Gentamicin Wet Compress and Hormone Therapy for Superficial Second-Degree Burns Complicated with Atopic Dermatitis

Background

One of the characteristics of burns is a large area of skin damage. The barrier function of the skin is destroyed, and the burn wound becomes the main way of an invasion of allergens and pathogenic bacteria. As a type of superficial burn, a superficial second-degree burn is usually characterized by local redness, severe pain, blisters of various sizes, and basal flushing containing yellow or reddish plasma like fluid after removal of the epidermis [4]. Once the burn wound is infected and allergic, it will lead to slow healing of the wound, and even after healing, it is often accompanied by scars and pigment deposition. Although it is not a fatal disease, the scars and itching that result from wound healing often adversely affect patients’ quality of life and physical and mental health [5]. Atopic dermatitis secondary to burns is rare and its treatment is unclear. At present, the traditional treatment is mainly glucocorticoid, but the curative effect is just acceptable and the course of disease is long. Allergies may lead to slower wound healing and more obvious scars, so how to treat patients with atopic dermatitis secondary to burns more effectively has become the focus of clinical treatment. We present a case of a superficial second-degree burn complicated with [6,7] atopic dermatitis managed with dexamethasone wet compress, gentamicin wet compress and hormone therapy which turn out to be a satisfying augmentation with less invasion as reported below [8].

Methods

A 24-year-old female patient was admitted with hydrothermal burns 36 hours after the burn. She was diagnosed with superficial second-degree burns on her right forearm and back of the right hand, covering an area of about 3%, without any complications [9]. Physical examination revealed scattered yellowish blisters of different sizes on the right forearm and back of the right hand, with partial epidermal exfoliation, basal flushing, local redness and swelling, accompanied by severe pain and anesthesia, meeting the diagnostic criteria for superficial second-degree burns (Figure 1). Before admission, the patient underwent dressing change for burns at a local hospital. The specific external medication was unknown, and no internal medicine treatment was provided.

Figure 1: Observation before burn treatment.

A. The burned area on the front of the right forearm.

B. The area on the back of the right hand.

C. The area on the back of the right forearm.

Local Treatment

On the first day of her admission, wound care and a dressing change was performed. The next day when removing the old dressing, we saw widely distributed intensive blisters with “needle point” and “green bean” sizes in her right forearm, slow yellow drainage outflow, and intensive and transparent blisters with “needle point” sizes distributed from nearness to farness in the skin surface of metacarpophalangeal joints. The patient complained of “an allergic constitution”, but the allergen was unknown. After consultation with a dermatologist, she was diagnosed as allergic dermatitis secondary to burns. Changing the treatment plan: We used a dilution of normal saline and iodophor according to a ratio of 1 to 1 to disinfect the wounds three times, mixed gentamicin injectable solution 4ml (Henan Runhong Pharmaceutical Co., LTD., GB: H41020318, Specification: 2ml: 80,000 U), dexamethasone injectable solution 2ml (Zhengzhou Zhuofeng Pharmaceutical Co., LTD., GB: H41020055, Specification: 1ml: 5mg) and 100ml 0.9% sodium chloride injectable solution and then soaked the sterile gauze in the mixture. The gauze was spread flat on the wound surface with vascular forceps and tweezers without dripping solution and applied for 20 minutes once a day [10]. After the application, we applied a piece of double sterile gauze to the wound, ensuring aseptic operation during the whole process.

Internal Medicine Treatment

On the first day of admission, two measures were taken: antiinfection: injecting cephalosporin injectable solution 0.5g (Hainan Hailing Chemipharma Co., LTD., GB: H10930215, Specification: 0.25g), and analgesia: dezocine injectable solution (Yangzijiang Pharmaceutical Group Co., LTD., GB: H20080329, Specification: 1ml: 5mg) IV drip treatment. In addition to anti-infection and analgesia treatment, we used methylprednisolone injectable solution (Pfizer Manufacturing Belgium NV approval number: H20170197, Specification: 40mg) IV drip treatment (injecting 80mg methylprednisolone injectable solution into 250ml 0.9% sodium chloride injectable solution at 8:00 a.m. each day and 40mg methylprednisolone injectable solution into 100ml 0.9% sodium chloride injectable solution at 8:00 p.m. each day). Additionally, 1 tablet loratadine BID (Shenzhen Salubris Pharmaceuticals Co., Ltd., GB: H20020092, Specification: 5mg) was taken orally according to the direction of a consultant dermatologist. This therapy was followed by a 4-day methylprednisolone injection reduction (injecting 60mg methylprednisolone injectable solution into 250ml 0.9% sodium chloride injectable solution at 8 a.m. each day) and loratadine discontinuation. Two days later, the drug was discontinued.

Results

During hospitalization, the patient had no adverse reactions and other complications, burn wounds was healed well, the pain was relieved, and blisters disappeared with a little pigmentation. Therefore, using wet compress, combined with anti-infection and anit-allergic therapy for the treatment of atopic dermatitis secondary to burns can obviously accelerate the subsiding of allergic symptoms [11], and the patient’s satisfaction is good, so it is worth clinical application and promotion (Figure 2).

Figure 2: Observation before burn treatment.

A. The burned area on the front of the right forearm.

B. The area on the back of the right hand.

C. The area on the back of the right forearm.

Discussion

Superficial burns are usually burns of less than two degrees. Superficial second-degree burns damage the epidermis and the superficial dermis, which are rich in nerves and sensitive to local pain. The etiology and pathogenesis of eczema secondary to burn wounds are different from that of common eczema. Most researchers argue that this is relevant to traumatic factors such as bacterial colonization and drugs for external use. To name but a few:

• Patients’ constitution are allergic to external medication for burns

• After the burn, the skin basal tissue is subjected to different degrees of heat damage, tissue protein in the wound denatured with a series of inflammatory reactions, tissue liquefied and necrosed, bacterial peptides, toxins and antigen-antibody complexes are recognized by antibodies of the immune system, causing allergic symptoms

• Patients’ burn wounds are in a stress state, and is easily affected by diet, contactants and weather changes during treatment, resulting in allergic symptoms

• The abnormality of the immune system is also one of the causes of allergies secondary to burns. To sum up, both internal factors and environmental factors can be allergens.

But the epidermis of the blisters in this patient did not fall off and rupture, so this may be the reason for the late allergic reaction of the patient. Once allergic symptoms occur, it is necessary to change the treatment in time. In addition to making thorough burn dressing change on the wound in time, applying appropriate antibiotics to avoid infection and using anti-allergic drugs, combined with wet compress therapy such a local treatment can achieve a good therapeutic effect. About the antihistamine for inhibiting allergic symptoms, oral desloratadine is the first choice in our hospital, which has a strong and selective antagonistic effect against peripheral H1 receptors. In addition to counteract histamine in the body, desloratadine also shows antiallergic and anti-inflammatory effects, which is worthy of clinical application and promotion. Glucocorticoid drugs have an anti-allergic effect, can relieve various symptoms of acute inflammatory reaction and prevent some inflammatory sequelae, such as tissue adhesion and scar formation. So local treatment of the wounds combined with methylprednisolone can effectively inhibit allergic reactions. But this kind of medicine has no inhibiting effects on pathogenic microorganism. Furthermore, because it can inhibit inflammatory reactions and immune responses, and weaken the body’s defense ability, it has the potential to activate or spread latent infectious lesions. Moreover, the long-term use of hormone drugs may cause hormone dependence, and more adverse reactions [12], is also very important so joint anti-infection treatment [13]. In conclusion, it’s necessary to combine anti-infective treatment. To sum up, wet compress combined with anti-infection drugs and anti-allergy drugs can significantly promote the wound healing and relieve symptoms in the treatment of burn complicated with allergy, with significant efficacy.

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Elizabethkingia Anopheles Infection after Hyaluronic Acid Injection: A Case Report and Review

Introduction

Elizabethkingia anopheles is an opportunistic pathogen commonly found in soil, fresh water, plants, hospital environments, and contaminated sinks [1]. Sporadic outbreaks of E. anopheles infection have been reported in medical institutions, though point-source outbreaks have also been documented in some countries [2-6]. E. anopheles was isolated and identified from the midgut of the mosquito Anopheles gambiae in Africa in 2011 [7]. E. anopheles infection was first reported in the Central African Republic, where it was reported as neonatal Chryseobacterium meningosepticum infection. Later, 16S rRNA gene sequencing revealed the causative organism as E. anopheles. Several follow-up retrospective tests confirmed that most reported cases of Chryseobacterium meningosepticum infection were actually caused by E. anopheles [4,8]. E. anopheles exhibits broad-spectrum drug resistance. If not promptly identified and treated with appropriate antibiotics, infected patients require more time to recover, and the treatment response may be poor. The mode of transmission of E. anopheles is not completely known [9]. Here, we report a case of E. anopheles infection in the chin after hyaluronic acid injection.

Case Presentation

A 64-year-old woman was diagnosed with cellulitis of the chin in a tertiary care hospital. She had received intravenous antibiotics for 11 days and undergone local incision and drainage (Figure 1A). However, swelling and pain in the mandible did not improve. She also complained of waist soreness and discomfort, pain, and morning stiffness in the metacarpophalangeal joints of both hands. She did not complain of tooth pain or report long-term low-grade afternoon fever, weight loss, night sweats, or history of rheumatoid disease. She had received two injections of hyaluronic acid in the chin at a hospital dedicated for plastic surgery once a year in the past two years. After being admitted to a hospital for the pain and swelling in the chin, she was treated with cefoperazonesulbactam sodium for five days. However, the chin, waist, and metacarpophalangeal joint pain did not resolve. After switching to piperacillin and tazobactam sodium between October 21 and 25, 2020, the symptoms of localized redness, swelling, heat, and pain improved, and the area of infection became darker. From October 26 to 28, 2020, the patient reported worsening of symptoms. Physical examination revealed that the localized redness, swelling, heat, and pain had spread to the skin and soft tissues on both sides (Figure 1B). Leukocyte count and CRP test results suggested that the patient’s infection had a tendency to spread. On October 30, 2020, intravenous moxifloxacin was initiated according to the Microbial DNA Test Report and relevant literature [5,6]. Oral doxycycline was added on November 3, 2020. Bilateral mandibular swelling, heat, pain, waist soreness, and morning stiffness of the metacarpophalangeal joints gradually subsided. The symptoms gradually improved until she was discharged from the hospital on November 9, 2020(Figures 1C-1E).

Figure 1: Extraoral photographs of the patient before, during, and after hospitalization.
A. The red arrow shows swelling in the bilateral mandibular region after incision and drainage, but the localized redness, heat, and pain did not show any significant improvement after antibiotic treatment (11 days before admission + 12 days after hospitalization).
B. The symptoms of redness, swelling, heat, and pain aggravated and the lesion showed a tendency to spread. Replacement of the drainage sheet is indicated by the arrow, and samples are taken for routine pathological and microbiological examination.
C. After switching to moxifloxacin, the localized symptoms of redness and swelling disappeared. Healing of the incision is indicated by the arrow.
D. Healing of the incision further improved after suture removal, though one swelling persisted at the left part of the incision as indicated by the arrow.
E. Healing after bilateral incision and drainage following moxifloxacin and doxycycline treatment.
F. The bilateral drainage incisions healed completely after antibiotic withdrawal.

Physical Examination

The mental protuberance and bilateral mandibular region showed pitting edema. Local incision and drainage of the rubber sheets which the tertiary hospital outpatient doctor had put in were observed. A small amount of blood was evident on drainage. No obvious purulent secretions were observed. The patient complained of pain on bending, which was bearable on slow bending. Localized swelling, tenderness, and reduced range of motion were evident in the distal segment of the left little finger. After 4 days of treatment with piperacillin-tazobactam sodium, the localized symptoms were relieved and the area of the swelling decreased, but the pigmentation persisted, tissue was hard, and elasticity was poor. Five days after the administration of piperacillin-tazobactam sodium, localized symptoms aggravated, intensity was greater than that before admission, and a new swelling had developed on the right side of the chin. Localized incision and drainage were performed, and a gray-white purulent discharge was observed. Treatment with moxifloxacin and doxycycline relieved redness, swelling, heat, pain, and symptoms of the waist.

Processing

On October 28, 2020, the patient underwent incision and drainage in the bilateral mandibular region. The wound pus smear was examined under a high-magnification microscope. No gram-negative bacilli were found on the pus swear, and no pathogenic microorganisms were found on the acid-fast stained smears. Meanwhile, the tuberculosis T-cell test, routine pathological examination, and deep-tissue microbial DNA examination were performed. Routine pathological reports suggest local foreign bodies and infections in the chin (Figures 2A-2C). On October 30, 2020, DIAN DIAGNOSTICS of Microbiology Company reported E. anopheles infection. Drug sensitivity and matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) tests were not performed because of the limited microbial DNA. According to the literature, we planned to start intravenous 0.4(mg) moxifloxacin Quaque Die (QD) from October 30, 2020. On November 12, 2020, oral doxycycline hydrochloride (0.1 g) QD was started On November 17, 2020 [6,9]. the patient was discharged and advised to continue the medications.

Figure 2: Pathological examination of deep-tissue specimens.
A. The red arrow shows the foreign body, and the blue arrow shows the macrophage reaction (5×10 times the field of view).
B. The red arrow shows the foreign body, the blue arrow shows the macrophage reaction, and the yellow arrow shows the neutrophil reaction (20×10 field of view).
C. Foreign body (40×10 view).

Results

During the 3-month follow-up period from the termination of moxifloxacin and doxycycline treatment, the symptoms in the area of the mental protuberance and bilateral mandibular region subsided, physical examination showed no abnormalities, and the blood leukocyte count, classification of leukocyte, and Antistreptolysin O results were within reference range.

Discussion

In the present report, the patient was diagnosed with a localized E. anopheles infection after injection of hyaluronic acid based on the results of pathological examination, microbiological DNA analysis and microbial infection test results. We did not conduct a follow-up microbiological epidemiological survey because of disputes between patients and hospitals using cosmetic products. It is unknown whether the infection was caused by the injection or use of a contaminated product. As that the patient was initially treated using multiple antibiotics, microbial DNA test results showed that microbial DNA level was low, making accurate diagnosis difficult. Specimens obtained from the lesional site may be contaminated by the normal flora (normal colonizing flora on the skin surface) of the site [10]. Therefore, strict disinfection and aseptic operation are advised to obtain samples from severely infected tissues for accurate diagnosis. Accordingly, microbial DNA and routine pathology sampling were completed simultaneously.

Table 1: The resistance genes were gathered from Mi-Soon Han, et al. [17]; Delaney Burnard, et al.[9]; Susanna [23]; and Amandine Perrin [6]; Drug resistance genes have only been reported by the authors listed above, more in practice, and constantly updated and supplemented. They can be verified using the Comprehensive Antibiotic Resistance Database. Quinolones omitted – floxacin, and tetracyclines omitted – cycline. S: sensitive, R: resistance, I: intermediate sensitivity, NE: non-Enterobacteriaceae, EU: EUCASR, DRG: drug-resistance genes reported in the literature. The numerator represents Elizabethkingia anopheles and the denominator represent the genus Elizabethkingia. The drug sensitivity test included the minimum inhibitory concentration (MIC) and the paper method. Many antibiotics have no breakpoint presently; the effectiveness could be interpreted in the experiment; only the most commonly used antibiotics for the treatment of Elizabethkingia anopheles.

The genus Elizabethkingia includes non-fermenting, non-sporing, non-motile, gram-negative aerobic bacilli. On discovery, CDC ((US Centers for Disease Control and Prevention) Group IIa was assigned to Flavobacterium, which was later reclassified as Chryseobacterium in 1994[11]. In 2005, it was reclassified into a new genus, Elizabethkingia, based on the genotypes and phylogenetic characteristics. The genus contains three medically important species, Elizabethkingia meningoseptica, Elizabethkingia anopheles, and Elizabethkingia miricola [12]. They cause clinical infections to spread mainly by mosquitoes of the genus Anopheles, which induce sepsis in immunocompromised patients and meningitis in neonates [8]. The clinical differential diagnosis of microbial infections is difficult because microbial gene phenotypes are very similar. Genome identification show that the nucleotide sequences of these three microorganisms have extremely high homology (> 98%) [6,8,9]. MALDI-TOF MS, 16S rRNA sequencing, DNA-DNA hybridization, and whole-genome sequencing (WGS) can be used to identify the microorganisms [13]. Owing to the rigid requirements of Food and Drug Adminstration (FDA) approval, strict laboratory requirements, and inadequate understanding of the constitution of E. anopheles, these microbial detection techniques are not commonly performed in ordinary laboratories to differential diagnosis of E.anopheles. Therefore, relevant microbial databases are not updated continually, rendering the diagnosis of their infections difficulty [14].

anopheles infections have been reported sporadically in the United States [6], Central African Republic [15], South Korea [16] Singapore [4], China [17], Chinese Taipei [5,18], and Chinese Hong Kong [19]. Moreover, the number of reports has gradually increased in recent years. Notably, E. anopheles inherently possesses almost all antibiotic-resistant nucleotide sequences (Table 1). However, genes for these hydrolytic antibiotic enzymes do not cause complete resistance in clinical practice. For example, vancomycin, quinones, rifampicin, and aminoglycosides have been reported as effective in clinical infections [14,20,21]. The choice of empirical treatment requires a complex antibiotic selection process involving a combination of literature reports and clinical observations. Patients with deep tissue or organ infections have higher mortality rates [9,22,23]. In the present case, intravenous moxifloxacin was more effective than oral administration in improving symptoms, though some reports indicate that oral antibiotics can effectively treat the infection [24].

The high phylogenetic diversity and temporal and geographic dynamics of E. anopheles render it difficult to develop an ideal treatment regimen. This means that antibiotic resistance may vary according to the species and the region and time of bacterial isolation. Clinically significant differences in the results of drug susceptibility tests for strains in the same region, different hospitals, and different years could be evident [4,6,8,9,17,25]. The common empirical anti-infective program is to choose from the following antibiotics: quinolones, ciprofloxacin, moxifloxacin, tetracycline, minocycline, doxycycline, trimethoprim sulfamethoxazole, rifampin, piperacillin-tazobactam, cefoperazone-sulbactam, and vancomycin, used alone or in combination [8,14,16-18]. However, drug resistance gene tests show that E. anopheles contains the genes for resistance to all these antibiotics. Consequently, it is moderately sensitive or resistant to these antibiotics, which increases the difficulty of antibiotic selection [14, 19]. Identifying the microorganism and selecting antibiotics based on drug sensitivity tests are the most reliable methods for shortening the duration of hospital stay and treatment [9,26].

The transmission route of Elizabethkingia has not been sufficiently investigated. The relationship between the species within the flora and global strain relatedness has not been defined because of continuous evolution of microorganisms [9]. An indwelling catheter in the patient's body has been reported as the primary risk factor for infection. The catheter should be removed during treatment [1,2,8,16]. The infection can spread through contact with contaminated sink taps during hand washing [3]. From 2012 to 2013, Wisconsin, USA, exhibited the largest point-source outbreak since the first report of E. anopheles infection. A CDC investigation confirmed exposure within the health care system prior to the detection of Elizabethkingia spp., of which 2 cases of infection were highly suspected to be related to indwelling catheters in the body, while the rest were not found to be clearly transmitted [6,22]. Water sources within the hospital environment were reported as the main routes of infection in England and Australia, and the concept of water-borne transmission was proposed [2,9]. A maternal amniocentesis/chorial infection has also been proposed [8]. E. anopheles infections have been reported after the consumption of freshwater fish [21,27]. Most literature reports are nosocomial or community-acquired infections. Cultures of various body fluids can test positive for E. anopheles, including blood, lower respiratory tract sputum, cerebrospinal fluid, pleural effusion, abdominal effusion, and synovial fluid. The transmission of this bacterium has not been fully investigated. Although E. anopheles was isolated from the midgut of the mosquito Anopheles gambiae in the Central African Republic, current clinical, environmental, and genetic analysis evidence does not support the theory of mosquito-borne infection [2,6,16,21]. The route of transmission among the population is not determined [24]. This is the first report of E. anopheles infection caused by local injection of medical products.

The clinical features of E. anopheles and other Elizabethkingia infections are not well documented [5]. The risk factors and clinical characteristics of Elizabethkingia infection in patients of South Korea have been reported [16]. Advanced age, malignancy, chemotherapy, residents of nursing homes, neonatal patients, organ transplantation, underlying diseases, indwelling central catheters, exposures within the health care system, hypoalbuminemia, intensive care unit admission, and continued use of carbapenems are risk factors for E. anopheles infection. In this report, the levels of Antistreptolysin O (ASO) were positively correlated with the efficacy of antibiotics. No related adverse reactions have been reported for hyaluronic acid injection products [28].

Conclusion

E. anopheles is a broad-spectrum antibiotic-resistant bacterium. Empirical treatment regimens involve single or combined administration of antibiotic. The choice of antibiotic changes with time and region vary attributed to the continuous evolution of microorganisms. We report the first case of E. anopheles infection after hyaluronic acid injection. Treatment with intravenous moxifloxacin showed better results than oral moxifloxacin. The effects of these treatments were positively correlated with ASO levels. Further studies are needed to determine whether ASO level can be used as an auxiliary diagnostic marker.

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A Comparison of Advanced Therapy to Anticoagulation Alone for Acute Pulmonary Embolism: Association with Clinical Outcomes and Cost

Introduction

Venous thromboembolism is a common cause of hospitalization with a high mortality rate [1,2]. Current guidelines recommend anticoagulation alone for patients that are hemodynamically stable and considered to have a low-risk Pulmonary Embolism (PE) [3,4]. Thrombolytic therapy is recommended for patients with hypotension, considered a high-risk PE, in the absence of contraindications [3-5]. The optimal management of intermediaterisk PE is less clear. Some have proposed treating intermediaterisk PE with intravenous thrombolytics; however, trials have demonstrated increased rates of bleeding without mortality benefits [6-9]. Other advanced therapies have been developed to treat life-threatening PE, including Catheter-Directed Thrombolysis (CDT), suction thromboembolectomy, surgical embolectomy and Extracorporeal Membrane Oxygenation (ECMO), [10-13] but robust evidence supporting their use is lacking.

Because the optimal management of intermediate- and high-risk PE with advanced therapies remains uncertain, some institutions have developed a multidisciplinary team of specialists to determine the best therapeutic approach for patients presenting with an acute PE called a PE response team (PERT) [14]. In spite of multiple institutions deploying PERTs, evidence on the effectiveness of a PERT is limited. In some reports, PERTs have led to increased utilization of advanced therapies, particularly catheter-directed therapy, without clearly demonstrating improvement in outcomes such as mortality, bleeding rates or length of stay [15,16]. Our institution is an academic medical center with ready access to advanced therapies for PE that does not rely on a PERT to guide treatment decisions. We believe our center is well-positioned to evaluate whether advanced therapies are associated with improved outcomes compared to anticoagulation alone in absence of a PERT. We hypothesized that patients who received advanced therapies compared to anticoagulation alone would have increased rates of bleeding, higher total direct costs and longer length of stay, without a difference in short-term mortality.

Methods

Study Design

We conducted a retrospective observational cohort study at the University of Utah Medical Center, a 528-bed academic medical center with one of the largest geographic referral areas in the United States. An electronic database query was used to identify patients who underwent chest Computed Tomography of the Pulmonary Arteries (CTPA) and/or ventilation/perfusion (V/Q) scan between April 1, 2017 and April 1, 2019. An internally validated Natural Language Processing (NLP) tool designed to scan and interpret the CTPA, or V/Q radiology report was used to identify PE events. This NLP tool has a sensitivity of 96.0% and a specificity of 97.7% for identification of acute PE. We used the NLP tool to identify eligible patients based on previous reports suggesting International Classification of Diseases (ICD) discharge codes cannot reliably identify acute thromboembolic events [17,18]. Baseline patient demographics, vital signs, medical comorbidities, lab results, medications, interventions, admission date, discharge date, and bleeding events with dates were extracted from the electronic health record. Four study investigators performed manual chart reviews to validate study data regarding presence of acute PE, echocardiography, thrombolytic eligibility, advanced therapy for PE, and bleeding events. Each chart was independently reviewed by two study investigators, with any discrepancies adjudicated by a third investigator (SAJ) blinded to the identity of the initial reviewers.

Patient Population

Inclusion criteria were age greater than 18 years and the presence of a PE identified by the NLP tool during the study period. Exclusion criteria included chronic PE or absence of PE identified through manual chart review. Study subjects were assigned to one of two cohorts based on the treatment they received for their acute PE:

1) Anticoagulation alone; or

2) Advanced therapy.

Advanced therapy was defined as receipt of systemic thrombolysis, CDT, Inferior Vena Cava (IVC) filter placement, ECMO, and/or surgical embolectomy. Thrombolytic ineligibility was defined as the presence of any of the following: active bleeding or DIC; cerebral vascular lesion or intracranial neoplasm; ischemic stroke in previous three months; prior intracranial hemorrhage; major surgery, trauma, obstetric delivery, GI bleeding, or invasive procedure within the previous 14 days intracranial, spinal, or retinal surgery within previous 30 days; CPR >10 minutes. These are based on our institutional criteria, adapted from the American College of Chest Physicians (ACCP) guidelines [3]. Patients were further stratified by pulmonary embolism severity index (PESI) [19] and PE location (main, interlobar, lobar, segmental, or subsegmental pulmonary arteries; and bilateral or unilateral involvement).

Study Outcomes

The primary efficacy outcome was 30-day mortality after acute PE identification. Secondary efficacy outcomes included 7-day mortality, hospital length of stay (LOS), and normalized mean of the total direct cost. The primary safety outcome was major bleeding within 90 days of PE diagnosis. Major bleeding was defined as fatal bleeding or bleeding into a critical site according to the International Society on Thrombosis and Haemostasis (ISTH) [20]. ICD codes were used to identify patients with bleeding into a critical location. We did not apply the 2gm/dL decrease in hemoglobin criteria proposed in the ISTH definition as we believed this criterion was subject to false positive results from reasons other than bleeding (eg. haemolysis, haemodilution, phlebotomy, anaemia of acute illness). Secondary safety outcomes included any bleeding, non-critical bleeding, and procedure-related bleeding events. Non-critical bleeding was defined as non-fatal bleeding into non-critical locations. Procedure-related bleeding was defined as bleeding associated with a recent surgical or interventional procedure. ICD codes use to identify bleeding events are listed in Appendix Table 1. All bleeding events and dates identified by ICD codes were confirmed on manual chart review. Total direct costs were determined by our institutionally derived Value Driven Outcomes tool [21].

Statistical Analysis

Baseline characteristics and unadjusted outcomes are reported as frequency and percent, mean with standard deviation (SD) for normally distributed variables, and median with interquartile range (IQR) for non-normally distributed variables. Baseline characteristics and unadjusted outcomes were compared using the Chi-squared or Fisher’s exact test, Student’s t-test, or Wilcoxon rank sum where appropriate. Multivariable regression analysis using generalized linear models with a log-link function and gamma distribution was used for continuous outcomes (eg. length of stay, cost). Survival analysis using univariate and multivariable Cox regression was used to compare the primary and secondary efficacy and safety outcomes, reported as a hazard ratio (HR) with 95% confidence interval (95% CI). Kaplan-Meier curves were used to graphically display differences in mortality and bleeding events. Multivariable logistic regression was used for binary outcomes. Covariates included in regression models were Charlson Comorbidity Index (CCI) [22], thrombolytic eligibility [4], and PESI score [19]. We chose CCI to adjust for any potential differences in chronic comorbidities, thrombolytic eligibility to adjust for differences in baseline bleeding risk, and PESI score as an indicator of acute illness related to the PE. Adjusted continuous outcomes were estimated using marginal effects at the means [23]. Total direct costs were normalized using the mean total direct cost of admission for patients receiving anticoagulation alone as the normalizing value. A p-value cutoff of 0.05 was used to determine statistical significance. Stata/IC version 16.1 (StataCorp, College Station, TX) was used for all analyses.

Results

Patient Characteristics

A total of 741 patients with either a CTPA or V/Q scan performed during the study period were identified. Of these, 134 patients met exclusion criteria, leaving 607 patients with an acute PE for analysis (Appendix Figure 1). 563 patients received anticoagulation alone and 44 received advanced therapy for PE treatment. Most patients in the advanced therapy group (79.5%) received an IVC filter, 13.6% received systemic thrombolysis and 9.1% received catheter-directed thrombolysis. Baseline patient demographics did not differ significantly between groups (Table 1). Overall, patients in the advanced therapy cohort presented with greater vital sign derangements and higher PESI scores compared to the anticoagulation alone cohort (median PESI score [IQR]; 112 [81, 145] vs. 142 [105, 209], p <0.001). More patients in the advanced therapy cohort were considered ineligible for thrombolytic therapy (46.0% vs. 68.2%, p <0.001). Elevated biomarkers suggestive of right ventricular (RV) dysfunction (eg. troponin, brain-natriuretic peptide, lactate) were observed more frequently among advanced therapy patients (Table 1), although echocardiographic evidence of RV dysfunction was not significantly different (p =0.19) between the advanced therapy (44.4%) and anticoagulation alone (32.6%) cohorts. More patients in the advanced therapy cohort had a PE identified in the main pulmonary artery compared to the anticoagulation alone cohort (27.3% vs. 13.1%, p = 0.02).

Table 1: Baseline Patient Characteristics of Patients Treated with Anticoagulation-Alone versus Advanced Therapy for Acute Pulmonary Embolism.

Note: †Defined as presence of active bleeding or DIC; cerebral vascular lesion or intracranial neoplasm; ischemic stroke in previous three months; prior intracranial hemorrhage; major surgery, trauma, obstetric delivery, GI bleeding, or invasive procedure within the previous 14 days intracranial, spinal, or retinal surgery within previous 30 days; CPR >10 minutes. *Risk classification based on European Society of Cardiology guidelines for the diagnosis and management of acute pulmonary embolism. Abbreviations: BMI= body mass index; BP= blood pressure; PE= pulmonary embolism; RV= right ventricle; IVC= inferior vena cava; ECMO= extracorporeal membrane oxygenation

Outcomes

Primary and Secondary Efficacy Outcomes

In unadjusted comparisons, the primary efficacy outcome of 30-day mortality was observed more often in patients treated with advanced therapy (18.2%) compared to patients treated with anticoagulation-alone (7.3%) (hazard ratio [95% CI]; HR=2.59 [1.22-5.53], p =0.014) (Table 2, Figure 1). No significant differences were noted in the secondary outcome of 7-day mortality (HR= 1.69 [0.51-5.64], p =0.391. The median LOS was nearly 7 days longer for patients treated with an advanced therapy (median LOS [IQR]; 8.93 [4.52, 21.55] days vs. 1.95 [0.54, 5.65] days, p <0.001). Normalized mean total direct costs were more than 3-fold higher for patients treated with an advanced therapy vs. anticoagulation alone (normalized mean cost [95% CI], 3.42 [2.46-4.38] vs. 1.00 [0.84-1.16], p <0.001).

Figure 1: Crude Incidence Rate of 30-Day Mortality following Pulmonary Embolism Diagnosis.

Table 2: Unadjusted Primary and Secondary Outcomes of Anticoagulation-Alone versus Advanced Therapy for Acute Pulmonary Embolism.

Following adjustments for PESI score, CCI, and thrombolytic eligibility, the observed differences in 30-day mortality were no longer apparent between the advanced therapy and anticoagulationalone cohorts (HR=0.96 [0.44-2.09], p =0.914) (Table 3). No significant differences were observed in 7-day mortality (HR=0.57 [0.17-1.93], p =0.367). The adjusted mean LOS was 4.53 days longer for patients treated with advanced therapy relative to those treated with anticoagulation alone (mean LOS [95% CI]; 8.37 days [4.48-12.26] vs. 3.84 days [3.34-4.33], p =0.002). Similarly, adjusted normalized mean costs remained more than 3-fold higher among patients treated with advanced therapy (normalized mean cost [95% CI]; 3.03 [1.62-4.43] vs. 1.00 [0.87-1.13], p <0.001).

Table 3: Adjusted Primary and Secondary Outcomes of Anticoagulation-Alone versus Advanced Therapy for Acute Pulmonary Embolism.

Note: Results adjusted for Charlson comorbidity index, thrombolytic ineligibility, and Pulmonary Embolism Severity Index score.

Primary and Secondary Safety Outcomes

Unadjusted analysis demonstrated the primary safety outcome of major bleeding was observed more frequently among patients treated with advanced therapy (9.1%) compared to patients receiving anticoagulation alone (1.2%) (HR=10.68 [3.12-36.53], p <0.001) (Table 2). Most major bleeding events occurred within the first 20 days following advanced therapy as demonstrated in Figure 2. The secondary outcomes of any bleeding event (HR= 4.79 [2.30- 9.96], p <0.001) and non-critical bleeding (HR= 4.30 [1.89-9.80], p =0.001) were also significantly increased and occurred early in the advanced therapy cohort (Appendix Figure 2). Following multivariable adjustment, major bleeding remained significantly increased among patients receiving advanced therapy (HR=9.05 [2.21-9.98], p <0.001). The secondary outcomes of any bleeding (HR= 3.42 [1.46-7.98], p =0.005) and non-critical bleeding (HR= 3.61 [1.54-8.47], p =0.003) remained significantly increased in the advanced therapy cohort after adjustments.

Figure 2: Crude Incidence Rate of 90-Day Major Bleeding Events following Pulmonary Embolism Diagnosis.

Discussion

In this retrospective cohort study at a single academic medical center, we examined the relationship between advanced therapy for acute PE and patient outcomes. Our multivariable analysis identified a significant association between utilization of advanced therapy and increases in hospital LOS, total cost, and bleeding likelihood with no significant difference in 30-day mortality, compared to treatment with anticoagulation alone. Optimal patient selection for use of advanced therapies in acute PE remains uncertain, particularly in the case of intermediate-risk PE. One solution to address this uncertainty has been the formation of a multidisciplinary PERT. In our study at an academic medical center without a PERT, 7.2% of patients received advanced therapy, the majority of these being an IVC filter, with 1.2% receiving CDT. Adoption of PERTs at these institutions was associated with increased utilization of advanced therapies at other academic institutions without PERTs or prior to PERTs, where IVC filters are generally utilized in < 10% of patients and CDT < 2%. [15,16,24] Adoption of PERTs at these institutions was associated with increased utilization of advanced therapies, with a 10-fold increase in CDT utilization. Across the PERT consortium utilization of advanced therapy ranges from 16-46%, [15,16,25]. However, the benefit of increased utilization of advanced therapies remains uncertain without consistently improved clinical outcomes, [15,16,25-29].

We observed the 30-day mortality was significantly higher in the patients who received advanced therapy (18.2% vs 7.3%), however, after adjusting for differences in PE severity and patient characteristics, no mortality difference was observed (HR=0.96 [0.44-2.09], p =0.914). This may be due to a lack of mortality benefit attributable to advanced therapies in these patients or limited power to detect a relatively uncommon outcome. We did identify a significantly increased risk of major bleeding within 90 days (HR=9.05 [2.21-9.98], p <0.001) in patients treated with advanced therapies. Because the overwhelming majority of advanced therapies utilized in our center were IVC filters, which are often placed due to elevated bleeding risk, this observation may be due to residual confounding by indication. We also compared LOS and total costs of care, which we found to be significantly higher in the advanced therapy group. This may be partially explained by the cost of the advanced therapy itself, however, increased costs in all categories (facilities, supply, imaging, pharmacy, lab) suggest total cost differences are not entirely explained by treatment modality for pulmonary embolism. It is conceivable that patients identified with a high- or intermediate-risk PE necessitating advanced therapy may have underlying comorbidities (eg. cancer) or acute illness that requires more resources than patients who are well enough to receive anticoagulation therapy alone.

Strengths of this study include thorough review of each clinical chart by multiple study investigators (who are all practicing hospitalists) to manually validate the diagnosis of acute pulmonary embolism, echocardiographic findings, and any clinical contraindications to thrombolytic therapy. Our normalized cost analysis and evaluation of categorized cost is novel in this field and of importance due to increasing consideration of high value care in health systems. Our study is not without limitations. We cannot exclude the possibility of unmeasured or residual confounding, though we did control for well-established prediction scores for pulmonary embolism severity, comorbidities, and bleeding risk in our multivariable model. Our analysis was conducted within a single academic medical canter, and our findings may not be generalizable to other populations. Lastly, utilization of advanced therapies was relatively low across our study population, and we lacked sufficient power for further subgroup analysis dependent on type of advanced therapy used.

In conclusion, we observed an association between advanced therapies for acute PE and increased cost of care, LOS, and major bleeding events, without a reduction in mortality. Given previously described significant increases in utilization of advanced therapies after adoption of PERTs, it will be important to carefully monitor patient-centered clinical outcomes with adoption of new care systems. Adequately powered randomized clinical trials are needed to identify the safest and most effective advanced therapies for acute PE management.

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