Weight-adjusted low molecular weight heparin with surgery morning dose administration: Impact on hip hemiarthroplasty early infections

Abstract

BACKGROUND

Several studies have questioned the efficacy of the standard perioperative low-molecular-weight heparin (LMWH) dose in preventing venous thromboembolic complications and have recommended dose escalation to a weight-based regimen. Other studies, however, have cautioned that higher anticoagulation regimens may be associated with an elevated risk of wound complications and periprosthetic joint infections. This dichotomy underscores the need for identifying the safety of the thromboprophylaxis approach in surgical settings.

AIM

To analyze the effect of LMWH regimen modification to weight-based with dose administration the morning of surgery on the incidence of early (within 3 months) postoperative prosthetic joint infection (PJI) in patients with hip hemiarthroplasty (HA).

METHODS

At our multi-hospital health system, LMWH dose escalation to the weight-based regimen without holding the morning dose on the day of surgery started in mid-June 2019. We have reviewed all cases of HA performed at our institution from 2007 to 2024 and divided them into two groups: Before and after the dose modification protocol. The number of early PJI cases has been studied in each group.

RESULTS

A total of 33 HA early PJI cases fit the study selection criteria and were included in this study. Of the 1517 cases performed before the new protocol, 19 cases (1.25%) had early infections, while within the modified protocol (weight-based with morning dose), 14 cases (1.49%) had infections out of a total of 937 cases. The difference between the two groups was found to be not statistically significant (z = -0.5, P = 0.6).

CONCLUSION

Our results indicate that LMWH dose escalation to a weight-based regimen without withholding the LMWH morning dose on the day of surgery did not lead to a significant change in the rate of early PJI in this study. A larger, multicenter study would be ideal for providing stronger evidence.

Key Words: Prosthetic joint; Periprosthetic; Infection; Hematoma; Anticoagulant; Enoxaparin; Hip hemiarthroplasty

Core Tip: This study evaluated whether switching to a weight-based low-molecular-weight heparin (LMWH) regimen with morning-of-surgery dosing affects early prosthetic joint infection (PJI) rates in patients with hip hemiarthroplasty. No statistically significant difference in early PJI rates was observed between the standard and modified LMWH protocols. These findings suggest that LMWH dose escalation does not significantly impact early PJI risk, although larger studies are warranted.

INTRODUCTION

Management of prosthetic joint infection (PJI) continues to be one of the most challenging issues in orthopedic surgery[1,2]. Identification of the risk factors for PJI has long been an area of interest in orthopedic research to decrease their incidence and subsequently the associated substantial morbidity and mortality[3,4]. Among the potential risk factors, delayed wound healing, wound dehiscence, and persistent wound drainage have been correlated with a higher incidence of PJI[5,6].

Over the past few decades, several studies have identified a direct correlation between the use and dosage of perioperative anticoagulation therapy and the development of PJI in patients undergoing orthopedic trauma surgery and total joint arthroplasty[7-9]. Given the progressively emerging evidence that questions the efficacy of the standard[10,11], fixed-dose low molecular weight heparin (LMWH) therapy in the prevention of postoperative venous thromboembolic (VTE) complications[12-16], several studies have recommended escalating the doses of these drugs to a precise weight-based regimen[11,12,14].

The timing of LMWH initiation and regimen is also a debatable subject. While holding the LMWH prophylactic dose the morning of surgery is widely practiced in several institutions to decrease the risk of intraoperative bleeding, other institutions do not routinely hold preoperative LMWH before surgery[17,18]. Whereas missing a single dose of prophylactic anticoagulants has been shown to increase the incidence of VTE complications[19], Moloney et al[20] in 2023 studied the effect of administering the morning dose of prophylactic enoxaparin in geriatric femoral fracture open reduction and internal fixation patients and found no increase in blood transfusion, wound drainage, and 30-day mortality compared to patients who had their surgery morning dose withheld. Surgeons must weigh the advantages and disadvantages of anticoagulant dose escalation with regard to the amount given and the timing of the last preoperative dose.

Hip hemiarthroplasty (HA) remains one of the most common treatment options for displaced femoral neck fractures[21,22]. It is mostly performed in older, frail patients who often have more medical comorbidities compared to patients undergoing total hip arthroplasty. The combination of these factors, along with variations in surgical settings and the presence of trauma, likely increases the susceptibility of HA patients to PJIs and their associated morbidity. This may account for the higher reported incidence of PJIs following HA compared with elective total hip arthroplasty (approximately 1.6%-10% vs 0.2%-2%, respectively)[23-25].

While most studies analyzing anticoagulation dosage and efficacy focused on total joint arthroplasty[6-9] or general orthopedic trauma and burns[10-14], no studies have attempted to analyze the effect of LMWH dosing on the development of postoperative PJIs in HA for trauma patients. In our multihospital health system, a standardized protocol for weight-based anticoagulant dosing, with preoperative administration on the day of surgery, was introduced in mid-June 2019. This retrospective review evaluated and compared the incidence of postoperative PJI before and after implementation of the revised protocol. To the best of our knowledge, no prior studies have specifically examined the effect of anticoagulant dose escalation on PJI risk in the context of hemiarthroplasty. Accordingly, this study is intended to provide preliminary evidence that may inform future investigations, rather than deliver definitive conclusions that require higher-level study designs.

MATERIALS AND METHODS

After institutional review board approval, we retrospectively evaluated our entire institutional electronic medical record database for all patients who underwent hemiarthroplasty for proximal femur fractures, as identified by their surgical codes. Data collected included patient demographics, clinical information, and radiographic evaluation. Detailed information about follow-up and postoperative clinical courses was collected.

Inclusion criteria

Patients who underwent hemiarthroplasty for hip fracture surgery, and had a diagnosis of postoperative PJI that required additional surgical intervention.

Exclusion criteria

Patients who had PJI presented more than 3 months after the hemiarthroplasty (index) surgery, i.e., late cases of PJI[26]; patients who had no records of perioperative LMWH administration; patients who had negative bacterial cultures.

At our institution, based on a multidisciplinary decision from the trauma, orthopedic, and pharmacy departments, the perioperative protocol for anticoagulant chemoprophylaxis with LMWH has been introduced since mid-June 2019. This was done to combat an unexpected increase in thromboembolic complications. Before this date, anticoagulant protocols were used per standard regimens (mostly 30-60 mg/day), which did not necessarily align with the patient's weight, and the LMWH dosing was held either the morning of surgery or the night before surgery in some cases. After this modification, the standard of care was modified to escalate the prophylactic anticoagulant protocol to a weight-based regimen (enoxaparin subcutaneous 0.5 mg/kg/quaque 12 hora) with a dose given on the morning of the surgery (i.e., weight-based + morning dose protocol). To analyze the effect of this protocol change, we have divided all the hemiarthroplasty cases at our institution into two groups: Before and after the modification. Cases with early postoperative infection in each group were identified and compared.

Statistical analyses

Statistical analyses were performed using Microsoft Excel version 2505. The mean values, standard deviation, and proportions were calculated. To compare the two groups’ statistical significance, a two-tailed Z-test, χ², or Fisher’s exact test, where applicable, was used to compare the proportional values, and the two-sample t test was used to compare the difference in the means. P > 0.05 was considered insignificant. A post-hoc power analysis was conducted using the infection rates observed in both study groups to determine the statistical power of the comparison. The analysis was performed using a two-sided Z-test for proportions, with a significance level (α) of 0.05.

RESULTS

A total of 2454 hemiarthroplasty cases, performed between 2007 and 2024, were reviewed in this study. Of them, a total of 33 early PJI cases (33 patients) fit the selection criteria and were included in the final analysis of the study. Patients were 23 women and 10 men (ratio 2.3:1) with a mean age of 79.9 years (range 52-98) at the time of surgery. Twenty-three cases had bipolar, and ten cases had unipolar hemiarthroplasty. Twenty-five cases had cemented, and eight had cementless stems. Twenty-seven cases had significant and often combined medical comorbidities, as shown in Table 1. The mean body mass index for the patients was 26.9 (range, 16.2-50.4). Nine patients (27.3%) died in the first 12 weeks after index surgery (average 8 weeks). The average follow-up for all cases was 40.5 months (range, 1.6-161 months).

Table 1 Medical comorbidities in the prosthetic joint infection cases.

Comorbidities	Cases
Diabetes mellitus	10
Heart failure	9
Chronic kidney disease	8
Hypothyroidism	4
Dementia	3
Epilepsy	3
Lymphoma	1

The cases presented after a mean of 4.56 weeks (range 1.2-11.1 weeks) postoperatively with either persistent wound drainage, wound sinus, hip pain, prosthesis dislocation, or wound swelling and inflammation. All of the cases underwent at least one surgical intervention to manage the infection, in the form of either wound debridement and irrigation, exchange of modular components, placement of an antibiotic spacer, revision arthroplasty, or Girdlestone procedure. Bacterial cultures were positive in all 33 cases.

A total of 1517 cases were performed within the standard protocol period; of these, 19 cases (1.25%) had early postoperative infections. From mid-June 2019, when the weight-based morning dose regimen started, 14 cases of infections were reported out of a total of 937 cases (1.49%, Table 2). The difference between the two groups was not found to be statistically significant (z = -0.5, P = 0.6; χ², P = 0.6), indicating no significant change in the incidence of PJI after LMWH dose modification. The characteristics of patients with early PJI in both groups are presented in Table 3. Distribution of the actually administered LMWH doses in the early PJI cases was presented in Figure 1.

Figure 1 Distribution of the administered low-molecular-weight heparin among the early prosthetic joint infection cases in each group. PJI: Prosthetic joint infection.

Table 2 Results for each patient’s group, n (%).

Measurement period	2007 to June 15, 2019	After June 15, 2019	P value (two-tailed z test)
Total number of hemiarthroplasty cases	1517	937
Number of cemented stem cases	1086 (71.58)	692 (73.8)	P = 0.2; z = -1.2 at a 95% confidence interval
Number of active smokers at the time of HA surgery	62 (4.09)	46 (4.9)	P = 0.33; z = -0.96 at a 95% confidence interval
Number of early PJI cases in the first 12 weeks	19 (1.25)	14 (1.49)	P = 0.6; z = -0.5 at a 95% confidence interval

The dose was routinely adjusted for renal function based on guidelines for surgical thromboprophylaxis. Adherence to the prescribed protocol was confirmed via review of the electronic medication administration record. HA: Hip hemiarthroplasty; PJI: Prosthetic joint infection.

Table 3 Characteristics of the cases with early postoperative infection, n (%)/mean ± SD.

Measurement period	2007 to June 15, 2019 (n = 19)	After June 15, 2019 (n = 14)	P value
Age (years)	80.96 ± 12.1	78.6 ± 8.5	P = 0.5 (NS, t test1)
BMI	27.9 ± 7.1	25.6 ± 7	P = 0.36 (NS, t test)
Diabetes mellitus	4 (21)	7 (50)	P = 0.136 (NS, Fisher’s exact test)
Chronic kidney disease	5 (26.3)	3 (21.4)	P = 1 (NS, Fisher’s exact test)
Time of presentation (weeks)	5 ± 2.5	4.5 ± 2.6	P = 0.58 (NS, t test)

¹Unpaired t test.

BMI: Body mass index; NS: Not significant.

As for the microbiology and management of infection, consistent with the typical presentation of early postoperative infection, all 33 cases may be classified as nosocomial (with symptoms presenting after the first 48 hours of admission), especially the cases presented within 30 days of admission (20 cases, 60.6%). The microbiological analysis revealed a diverse spectrum of pathogens. The most frequently identified organisms were Gram-positive cocci, which dominated the etiological landscape. Methicillin-resistant Staphylococcus aureus was the single most common pathogen, identified in 10 out of the 33 cases (30.3%). Other significant Gram-positive isolates included methicillin-sensitive Staphylococcus aureus and various species of Enterococcus. Polymicrobial infections were a notable feature, present in 7 cases (21.2%), often involving combinations of Gram-positive bacteria with Gram-negative rods such as Escherichia coli, Pseudomonas aeruginosa, and Enterobacter species, or less commonly, with Candida species. Following surgical intervention, all 33 patients universally received courses of culture-directed intravenous antibiotics as a mandatory component of the standard institutional protocol for managing confirmed PJIs.

A post-hoc power analysis revealed a study power of 7.9%, which is substantially low to detect a meaningful difference. To achieve 80% power to detect an absolute risk difference of 1% (from a baseline of 1.25%), a total sample size of approximately 5286 patients (2643 per group) would be required to achieve this power. In a trial of minimizing potential confounders, a separate analysis was performed, excluding the patients who died within the first 30 days postoperatively, who may not have had sufficient exposure time to develop PJI. Accordingly, a total of 165 cases that died within 30 days after the index HA surgery and did not have a history of early PJIs were excluded, leaving 2289 cases for analysis (Table 4). The incidence of early PJIs, the number of diabetic cases, and the number of cases with body mass index ≥ 30 did not show statistically significant differences (P > 0.05; Table 4).

Table 4 Subgroup analysis after excluding the cases that died within 30 days post-op, n (%).

Measurement period	2007 to June 15, 2019	After June 15, 2019	P value (two-tailed z test)
Total number of hemiarthroplasty cases	1395	894
Number of early PJIs in the first 12 weeks	19 (1.36)	14 (1.56)	P = 0.69; z = -0.4 at a 95% confidence interval
Number of diabetic cases	43 (3.08)	35 (3.91)	P = 0.28; z = -1 at a 95% confidence interval
Number of cases with BMI ≥ 30	225 (16.12)	160 (17.89)	P = 0.27; z = -1 at a 95% confidence interval

BMI: Body mass index; PJIs: Prosthetic joint infections.

DISCUSSION

This retrospective study investigated the effect of changing the perioperative LMWH dosing protocol to a weight-based regimen without holding the morning surgery dose on the development of early periprosthetic infection in patients undergoing hip hemiarthroplasty. Our results suggest that protocol modification did not increase the incidence of early PJI. Given the low study power, our findings are preliminary, and a much larger and ideally multicenter study would be required to achieve adequate power to detect or rule out a clinically significant difference.

Displaced femoral neck fractures in elderly patients are frequently managed with HA[21]. Deep periprosthetic infection after arthroplasty is a devastating complication that is associated with high morbidity and mortality[3]. Several studies have analyzed the potential risk factors for developing postoperative infections after HA[27-29]. Factors such as pressure sores, urinary tract infections, diabetes mellitus, delayed wound healing, presence of malignancies and administration of chemotherapy or local radiotherapy, and poor nutritional status have all been identified as potential risk factors[27-29]. These factors are frequently present in combination in elderly patients with displaced femoral neck fractures[30]. Among all these factors, delayed wound healing and the occurrence of hematoma have been subjects of concern in orthopedic research, given their strong correlation with the development of PJI in multiple studies[5,6].

Another potentially devastating complication in hip fracture surgery is venous thromboembolism (VTE). With increased mindfulness of VTE complications after hip fracture surgery and advances in the diagnostic tools, it has been estimated that the incidence of deep vein thrombosis reaches as high as 70%, and fatal pulmonary embolism ranges between 6.7% and 8% of patients within 3 months of hip surgery[16,31]. As anticoagulation chemoprophylaxis was found to reduce the rate of deep vein thrombosis by approximately 68%[32], routine pharmacological thromboprophylaxis is recommended in hip fracture surgery according to the American College of Chest Physicians and the American Academy of Orthopedic Surgeons guidelines[33,34]. On many occasions, though, the surgeon is left to decide which drug to use, when to start it, at what dose and frequency, and how long to use it, given the recent development in VTE diagnostic tools and the debated best strategies among various governing bodies, especially in trauma patients[16,20].

For perioperative chemoprophylaxis against VTE complications, enoxaparin 40 mg daily or 30 mg twice daily, or fondaparinux 2.5 mg daily, without strict weight-based titration, are the standard regimens in orthopedic trauma[16,20,35,36]. Since VTE rates in orthopedic trauma patients still reach 13.4% despite the standard chemoprophylaxis[10], the effectiveness of this dosage for the prevention of VTE complications was questioned in several studies[10-16,37]. Jones et al[16] found that standard fixed-dose enoxaparin provided inadequate chemoprophylaxis in 43% of postoperative orthopedic trauma patients, which significantly improved with dose escalation to weight-based doses. The authors also concluded that inadequate enoxaparin dosing may functionally be equivalent to a delay in prophylaxis, as inadequate dosing resulted in a decreased amount of anti-factor Xa, an indicator of the effectiveness of VTE prevention. Similarly, Faraklas et al[12] found that weight-based dosing of enoxaparin resulted in an increased portion of patients with the required range of anti-factor Xa from 32% to 73%. Several studies recommend dose modification of enoxaparin to a weight-based dosing regimen for trauma, obese, and critically ill patients[11-14,38,39].

The timing and frequency of anticoagulant administration also remain a subject for debate. Despite the widely accepted protocol of holding the LMWH dose the morning of surgery[17], other providers continue to use LMWH on the morning of surgery[18]. Only one study[19], which included both general surgery and trauma patients, found that missing even a single dose of enoxaparin was an independent risk factor for increased rates of VTE. To date, only one study discussed the outcome of the administration of the morning dose of LMWH in trauma patients[20]. In this study, which included 507 patients, Moloney et al[20] found that administration of a prophylactic dose of enoxaparin on the morning of surgery did not increase the blood transfusion rates, wound complications, or 30-day mortality after fixation of geriatric femur fractures.

On the other hand, several studies have found a correlation between “excessive” anticoagulant prophylaxis and the development of hematoma, persistent wound drainage, and periprosthetic infections in orthopedic patients undergoing elective total hip, total knee, and total shoulder arthroplasty[7-9,40,41]. McDougall et al[8] found a revision rate of 5.61% in therapeutically anticoagulated total hips and knees with warfarin compared with 2.23% in controls. Similarly, Cancienne et al[9] found that wound complications and revision rates in shoulder arthroplasty patients on therapeutic anticoagulation (with different oral and injectable anticoagulants) are significantly elevated compared with controls. Nevertheless, the previous studies differ from the current study in the anticoagulant dosing (therapeutic vs prophylactic), the anticoagulant bridging, the anticoagulant types, and the evaluation of surgical procedures. Total joint replacement involves longer-duration surgery and potentially more invasive surgical approaches compared to hemiarthroplasty. The trend towards the use of cementless components in total joint arthroplasties compared to hemiarthroplasty in elderly patients may also influence the development of infection, as cemented components and the use of antibiotic-loaded bone cement (ALBC) have been associated with a lower incidence of postoperative infections[42-46].

HA remains the most common treatment option for displaced femoral neck fractures in the elderly[21,22,47]. With most of the studies about the outcomes of anticoagulation discussing total joint arthroplasty cases, and while hemiarthroplasty is performed in different settings and in elderly, and often more frail trauma patients, our current series is the first to analyze the effect of LMWH dose modification, the weight-based + morning dose, on the incidence of wound complications in hemiarthroplasty. Our results, based on a relatively small number of infection cases, suggest that this regimen modification did not increase the incidence of postoperative infections in hemiarthroplasty cases.

It is important to highlight that the use of ALBC in stem fixation could have affected the outcomes and remains a significant confounding factor in our study. The use of ALBC in primary and revision arthroplasty has been extensively studied as a strategy to mitigate the risk of periprosthetic joint infection[48]. Recent systematic reviews and meta-analyses indicate that ALBC significantly reduces the incidence of PJI following primary total joint arthroplasty, with reported risk reductions ranging from 20% to 84% compared to plain cement. Specifically, a meta-analysis of randomized controlled trials demonstrated that ALBC was associated with a 64% relative risk reduction in PJI (relative risk = 0.36; 95% confidence interval: 0.16-0.80; P = 0.01), particularly in knee arthroplasties where cefuroxime-loaded cement showed a marked protective effect (relative risk = 0.08; 95% confidence interval: 0.01-0.63; P = 0.02)[49]. However, the evidence is not without controversy; some umbrella reviews suggest that while ALBC may lower revision rates for PJI, the overall quality of evidence remains low, and high-quality, large-scale studies are needed to confirm its efficacy and address concerns about antibiotic resistance and systemic toxicity[50]. While the number of cemented cases was not statistically different in the PJI cases of each group (Table 2), data on the use of ALBC were not consistently available in our entire retrospective database that spans 17 years and hence could not be reliably analyzed.

This study has several limitations. This is a retrospective study, and the limitations associated with a retrospective review also apply to this study. Second, due to the relatively small incidence of postoperative infections requiring secondary surgery in general, our sample size is limited, and the fact that these results are from a single health system may limit the generalizability of the outcomes. Confounding factors, such as medical comorbidities, ALBC use, previous history of infections, surgical times and durations, surgeon’s volume, and other drugs, were not analyzed, ideally with regression analysis, and could have affected the development of infections among each study group. Finally, despite the comparison between infection rates in patients receiving standard vs higher LMWH doses not yielding a statistically significant difference (P = 0.6), the power of the study test was only 7.9%, indicating that the study is substantially underpowered to detect such a small difference. While a well-powered study typically requires at least 80% power to detect true effects confidently, a statistically significant difference would have been observed if the number of infection cases in the higher-dose group had exceeded 22, corresponding to an infection rate of more than 2.348%, which was not the case in our study.

CONCLUSION

Dose escalation of prophylactic LMWH to the weight-based regimen, including the surgery morning dose in trauma patients undergoing hip HA, did not significantly change the incidence of postoperative deep infections. More studies, ideally large multicenter, are needed to obtain stronger evidence.