Venous Thromboembolism in Patients with Thermal Injury

Venous thromboembolism (VTE) can be a life-threatening or limb-threatening complication of thermal injury. The severity of burn injury can be used to predict VTE risk among patients with thermal injury, and a weighted risk-stratification tool has been developed. This article reviews the incidence, diagnosis, and management of thromboembolic events in patients with burns. The article particularly focuses on identifying those patients who are at highest risk for VTE and provides recommendations on mechanical and chemical prophylaxis.

Key points

  • Venous thromboembolism is an important patient safety issue in patients with thermal injury.

  • Large database research is an excellent way to research rare events.

  • Further research into the optimal means to provide chemical prophylaxis to burn patients is needed.

Introduction

Virchow’s triad of stasis, hypercoagulability, and intimal damage describes the broad categories of factors that contribute to thrombotic risk. Patients with thermal injury seem to have the ideal physiologic predisposition to the Virchow’s triad, and thus should be at high risk for postinjury venous thromboembolism events. Endothelial dysfunction via disruption of junctional proteins and stress fibers results in altered paracellular flow of solutes or capillary leak, manifested by edema and altered fluid balance. Alterations in coagulation, including deficiency of natural anticoagulant antithrombin and altered fibrinogen, predispose toward a prothrombotic state. In addition, burn dressings and use of split-thickness skin grafts make immobilization and resulting venous stasis inevitable in the current treatment paradigm of major cutaneous burns.

Virchow’s triad notwithstanding, venous thromboembolism (VTE) is a rare event (0.6%) in the burn population. However, more than 10-fold variability in postinjury VTE risk exists among the overall population with thermal injury. As a rare event, VTE in thermally injured patients cannot rigorously be studied using case series or small, single-center studies. This article reviews the current knowledge of VTE in the thermally injured populations, with a focus on (1) the utility of large-database approaches for VTE research, and (2) an overview of VTE risk stratification and prevention.

Introduction

Virchow’s triad of stasis, hypercoagulability, and intimal damage describes the broad categories of factors that contribute to thrombotic risk. Patients with thermal injury seem to have the ideal physiologic predisposition to the Virchow’s triad, and thus should be at high risk for postinjury venous thromboembolism events. Endothelial dysfunction via disruption of junctional proteins and stress fibers results in altered paracellular flow of solutes or capillary leak, manifested by edema and altered fluid balance. Alterations in coagulation, including deficiency of natural anticoagulant antithrombin and altered fibrinogen, predispose toward a prothrombotic state. In addition, burn dressings and use of split-thickness skin grafts make immobilization and resulting venous stasis inevitable in the current treatment paradigm of major cutaneous burns.

Virchow’s triad notwithstanding, venous thromboembolism (VTE) is a rare event (0.6%) in the burn population. However, more than 10-fold variability in postinjury VTE risk exists among the overall population with thermal injury. As a rare event, VTE in thermally injured patients cannot rigorously be studied using case series or small, single-center studies. This article reviews the current knowledge of VTE in the thermally injured populations, with a focus on (1) the utility of large-database approaches for VTE research, and (2) an overview of VTE risk stratification and prevention.

Large-database approaches to risk modeling

Large-Database Research in Plastic Surgery, with a Focus on Rare Events

In outcomes analysis of dichotomous events (such as a yes/no VTE event), statistical analysis can examine observed differences in event frequency between patients with or without a certain risk factor, or with or without a certain intervention. Sample size calculation for dichotomous outcomes are based on the study’s tolerance for type I (alpha) and type II (beta) errors, as well as the expected event rate in the two groups. Large-database research is ideally suited for outcome events that occur infrequently, or for more common outcome events in which the expected difference between 2 interventions is small. Large-database approaches allow the use of regression-based techniques to control for identified confounding variables. This method, in turn, allows more rigorous estimation of risk directly attributable to different factors. Regression is a powerful tool when used correctly but admittedly requires a high number of outcome events. In general, the so-called “rule of 10s” states that, for each additional degree of freedom in the model, 10 outcome events are required. Thus, for a regression model that contains 10 dichotomous independent variables, approximately 100 outcomes events would need to be present in the data set in order for the regression to be valid. The advantage of large-database research for rare events becomes immediately apparent here.

Large-database approaches have been used in the plastic surgery literature to examine many rare but important complications, and to examine small but important differences between two treatment modalities. Examples include use of the National Surgical Quality Improvement Program (NSQIP) and the Tracking Operations and Outcomes in Plastic Surgery databases to examine complications associated with acellular dermal matrix in breast reconstruction, the NSQIP to examine readmission rates after reconstructive surgery, Medicare data to examine practice patterns in rheumatoid hand surgery, and the State Inpatient Database of New York to examine the effect of Medicaid expansion on access to reconstructive breast surgery. Several large-database approaches toward VTE risk model generation in surgical patients have been developed using the Veterans’ Affairs Patient Safety Study, the NSQIP, and the Michigan Surgical Quality Collaborative, although none are specific to patients with thermal injury. The authors have previously used the American Burn Association’s National Burn Repository (NBR) to create a condition-specific VTE risk assessment model for thermally injured patients, as discussed later.

Universal Risk Calculators Versus Condition-Specific Risk Calculators

Bilimoria and colleagues published a universal risk calculator based on more than 1 million cases in the NSQIP. This model uses a 21-point, Web-based, behind-the-scenes calculator to conceptualize and quantify risk for perioperative 30-day morbidity, 30-day mortality, and 6 additional postoperative complications. Their analysis showed that prediction for the universal calculator was similar to condition-specific models. The model was validated in a large cohort of colon surgery patients, in which the universal model and the colon-specific model performed similarly.

The advantage of such a universal risk calculator is that the maximum amount of information can be obtained from a minimum amount of effort. However, this assumes that risk calculation is being performed by a person. As the interface between medicine and technology continues to improve, risk calculators will likely be run behind the scenes by computers, instead of calculated by hand by individual providers. Our prior research has shown that a computer-based VTE risk score calculation, based on administrative data, is more accurate than a physician-reported VTE risk score. In this regard, it is noteworthy that, for examined complications in the study by Bilimoria and colleagues (including mortality, morbidity, pneumonia, cardiac, surgical site infection, urinary tract infection, VTE, and renal failure), the colon-specific model c-statistics were slightly higher and the Brier score slightly lower. These data indicate that the procedure-specific risk assessment tool may have slightly improved calibration and discrimination compared with the universal calculator. VTE risk stratification may evolve to a behind-the-scenes calculation, and, if calculations are being performed behind the scenes by computers (eg, with no additional human effort), then the most accurate model should be used. In this regard, the authors support ongoing development of procedure-specific or injury-specific VTE risk models, if their ability to risk-stratify exceeds that of a universal calculator.

Venous thromboembolism incidence and risk factors in patients with burns

Incidence

Single-center studies have a reported VTE incidence as low as 0.25% when only clinically symptomatic VTE is considered, and as high as 23.3% when patients are routinely surveyed via duplex ultrasonography for asymptomatic thrombosis. This wide range of variability is highlighted by other single-center studies reporting VTE incidences of 1.8%, 5.9%, and 6.0%. The variation in reported incidence can in some part be explained by the heterogeneity of the thermally injured patient population. This heterogeneity is highlighted by a recent analysis of the American Burn Association’s NBR, which was used to examine VTE in a population of more than 33,000 patients. The overall incidence for postburn VTE was low (0.61%), including deep venous thrombosis (DVT) (0.48%) and PE (0.18%). However, a large volume of patients had only minor injuries, biasing the results to represent patients with less severe injuries.

Among patients with total body surface area (TBSA) burns of greater than 10%, VTE rates double to 1.22%, approximating the incidence of VTE in hospitalized general, urologic, and vascular surgery patients (1.44%). Independent predictors for VTE included increased total burn size, increased length of intensive care unit (ICU) stay, and increased number of operative procedures. When controlling for other baseline risk and comorbidities, VTE carries a 3-fold increased risk of death. This fact underscores the importance of VTE risk stratification and prevention.

Risk Factors

Previous studies have identified multiple risk factors for VTE among patients with thermal injury. Most of these risk factors are acquired during the patient’s inpatient stay. Identified risk factors include increased age, increased body mass index, increased TBSA burned, infected burn wounds, central venous access, increased mechanical ventilation days, longer ICU stays, and increased number of operative procedures. In addition, patients with thermal injury are known to have normal coagulation parameters at admission but become hypercoagulable during hospitalization, as shown by increased fibrinogen, protein C, protein S, and antithrombin III levels.

Venous thromboembolism risk modeling in patients with thermal injury

The Caprini Risk Assessment Model is a widely used and well-validated risk prediction tool. The 2005 Caprini score has been validated to predict perioperative VTE risk in multiple surgical populations, including general, vascular, and urology surgery ; otolaryngology head and neck surgery ; plastic and reconstructive surgery ; patients in the surgical ICU ; gynecology-oncology patients ; and general hospitalized patients. However, the 2005 Caprini score was designed to be used in the preoperative setting based on a patient’s baseline risk factors, and injury severity or extent of surgery are small contributors to the aggregate risk score. Similarly, existing VTE risk-stratification tools derived from large-database research are ill-suited to the specifics of patients with thermal injury. Recognizing this fact, the authors previously used a large-database approach to examine VTE risk in thermally injured patients through an analysis of the American Burn Association’s NBR. The NBR is a voluntary database that acquires patient-level, deidentified, Health Insurance Portability and Accountability Act–compliant data from participating burn centers in the United States and Canada. The database contains comprehensive information on patient demographics and comorbid conditions; the nature and extent of their thermal injuries; and hospital course, including operative interventions and identified complications. The NBR has previously been described in detail.

Potential risk factors incorporated into the regression model included those that were either available or could be derived at the initial patient contact. The risk model specifically excluded risk factors that were acquired after admission (such as central venous line or infectious complications), and this was done for 2 reasons. First, the NBR database does not contain a time-to-event variable for complications or International Classification of Diseases, Ninth Revision, procedural codes. Thus, the authors were unable to ascertain whether complications or procedures that might contribute to VTE risk occurred before or after the VTE event was diagnosed. Second, a risk score that encompasses risk factors acquired in hospital can, by definition, only estimate VTE risk at the end of a patient’s hospital stay. At this point, the opportunity for acute prophylaxis has been missed.

The tool was created using statistically rigorous methods, including multivariable regression to control for identified confounders. The tool was derived based on an analysis of 16,581 adult patients with thermal injury, and was subsequently validated in a separate group of 5761 thermally injured patients. Independent risk factors were weighted, or assigned an increasing number of points in the final risk model, based on the adjusted odds ratios in the final regression model. In this analysis, TBSA burned and presence of inhalation injury were the most important predictors of downstream VTE events. The risk prediction tool ( Fig. 1 ) explained more than 75% of the variability in patients who did or did not develop VTE during their hospitalizations, and also identified a wide variation in risk among patients (from <1.0% to >5.0%). Similar trends were seen in both the working and validation data sets ( Fig. 2 ). VTE risk increased linearly with risk score. The calculated risk score can identify patients at particularly high VTE risk using risk factors identified at their initial presentation, and may be an appropriate guide to risk-stratify patients for VTE prophylaxis.

Fig. 1
Weighted, validated risk scoring model for VTE after thermal injury.
( From Pannucci CJ, Osborne NH, Wahl WL. Creation and validation of a simple venous thromboembolism risk scoring tool for thermally injured patients: analysis of the National Burn Repository. J Burn Care Res 2012;33:20–5.)

Fig. 2
Observed rates of VTE in patients with thermal injury stratified by risk score from Fig. 1 . Gray bars represent the working data set and black bars the validation data set. The validation data set was an independent cohort not used to create the model in Fig. 1 .
( From Pannucci CJ, Osborne NH, Wahl WL. Creation and validation of a simple venous thromboembolism risk scoring tool for thermally injured patients: analysis of the National Burn Repository. J Burn Care Res 2012;33:20–5.)

The 2005 Caprini Risk Assessment Model has been validated in multiple North American and international studies in a wide variety of surgical and medical patients. However, its utility in patients with thermal injury has never been examined. The Caprini score incorporates many patient-level variables and may be construed as a calculator for general medical fitness. To that end, the 2005 Caprini score has been shown to predict non-VTE complications. However, in patients with burn injury, injury severity, as quantified by TBSA burned and inhalation injury, seems to be the major driver of VTE risk, and trumps the influence of patient-level factors.

Venous thromboembolism prevention in patients with thermal injury

Sequential Compression Devices

Intermittent pneumatic compression devices recreate the normal action of the calf muscle pump in nonambulatory patients, including those who are paralyzed for operations or critical illness. Venous stasis is known to promote venous dilation with resultant intimal microtears. Operative venodilation is known to be an independent predictor of postoperative VTE. The calf muscle pump action minimizes venous stasis in the lower legs, decreasing the likelihood of venous dilation and increasing endogenous fibrinolytic potential. Thus, intermittent pneumatic compression devices directly address 2 components of the Virchow’s triad (stasis and intimal damage) and may indirectly affect the third (hypercoagulable state, via fibrinolysis activation). Prior meta-analyses have shown that intermittent pneumatic compression can substantially reduce risk for DVT, but not necessarily for pulmonary embolus. In other surgical populations, combination prophylaxis, which includes intermittent pneumatic compression and chemoprophylaxis, has been shown to significantly reduce VTE risk compared with intermittent pneumatic compression alone. Thus, for high-risk patients, the combination of intermittent pneumatic compression and chemoprophylaxis is desirable, because the addition of chemoprophylaxis is associated with significantly lower VTE risk. However, when a patient’s clinical situation precludes chemoprophylaxis, intermittent pneumatic compression alone is of substantial benefit.

Chemoprophylaxis Benefits

At present, no randomized controlled studies have examined chemoprophylaxis effectiveness specific to patients with thermal injury. Of note, recommendations regarding this population have been removed from the latest edition of the widely cited American College of Chest Physicians’ (ACCP) evidence-based clinical practice guidelines for the prevention of VTE. The ACCP guidelines are an exhaustively referenced compendium on surgery-specific VTE prophylaxis. It is noteworthy that the 2008 ACCP guidelines make VTE prophylaxis recommendations for patients with thermal injury, but that these were removed from the 2012 version; this omission is likely from a paucity of data specific to the thermally injured population.

Data from retrospective studies suggest a low incidence of VTE when low-dose unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) are administered as routine thromboprophylaxis in burned patients. Survey data from European burn centers found the lowest rates of DVT and heparin-induced thrombocytopenia (HIT) in units using routine LMWH for thromboprophylaxis compared with those without standard protocol or those administering low-dose intravenous UFH. These data have yet to be confirmed in a prospective randomized fashion. Although it is certain that thermally injured patients have a definite risk of VTE, the relative risk reduction by prophylaxis with low-dose UFH or LMWH remains undefined.

Anti-Xa Levels in Thermal Injury

Enoxaparin accelerates the activity of antithrombin, which, in turn, accelerates the rate at which factor Xa is inactivated. Factor Xa inactivation results in decreased conversion of prothrombin to thrombin. Inhibition of this critical step in the coagulation cascade decreases the likelihood that clot will form. Anti–factor Xa (aFXa) levels can be used as a marker of enoxaparin activity. Peak aFXa level, drawn at 4 hours after subcutaneous injection, is the most accurate marker of enoxaparin activity and safety.

Established recommendations from both the Plastic Surgery Foundation–funded Venous Thromboembolism Prevention Study (VTEPS) and the American Society of Plastic Surgeons (ASPS) consensus guidelines support the clinical effectiveness of once-daily enoxaparin dosing. However, the standard doses of enoxaparin (40 mg subcutaneously daily) supported by the ASPS may be insufficient in patients with thermal injury. Our institution has previously studied enoxaparin metabolism in thermally injured patients. Standard dosing has been shown to be inadequate, with only 21% to 34% of patients having an acceptable initial steady-state aFXa level. Real-time enoxaparin dose adjustment in response to a written protocol can substantially increase the proportion of patients with in-range levels (from 21% to 79%). Our institution has previously created a linear regression–based equation to determine initial enoxaparin prophylaxis dose based on patient-level characteristics in patients with burns. The equation (22.8 + [3.3 × %TBSA burned/10] + [1.89 × (weight in kilograms)]/10) can be used to predict the starting dose of subcutaneous enoxaparin in milligrams, and enoxaparin should be provided twice daily. Thermally injured patients dosed based on this equation were significantly more likely have initial steady-state aFXa levels that were in range (73% vs 32%; P = .002) and were significantly more likely to achieve in-range aFXa levels than patients in whom standard dosing was used (85% vs 68%; P = .006). In a series of 35 pediatric patients with burns, 60% had an undetectable aFXa level based on initial dosing, and only 34% were in range. Importantly, dose escalation based on aFXa levels does not substantially increase bleeding events.

Case series of thermally injured patients who receive dose adjustment have a low rate of VTE (2.9%), although no controlled studies exist to definitely correlate real-time aFXa monitoring and dose adjustment with decreased VTE. Importantly, inadequate initial peak aFXa levels have been shown to be significantly associated with DVT in the trauma and orthopedic surgery populations.

Chemoprophylaxis Risks

Recent survey data suggest that the proportion of North American burn centers that routinely prescribe VTE prophylaxis ranges from 50% to 75%. Among those centers that use prophylaxis, 22% use mechanical prophylaxis such as intermittent pneumatic compression but do not use chemoprophylaxis. The primary reason provided by plastic surgeons for not using chemoprophylaxis is risk of postoperative bleeding. Concerns regarding HIT are also present. The reported incidence of HIT as a result of low-dose UFH in this patient population ranges from 0.0% to 3.1%, with some investigators postulating that the severely burned are among the highest-risk patient populations for development of this complication. HIT diagnosis is complicated by postburn platelet consumption and hemodilution from massive fluid resuscitation, resulting in thrombocytopenia that renders the standard diagnostic criteria largely irrelevant. Episodes of HIT secondary to LMWH are less common in both general postoperative patients (0.68%) and the burn population in particular (0.0%–0.2%). HIT is an important issue among thermally injured patients, and patients with a clinical picture concerning for HIT are typically transitioned to a direct thrombin inhibitor such as argatroban. Of note, use of argatroban is an independent predictor of red blood cell and plasma transfusion after thermal injury. LMWH is ideally dosed using real-time dose adjustment and the substantial decreased likelihood of HIT supports LMWH as a first-line agent for VTE prophylaxis in the burn population.

Despite blood conservation techniques and judicious use of blood products, transfusion requirement for patients undergoing major burn excision remains substantial. In addition, nonmajor bleeding in this patient population, such as wound hematoma, can be a significant source of morbidity. Graft loss from hematoma can result in repeat operations, thus further increasing VTE risk. In the absence of chemoprophylaxis, baseline risk of hematomas among plastic and reconstructive patients is 0.5% to 2.7%. In an analysis of the VTEPS study, including 3681 general plastic and reconstructive surgery patients, receipt of postoperative enoxaparin was not associated with statistically significant increases in 60-day reoperative hematoma; the absolute risk increase in the enoxaparin group was 0.7%. In thermally injured patients, prophylactic anticoagulation does not substantially increase red blood cell transfusion, although therapeutic anticoagulation is an independent predictor. Increased TBSA burned is known to have a linear relationship with red blood cell transfusion requirements, and patients with inhalation injury are known to have higher rates of red blood cell transfusion than patients without.

Existing data support that red blood cell transfusion is not an independent predictor of mortality and that VTE is an independent predictor of mortality. However, based on existing data, the risks of major and nonmajor bleeding complications need to be better defined to identify the subset of patients in whom the benefits of prophylactic anticoagulants outweigh the risks. However, until such data become available, the authors strongly support the opinions voiced by Davison and Massoumi in a 2007 Plastic and Reconstructive Surgery editorial. They remind readers that the consequences of hematomas can typically be addressed with hospital admission, transfusion, and/or an additional operative procedure; these usually represent a transient issue for patients that can be completely resolved. In contrast, the consequences of pulmonary embolus, in which 10% of symptomatic patients are dead within 60 minutes, cannot necessarily be fixed.

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Nov 21, 2017 | Posted by in Dental Materials | Comments Off on Venous Thromboembolism in Patients with Thermal Injury
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