of

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developing PJI. The association between the aforementioned nutritional markers and PJI was

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evaluated in a series of bivariate analyses followed by multivariate logistic regression. This

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relationship was examined both considering the nutritional markers as a continuous variable and

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stratifying based on categories (with cutoffs described above). Categorical variables were

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analyzed with a Chi square test and continuous variables with a Student's t-test. Variables that

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demonstrated an association with postoperative infection (defined as a p<0.2) in bivariate

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analysis were included in the logistic regression model after being scanned for multicollinearity.

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Sensitivity and specificity of each of these markers were calculated as well. Finally, a receiver

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operator characteristic (ROC) curve analysis was performed and the area under the curve (AUC)

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was calculated for the risk of PJI. AUC scores are typically considered acceptable if they exceed

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0·7, with an AUC of 0·5 representing a poor test (no better than chance) and an AUC of 1·0

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signifying a perfect test.

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Results

Overall 30,863 patients undergoing 17,554 THA and 15,483 TKA procedures were

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included in the present study. Mean age was 63.48 (SD ± 11.7), average BMI was 30.04 kg/m2

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(SD ± 6.8), and 43.72% of patients were men (n=14,446). In total, 314 patients (1.02%)

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developed PJI within 2 years of surgery. The characteristics of the patient population are

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presented in Table 1 and Table 2.

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In the bivariate analysis (Table 3), patients with low albumin levels (p<0.001), low

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platelet count (p=0.005), low hemoglobin (p<0.001) and low platelets to WBC ratio (p<0.001)

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were more likely to develop PJI. However, in the multivariate logistic regression analysis (Table

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3), only low albumin (adjusted odds ratio (OR) 4.69, 95% confidence interval (CI) 2.428-9.085,

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p<0.001) and low hemoglobin (adjusted OR 2.718, 95% CI 1.100-2.718, p=0.018) were found to

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be independent factors associated with PJI. Albumin was also the most specific marker (95% CI 97.8%-98.4%) and had the highest

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positive predictive value (PPV) compared to all other markers (Table 4). The highest sensitivity

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was seen with platelet to WBC ratio (95% CI 29.5%-40.3%). The area under curve (AUC)

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(Table 5) was greatest for albumin (0.61, 95% CI 0.55-0.67) followed by hemoglobin (0.57, 95%

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CI 0.51-0.63), platelets (0.56, 95% CI 0.50-0.62), and platelets to WBC ratio (0.54, 95% CI 0.49-

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0.60).

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Discussion

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Because of its dire nature, prevention of periprosthetic joint infection (PJI) has become a priority for the orthopedic community [18–20]. In recent years efforts have been invested to

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identify modifiable risk factors that result in PJI following total joint arthroplasty (TJA)[21–24].

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One potentially modifiable factor that has been demonstrated to be associated with postsurgical

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infections in various surgical disciplines is malnutrition[2,6,25,26]. The literature has shown

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specific parameters to be indicative of malnutrition, these values include total lymphocyte count

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<1500 cells/mm3, albumin <3.5g/dL, transferrin <200mg/dL and prealbumin <15gm/dL

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[13,14,27–29]. Albumin, in particular, is a widely utilized marker for indicating a patients overall

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nutrition status in orthopedics [14]. Hypoalbuminemia can be defined as being less than

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<3.5g/dL and is the standard cut off measure used in defining malnutrition[13,14]

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It is believed that over half of patients undergoing total knee arthroplasty (TKA) are

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found to have abnormal nutritional parameters in the postoperative period [30]. In recent years,

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and with the rising interest in prevention of postoperative infections, the issue of malnutrition

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and its influence on infections has gained further attention[2,7,26,31]. Although laboratory tests

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to assess nutritional status are available, it is not known which of the laboratory tests measured is

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most significantly associated with subsequent infection. Further, it is not known which group of

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patients are likely to be “malnourished” and should be assessed. This study was designed to

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study which, if any, definitive surrogate marker for nutritional status would be valuable in

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predicting the development of PJI in patients undergoing primary TJA. Of the aforementioned

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laboratory values analyzed in our study, we found albumin to have the highest specificity and

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highest PPV of the measured parameters. While the platelet to WBC ratio was the most sensitive

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of the parameters examined for predicting the development of PJI, none of our measured

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parameters exhibited a high sensitivity. A multivariate analysis was conducted to isolate the

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independent factors associated with PJI in this cohort. Serum albumin and hemoglobin were

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found to be independently associated with PJI.

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Both malnutrition and undernourishment are relatively common in hospitalized patients

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with a prevalence of 25% at admission in some European hospital systems [32]. Malnutrition is

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not solely limited to underweight patients with caloric deprivation, it is also seen in those with

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elevated BMIs and obesity[33]. Courtney et al. retrospectively reviewed a series of 670 patients

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undergoing TJA for morbid obesity and nutritional status in accordance with postoperative

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complication rates [33]. They found there to be an increased prevalence of malnutrition in the

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morbidly obese group of patients in comparison to those who were not morbidly obese. They

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also observed that an increased rate of complications occurred in the malnourished group of

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patients independent of obesity. They concluded that morbidly obese patients with poor nutrition

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had an increased risk for complications [33].

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In another study, Huang et al. in a prospective study examined the rate of complications during a 12 month period after TJA in patients who had nutritional parameters measured prior to

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their index arthroplasty[25]. They found a higher rate of complications, including infection, in

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patients with low albumin (<3.5g/dL) [7]. Various other studies have also shown an increased

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rate of surgical site infections after revision and primary TKA in patients with albumin levels

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below 3.5g/dL [6,34]. Bohl et al., in examining patients who had undergone revision THA and

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TKA, noticed a higher rate of hypoalbuminemia (42.8% vs. 11.8%) in patients undergoing

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revision for septic indications in comparison to those undergoing aseptic revision [5]. Of the

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patients with aseptic indication for revision, patients with hypoalbuminemia had a higher rate of

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PJI (4.5% vs. 2.1%) in comparison to those with normal serum albumin levels.

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In concordance with prior studies, the current study found albumin to have the greatest association (OR=4.697, p<.001) with subsequent PJI. It is not surprising to observe that patients

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with low albumin had a higher incidence of PJI. Albumin is an essential constituent of serum that

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plays a critical role in wound healing and immune function [30,35–37]. Albumin is also one of

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the most abundant proteins in the serum that transports a variety of fatty acids, steroids, and

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hormones[38]. Its ubiquitous nature allows it to serve its primary function in regulating the

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colloid osmotic pressure of blood.

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The reason for the association between hypoalbuminemia and PJI is most likely

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multifactorial. Patients with low albumin are likely to suffer from a global malnutrition and lack

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of other important vitamins and dietary essentials that are important for wound healing and

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proper immune function [35,36]. Malnourished patients undergoing elective TJA may be

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exhibiting poor immunocompetence as result of a lack in nutrients necessary for optimal cellular

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function. A clinical trial by Cao et al. had primary TKA patients undergo a multimodal

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nutritional management supplement prior to surgery. These patients had lower rates of both

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superficial and deep infection in comparison to the group that did not have nutritional

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interventions[39]. Another reason for the association between hypoalbuminemia and subsequent

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PJI, can be that patients with low albumin are more likely to suffer from comorbidities such as

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liver disease, cardiac disease, or renal malfunction, all of which are associated with a higher

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complications, including infection, following surgical procedures [40,41]. Finally, those

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consuming alcohol or cigarettes may be at greater risk for malnutrition as well as complications

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following surgical procedures[42–45].

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Another finding of this study, which reflects what is already known, was that patients

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with low hemoglobin were more likely to develop PJI following TJA[46]. There is again a

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multitude of reasons to explain this association. Patients with anemia may suffer from chronic

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conditions such as renal disease. Low hemoglobin, and low oxygen carrying capacity of the

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blood, may result in poor wound healing and subsequent infection [47,48]. Patients with anemia

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may require allogeneic blood transfusion, with its immunomodulating effect [49,50].

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The current study highlights some important findings. First, the study found that among all nutritional parameter examined, albumin had the highest association with subsequent PJI.

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Based on this compelling data, we believe it is justified to measure serum albumin level in

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patients undergoing elective arthroplasty. Although not proven by the current study, we speculate

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that work up of patients with low albumin and correction of this nutritional parameter is likely to

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lower the incidence of all time complications, including PJI. Based on the findings of this study,

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we will be implementing institution wide practice to measure, and if necessary correct, the level

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of albumin in patients undergoing elective arthroplasty.

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It is important to note that the current study suffers some limitations. The most important

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limitation relates to the retrospective nature of the study, with all its inherent shortfalls. Another

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limitation of the study was that not all patients had nutritional parameters measured and among

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those with assessed nutritional parameters, prominent nutritional markers (transferrin,

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prealbumin, total lymphocyte count) were unavailable in our institutional database. Thus, we

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were unable to examine the influence of these values on subsequent PJI.

We believe that the nutritional paradigm regarding surgical patients and adverse outcomes

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extends deeply into the realm of orthopedics. Our study falls in line with current literature to

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support the notion that poor nutritional status may serve as a predictor for PJI. Further work

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should focus on the outcomes after correctional measures have been taken to offset nutritional

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deficits in TJA patients.

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[31] Bohl DD, Shen MR, Kayupov E, Della Valle CJ. Hypoalbuminemia Independently Predicts Surgical Site Infection, Pneumonia, Length of Stay, and Readmission After Total Joint Arthroplasty. J Arthroplasty 2016;31:15–21. doi:10.1016/j.arth.2015.08.028. [32] Löser C. Malnutrition in Hospital. Dtsch Ärztebl Int 2010;107:911–7. doi:10.3238/arztebl.2010.0911. [33] Courtney PM, Rozell JC, Melnic CM, Sheth NP, Nelson CL. Effect of Malnutrition and Morbid Obesity on Complication Rates Following Primary Total Joint Arthroplasty. J Surg Orthop Adv 2016;25:99–104. [34] Nelson CL, Elkassabany NM, Kamath AF, Liu J. Low Albumin Levels, More Than Morbid Obesity, Are Associated With Complications After TKA. Clin Orthop 2015;473:3163–72. doi:10.1007/s11999-015-4333-7. [35] Jones RE. Wound healing in total joint arthroplasty. Orthopedics 2010;33:660. doi:10.3928/01477447-20100722-35. [36] Gherini S, Vaughn BK, Lombardi AV, Mallory TH. Delayed wound healing and nutritional deficiencies after total hip arthroplasty. Clin Orthop 1993:188–95. [37] Karahan A, AAbbasoğlu A, Işık SA, Çevik B, Saltan Ç, Elbaş NÖ, et al. Factors Affecting Wound Healing in Individuals With Pressure Ulcers: A Retrospective Study. Ostomy Wound Manage 2018;64:32–9. [38] Farrugia A. Albumin Usage in Clinical Medicine: Tradition or Therapeutic? Transfus Med Rev 2010;24:53–63. doi:10.1016/j.tmrv.2009.09.005. [39] Cao G, Huang Q, Xu B, Huang Z, Xie J, Pei F. Multimodal Nutritional Management in Primary Total Knee Arthroplasty: A Randomized Controlled Trial. J Arthroplasty 2017;32:3390–5. doi:10.1016/j.arth.2017.06.020. [40] Poultsides LA, Triantafyllopoulos GK, Sakellariou VI, Memtsoudis SG, Sculco TP. Infection risk assessment in patients undergoing primary total knee arthroplasty. Int Orthop 2018;42:87–94. doi:10.1007/s00264-017-3675-z. [41] Abblitt WP, Chan EW, Shinar AA. Risk of Periprosthetic Joint Infection in Patients With Multiple Arthroplasties. J Arthroplasty 2018;33:840–3. doi:10.1016/j.arth.2017.10.024. [42] Kunutsor SK, Whitehouse MR, Blom AW, Beswick AD, INFORM Team. Patient-Related Risk Factors for Periprosthetic Joint Infection after Total Joint Arthroplasty: A Systematic Review and Meta-Analysis. PloS One 2016;11:e0150866. doi:10.1371/journal.pone.0150866. [43] Alijanipour P, Heller S, Parvizi J. Prevention of periprosthetic joint infection: what are the effective strategies? J Knee Surg 2014;27:251–8. doi:10.1055/s-0034-1376332. [44] World MJ, Ryle PR, Thomson AD. Alcoholic malnutrition and the small intestine. Alcohol Alcohol Oxf Oxfs 1985;20:89–124. [45] Preston AM. Cigarette smoking-nutritional implications. Prog Food Nutr Sci 1991;15:183– 217. [46] Greenky M, Gandhi K, Pulido L, Restrepo C, Parvizi J. Preoperative anemia in total joint arthroplasty: is it associated with periprosthetic joint infection? Clin Orthop 2012;470:2695–701. doi:10.1007/s11999-012-2435-z. [47] Hunt TK, Rabkin J, von Smitten K. Effects of edema and anemia on wound healing and infection. Curr Stud Hematol Blood Transfus 1986:101–13. [48] Aksamija G, Mulabdic A, Rasic I, Aksamija L. Evaluation of Risk Factors of Surgical Wound Dehiscence in Adults After Laparotomy. Med Arch Sarajevo Bosnia Herzeg 2016;70:369–72. doi:10.5455/medarh.2016.70.369-372.

AC C

292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337

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[49] Janssen SJ, Braun Y, Wood KB, Cha TD, Schwab JH. Allogeneic blood transfusions and postoperative infections after lumbar spine surgery. Spine J Off J North Am Spine Soc 2015;15:901–9. doi:10.1016/j.spinee.2015.02.010. [50] Prittie JE. Controversies related to red blood cell transfusion in critically ill patients. J Vet Emerg Crit Care San Antonio Tex 2001 2010;20:167–76. doi:10.1111/j.14764431.2010.00521.x.

RI PT

338 339 340 341 342 343 344

AC C

EP

TE D

M AN U

SC

345

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Table 1. Patient Demographics

Parameters

Value of number 30863

No. Joints (Hip/Knee)

of

33037 (17554/15483)

Stay

3.2

SC

Mean Length (days)

Mean age (y) at surgery

M AN U

63.48 ±11.7

Gender (male/female)

14446/18591

Mean BMI (kg/m2)

30.04±6.8

5

6

7

8

EP

4

AC C

3

314/30,053

TE D

PJI/Non-PJI 2

RI PT

No. of patients

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Table 2. Patient Lab Markers

Abnormal

Normal

Albumin

178 (<3.5g/dL)

8823 (>3.5g/dL)

1.97%

98.02%

M AN U

96.49%

575 (<4 cells x 103/µL)

29792 (>4 cells x 103/µL)

1.89%

98.11%

4185 (<12g/dL)

26184 (>12g/dL)

EP AC C

Platelet to White Blood Cell

2

29288 (>150 cells x 103/µL)

3.51%

TE D

White Blood Cells

Hemoglobin

SC

1064 (<150cells x 103/µL)

Platelets

RI PT

Lab Markers

13.78%

86.21%

7566 (< 28.57)

22783 (>28.57)

24.92%

75.07%

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Bivariate

Multivariate

PJI

No PJI

P-Value

Adjusted OR

95% CI

P-Value

Albumin <3.5g/dL

13/112 (11.6%)

165/8684 (1.9%)

p<0.001

4.697

2.428-9.085

0.000

Platelets <150cellsx 103/µL

21/313 (6.7%)

1043/29800 (3.5%)

p=0.005

1.472

0.729-2.972

0.281

7/318 (2.2%)

568/29895 (1.9%)

p=0.673

-

-

-

82/314 (26.1%)

4103/29949 (13.7%)

p<0.001

1.729

1.100-2.718

0.018

109/314 (34.7%)

7457/30069 (24.8%)

p<0.001

1.227

0.799-1.885

0.351

2/314 (0.01%)

274/ 30069 (0.01%)

p=0.758

-

-

-

Hemoglobin <12g/dL Platelet to White Blood Cell ratio < 28.57 BMI <18.5

2

EP

5

Table 3. Bivariate and Multivariate Analysis of Lab Test and PJI

AC C

4

TE D

3

M AN U

103/µL

SC

White Blood Cells <4 cells x

RI PT

Test

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1 Test Result Albumin <3.5g/dL

Sensitivity

Specificity

PPV

11.6% (6.3%-19.0%)

98.1% (97.8%-98.4%)

7.3% (4.4%-11.8)

NPV 98.9% (98.8%-

6.7% (4.2%-10.0%)

26.0%(21.3%-31.3%)

Hemoglobin <12g/dL

34.7% (29.5%-40.3

Platelet to White Blood Cell ratio < 28.57

3

86.4% (85.9%-86.7%)

75.2% (74.7%-75.7%)

M AN U

2

96.5% (96.3%-96.7%)

2.0% (1.3%-3.0%)

2.0% (1.6%-2.4%)

SC

Platelets <150cellsx 103/µL

RI PT

98.95%)

1.4%(1.2%-1.7%)

Table 4. Lab Test Sensitivity, Specificity, PPV and NPV

AC C

EP

TE D

4

99.0% (98.9%99.0%) 99.1%(99.1%99.2%) 99.1% (99.0%99.2%)

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Test Result Variable(s)

Area Under Curve

Std. Error

Albumin

0.61

Platelet

Upper Bound

0.029

0.554

0.666

0.559

0.031

0.497

0.62

Hemoglobin

0.568

0.03

0.509

0.627

Plt to wbc ratio

0.543

0.028

0.488

0.598

SC

RI PT

Lower Bound

2

Table 5. Area Under the Curve (AUC) Data for Various Laboratory Markers Assessed.

M AN U

3

Asymptotic 95% Confidence Interval

AC C

EP

TE D

4