User login
Survey finds high rate of misdiagnosed fungal infections
Fungal skin infections may be missed or misdiagnosed by many dermatologists, according to the results of a survey published online in the Journal of the American Academy of Dermatology.
For the interactive survey, conducted during a session on fungal infections at the 2016 Orlando Dermatology Aesthetic and Clinical Conference, board-certified dermatologists viewed 13 clinical images (which included other conditions such as secondary syphilis and pityriasis rosea) and were asked via an audience response system whether or not they thought the case was a fungal skin infection. In only 1 of the 13 cases presented did 90% of the dermatologists correctly categorize the case as either a dermatomycosis or not, reported Ramsin Joseph Yadgar of George Washington University in Washington, D.C., and colleagues.
Although most cases (8 of 13) “were appropriately categorized by more than 50% of the audience, this percentage decreased as accuracy of categorization increased,” they wrote. “For example, in only 4 of the 13 cases did audience members accurately categorize the cases with more than 75% accuracy,” they said (J Am Acad Dermatol. 2016 Nov 11. pii: S0190-9622[16]30883-0. doi: 10.1016/j.jaad.2016.09.041).
“Dermatology is full of doppelgangers,” Dr. Friedman, director of the residency program and of translational research in the department of dermatology at George Washington University, said in an interview.
“While we [dermatologists] pride ourselves on our visual prowess, there are many skin diseases which do not follow the textbook and can be quite protean in their presentations,” he said.
The variability in presentation makes diagnosing fungal infections especially challenging, he noted. “Fungal infections of the skin can have many clinical flavors and can infect skin, hair and nails. Also, inappropriate treatment can obscure the appearance of the infection, and the fact that there are multiple other conditions that can look like these [fungal] infections makes proper identification difficult.”
Although the results were limited by several factors including possible selection bias, lack of measurable response rate, and small sample size, the findings highlight how easy it can be to miss a diagnosis of fungal infection, “which can result in inappropriate therapy, worsening of symptoms, and even additional skin and soft-tissue infections,” the researchers wrote.
“Keep an open mind and cast a wider differential,” to help catch fungal infections, and use all the dermatologic tools, including slide preps, cultures, and biopsies, Dr. Friedman said. Better diagnostic tools and improved training for clinicians outside of dermatology also could reduce the misdiagnosis of fungal infections, he added. “Many of these patients are misdiagnosed in the emergency department, urgent care, or primary care settings,” and delayed treatment increases associated morbidity, he said.
Mr. Yadgar, Dr. Friedman, and another coauthor, Neal Bhatia, MD, of Therapeutics Clinical Research, San Diego, Calif., had no financial conflicts to disclose. There was no funding source.
Fungal skin infections may be missed or misdiagnosed by many dermatologists, according to the results of a survey published online in the Journal of the American Academy of Dermatology.
For the interactive survey, conducted during a session on fungal infections at the 2016 Orlando Dermatology Aesthetic and Clinical Conference, board-certified dermatologists viewed 13 clinical images (which included other conditions such as secondary syphilis and pityriasis rosea) and were asked via an audience response system whether or not they thought the case was a fungal skin infection. In only 1 of the 13 cases presented did 90% of the dermatologists correctly categorize the case as either a dermatomycosis or not, reported Ramsin Joseph Yadgar of George Washington University in Washington, D.C., and colleagues.
Although most cases (8 of 13) “were appropriately categorized by more than 50% of the audience, this percentage decreased as accuracy of categorization increased,” they wrote. “For example, in only 4 of the 13 cases did audience members accurately categorize the cases with more than 75% accuracy,” they said (J Am Acad Dermatol. 2016 Nov 11. pii: S0190-9622[16]30883-0. doi: 10.1016/j.jaad.2016.09.041).
“Dermatology is full of doppelgangers,” Dr. Friedman, director of the residency program and of translational research in the department of dermatology at George Washington University, said in an interview.
“While we [dermatologists] pride ourselves on our visual prowess, there are many skin diseases which do not follow the textbook and can be quite protean in their presentations,” he said.
The variability in presentation makes diagnosing fungal infections especially challenging, he noted. “Fungal infections of the skin can have many clinical flavors and can infect skin, hair and nails. Also, inappropriate treatment can obscure the appearance of the infection, and the fact that there are multiple other conditions that can look like these [fungal] infections makes proper identification difficult.”
Although the results were limited by several factors including possible selection bias, lack of measurable response rate, and small sample size, the findings highlight how easy it can be to miss a diagnosis of fungal infection, “which can result in inappropriate therapy, worsening of symptoms, and even additional skin and soft-tissue infections,” the researchers wrote.
“Keep an open mind and cast a wider differential,” to help catch fungal infections, and use all the dermatologic tools, including slide preps, cultures, and biopsies, Dr. Friedman said. Better diagnostic tools and improved training for clinicians outside of dermatology also could reduce the misdiagnosis of fungal infections, he added. “Many of these patients are misdiagnosed in the emergency department, urgent care, or primary care settings,” and delayed treatment increases associated morbidity, he said.
Mr. Yadgar, Dr. Friedman, and another coauthor, Neal Bhatia, MD, of Therapeutics Clinical Research, San Diego, Calif., had no financial conflicts to disclose. There was no funding source.
Fungal skin infections may be missed or misdiagnosed by many dermatologists, according to the results of a survey published online in the Journal of the American Academy of Dermatology.
For the interactive survey, conducted during a session on fungal infections at the 2016 Orlando Dermatology Aesthetic and Clinical Conference, board-certified dermatologists viewed 13 clinical images (which included other conditions such as secondary syphilis and pityriasis rosea) and were asked via an audience response system whether or not they thought the case was a fungal skin infection. In only 1 of the 13 cases presented did 90% of the dermatologists correctly categorize the case as either a dermatomycosis or not, reported Ramsin Joseph Yadgar of George Washington University in Washington, D.C., and colleagues.
Although most cases (8 of 13) “were appropriately categorized by more than 50% of the audience, this percentage decreased as accuracy of categorization increased,” they wrote. “For example, in only 4 of the 13 cases did audience members accurately categorize the cases with more than 75% accuracy,” they said (J Am Acad Dermatol. 2016 Nov 11. pii: S0190-9622[16]30883-0. doi: 10.1016/j.jaad.2016.09.041).
“Dermatology is full of doppelgangers,” Dr. Friedman, director of the residency program and of translational research in the department of dermatology at George Washington University, said in an interview.
“While we [dermatologists] pride ourselves on our visual prowess, there are many skin diseases which do not follow the textbook and can be quite protean in their presentations,” he said.
The variability in presentation makes diagnosing fungal infections especially challenging, he noted. “Fungal infections of the skin can have many clinical flavors and can infect skin, hair and nails. Also, inappropriate treatment can obscure the appearance of the infection, and the fact that there are multiple other conditions that can look like these [fungal] infections makes proper identification difficult.”
Although the results were limited by several factors including possible selection bias, lack of measurable response rate, and small sample size, the findings highlight how easy it can be to miss a diagnosis of fungal infection, “which can result in inappropriate therapy, worsening of symptoms, and even additional skin and soft-tissue infections,” the researchers wrote.
“Keep an open mind and cast a wider differential,” to help catch fungal infections, and use all the dermatologic tools, including slide preps, cultures, and biopsies, Dr. Friedman said. Better diagnostic tools and improved training for clinicians outside of dermatology also could reduce the misdiagnosis of fungal infections, he added. “Many of these patients are misdiagnosed in the emergency department, urgent care, or primary care settings,” and delayed treatment increases associated morbidity, he said.
Mr. Yadgar, Dr. Friedman, and another coauthor, Neal Bhatia, MD, of Therapeutics Clinical Research, San Diego, Calif., had no financial conflicts to disclose. There was no funding source.
FROM JAAD
Key clinical point: Fungal infections may often be missed or misdiagnosed by dermatologists.
Major finding: In 1 of 13 cases did 90% of an audience of dermatologists correctly categorize the condition.
Data source: A survey of board-certified dermatologists, asked whether or not 13 clinical images were a fungal infection or not, during a session on fungal infections at a dermatology meeting.
Disclosures: The research team had no relevant financial conflicts to disclose.
Comparing Cost, Efficacy, and Safety of Intravenous and Topical Tranexamic Acid in Total Hip and Knee Arthroplasty
Total hip arthroplasty (THA) and total knee arthroplasty (TKA) can be associated with significant blood loss that in some cases requires transfusion. The incidence of transfusion ranges from 16% to 37% in patients who undergo THA and from 11% to 21% in patients who undergo TKA.1-3 Allogeneic blood transfusions have been associated with several risks (transfusion-related acute lung injury, hemolytic reactions, immunologic reactions, fluid overload, renal failure, infections), increased cost, and longer hospital length of stay (LOS).4-7 With improved patient outcomes the ultimate goal, blood-conserving strategies designed to decrease blood loss and transfusions have been adopted as a standard in successful joint replacement programs.
Tranexamic acid (TXA), an antifibrinolytic agent, has become a major component of blood conservation management after THA and TKA. TXA stabilizes clots at the surgical site by inhibiting plasminogen activation and thereby blocking fibrinolysis.8 The literature supports intravenous (IV) TXA as effective in significantly reducing blood loss and transfusion rates in elective THA and TKA.9,10 However, data on increased risk of thrombotic events with IV TXA in both THA and TKA are conflicting.11,12 Topical TXA is thought to have an advantage over IV TXA in that it provides a higher concentration of drug at the surgical site and is associated with little systemic absorption.2,13Recent prospective randomized studies have compared the efficacy and safety of IV and topical TXA in THA and TKA.9,14 However, controversy remains because relatively few studies have compared these 2 routes of administration. In addition, healthcare–associated costs have come under increased scrutiny, and the cost of these treatments should be considered. More research is needed to determine which application is most efficacious and cost-conscious and poses the least risk to patients. Therefore, we conducted a study to compare the cost, efficacy, and safety of IV and topical TXA in primary THA and TKA.
Materials and Methods
Our Institutional Review Board approved this study. Patients who were age 18 years or older, underwent primary THA or TKA, and received IV or topical TXA between August 2013 and September 2014 were considered eligible for the study. For both groups, exclusion criteria were trauma service admission, TXA hypersensitivity, pregnancy, and concomitant use of IV and topical TXA.
We collected demographic data (age, sex, weight, height, body mass index), noted all transfusions of packed red blood cells, and recorded preoperative and postoperative hemoglobin (Hgb) levels and surgical drain outputs. We also recorded any complications that occurred within 90 days after surgery: deep vein thrombosis (DVT), pulmonary embolism (PE), cardiac events, cerebrovascular events, and wound drainage. Wound drainage was defined as readmission to hospital or return to operating room for wound drainage caused by infection or hematoma. Postoperative care (disposition, LOS, follow-up) was documented. Average cost of both IV and topical TXA administration was calculated using average wholesale price.
Use of IV TXA and use of topical TXA were compared in both THA and TKA. Patients in the IV TXA group received TXA in two 10-mg/kg doses with a maximum of 1 g per dose. The first IV dose was given before the incision, and the second was given 3 hours after the first. Patients in the topical TXA group underwent direct irrigation with 3 g of TXA in 100 mL of normal saline at the surgical site after closure of the deep fascia in THA and after closure of the knee arthrotomy in TKA. The drain remained occluded for 30 minutes after surgery. The wound was irrigated with topical TXA before wound closure in the THA group and before tourniquet release in the TKA group. TXA dosing was based on institutional formulary dosing restrictions and was consistent with best practices and current literature.3,9,14,15Primary outcomes measured for each cohort and treatment arm were Hgb levels (difference between preoperative levels and lowest postoperative levels 24 hours after surgery), blood loss, transfusion rates, and cost. Secondary outcomes were LOS and complications that occurred within 90 days after surgery (DVT, PE, cardiac events, cerebrovascular events, wound drainage).
Calculated blood loss was determined with equations described by Konig and colleagues,3 Good and colleagues,16 and Nadler and colleagues.17 Total calculated blood loss was based on the difference in Hgb levels before surgery and the lowest Hgb levels 24 hours after surgery:
Blood loss (mL) = 100 mL/dL × Hgbloss/Hgbi
Hgbloss = BV × (Hgbi – Hgbe) × 10 dL/L + Hgbt
= 0.3669 × Height3 (m) + 0.03219 × Weight (kg) + 0.6041 (for men)
= 0.3561 × Height3 (m) + 0.03308 × Weight (kg) + 0.1833 (for women)
where Hgbi is the Hgb concentration (g/dL) before surgery, Hgbe is the lowest Hgb concentration (g/dL) 24 hours after surgery, Hgbt is the total amount (g) of allogeneic Hgb transfused, and BV is the estimated total body blood volume (L).17 As Hgb concentrations after blood transfusions were compared in this study, the Hgbt variable was removed from the equation. Based on Hgb decrease data in a study that compared IV and topical TXA in TKA,14 we determined that a sample size of least 140 patients (70 in each cohort) was needed in order to have 80% power to detect a difference in Hgb decrease of 0.36 g/dL in IV and topical TXA.
All data were reported with descriptive statistics. Frequencies and percentages were reported for categorical variables. Means and standard deviations were reported for continuous variables. The groups of continuous data were compared with unpaired Student t tests and 1-way analysis of variance. Comparisons among groups of categorical data were analyzed with Fisher exact tests. Statistical significance was set at P < .05.
Results
Data were collected on 291 patients (156 THA, 135 TKA). There was a significant (P = .044) sex difference in the THA group: more men in the topical TXA subgroup and more women in the IV TXA subgroup. Other patient demographics were similarly matched with respect to age, height, weight, and body mass index (Table 1). 
The secondary outcomes (differences in complications and LOS) are listed in Table 3. 
Discussion
TXA, an analog of the amino acid lysine, is an antifibrinolytic agent that has been used for many years to inhibit fibrin degradation.3,18 TXA works by competitively inhibiting tissue plasminogen activation, which is elevated by the trauma of surgery, and blocking plasmin binding to fibrin.3,19 The mechanism of action is not procoagulant, as TXA prevents fibrin breakdown and supports coagulation that is underway rather than increasing clot formation. These characteristics make the drug attractive for orthopedic joint surgery—TXA reduces postoperative blood loss in patients who need fibrinolysis suppressed in order to maintain homeostasis without increasing the risk of venous thromboembolism. IV TXA has been well studied, which supports its efficacy profile for reducing blood loss and transfusions; there are no reports of increased risk of thromboembolic events.20-22 Despite these studies, the risk of adverse events is still a major concern, especially in patients with medical conditions that predispose them to venothrombotic events. Topical TXA has become a viable option, especially in high-risk patients, as studies have shown 70% lower systemic absorption relative to IV TXA plasma concentration.23 Still, too few studies have compared the efficacy, safety, and cost of IV and topical TXA in both THA and TKA.
Topical TXA costs an average of $2100 per case, primarily because standard dosing is 3 g per case. Despite repeat dosing for IV TXA (first dose at incision, second dose 3 hours after first), IV TXA costs were much lower on average: $939 less for THA and $829 less for TKA. As numerous studies have outlined results similar to ours, cost-effectiveness should be considered in decisions about treatment options.
Patel and colleagues14 reported that the efficacy of topical TXA was similar to that of IV TXA and that there were no significant differences in Hgb decrease, wound drainage, or need for transfusions after TKA. Their report conflicts with our finding significant differences favoring topical TXA for Hgb change (P = .015) and reduced calculated blood loss (P = .019) in TKA. A potential reason for these differing results is that the topical TXA doses were different (2 g in the study by Patel and colleagues,14 3 g in our study). Martin and colleagues24 compared the effects of topical TXA and placebo and found a nonsignificant difference in reduced blood loss and postoperative transfusions when the drug was dosed at 2 g. Konig and colleagues3 found that topical TXA dosed at 3 g (vs placebo) could reduce blood loss and transfusions after THA and TKA. These studies support our 3-g dose protocol for topical TXA rather than the 2-g protocol used in the study by Patel and colleagues.14 Our results are congruent with those of Seo and colleagues,25 who found topical TXA superior in decreasing blood loss in TKA. Furthermore, our study is unique in that it compared costs and found topical TXA to be more expensive by almost $1000 on average.
Wei and Wei9 concluded that IV TXA 3 g and topical TXA 3 g were equally effective in reducing total blood loss, change in hematocrit, and need for transfusion after THA. In contrast, we found a significant (P = .031) difference favoring topical TXA for Hgb change. The 2 studies differed in their dosing protocols: Wei and Wei9 infused a 3-g dose, whereas we gave a maximum of two 1-g IV doses. The higher IV dose used by Wei and Wei9 could explain why they found no difference between IV and topical TXA, whereas we did find a difference. Our study was unique in that it measured Hgb change, blood loss, and cost.
Our study included an in-depth analysis of blood loss: estimated blood loss, drain outputs, calculated blood loss, and Hgb change. The equation we used for calculated blood loss is well established and has been used in multiple studies.3,16,17 To thoroughly assess the safety of TXA, we reviewed and documented complications that occurred within 90 days after surgery and that could be attributed to TXA. This study was adequately powered and exceeded the required sample size to detect a difference in one primary outcome measure, perioperative Hgb change, as calculated by the prestudy statistical power analysis.
Our study had several limitations. First, it was a retrospective chart review; documentation could have been incomplete or missing. Second, the study was not randomized and thus subject to drug selection bias. Third, patients were selected for topical TXA on the basis of perceived risk factors, such as prior or family history of DVT, PE, cardiac events, or cerebrovascular events. It was thought that, given the decrease in systemic absorption with topical TXA, these high-risk patients would be less likely to have a thromboembolic event. Their complex past medical histories may explain why the topical TXA group had more cardiac events. Furthermore, 1 orthopedic surgeon used topical TXA exclusively, and the other 3 used it selectively, according to risk factors. In addition, unlike TKA patients, not all THA patients received drains. This study was powered to measure a difference in perioperative Hgb change but may not have been powered to detect the statistically significant difference favoring topical TXA for calculated blood loss in TKA. In the THA group, a statistically significant difference was found for reduced Hgb decrease but not for estimated or calculated blood loss. This finding reinforces some of the disparities in measurements of the effects of blood conservation strategies. The study also lacked a placebo or control group. However, several other studies have found that both IV TXA and topical TXA are superior to placebo in decreasing blood loss, Hgb change, and transfusion requirements.10,12,20,22 In addition, the effects of TXA are based on estimates of blood conservation and are not without their disparities.
Conclusion
The present study found that both IV TXA and topical TXA were effective in decreasing blood loss, Hgb levels, and need for transfusion after THA and TKA. Topical TXA appears to be more effective than IV TXA in preventing Hgb decrease during THA and TKA and calculated blood loss during TKA. This increased efficacy comes with a higher cost. Thromboembolic complications were similar between groups. More studies are needed to compare the efficacy and safety profiles of topical TXA against the routine standard of IV TXA, especially in patients with perceived contraindications to IV TXA.
Am J Orthop. 2016;45(7):E439-E443. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.
1. Bierbaum BE, Callaghan JJ, Galante JO, Rubash HE, Tooms RE, Welch RB. An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg Am. 1999;81(1):2-10.
2. Yue C, Kang P, Yang P, Xie J, Pei F. Topical application of tranexamic acid in primary total hip arthroplasty: a randomized double-blind controlled trial. J Arthroplasty. 2014;29(12):2452-2456.
3. Konig G, Hamlin BR, Waters JH. Topical tranexamic acid reduces blood loss and transfusion rates in total hip and total knee arthroplasty. J Arthroplasty. 2013;28(9):1473-1476.
4. Stokes ME, Ye X, Shah M, et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res. 2011;11:135.
5. Lemos MJ, Healy WL. Blood transfusion in orthopaedic operations. J Bone Joint Surg Am. 1996;78(8):1260-1270.
6. Vamvakas EC, Blajchman MA. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood. 2009;113(15):3406-3417.
7. Kumar A. Perioperative management of anemia: limits of blood transfusion and alternatives to it. Cleve Clin J Med. 2009;76(suppl 4):S112-S118.
8. Hoylaerts M, Lijnen HR, Collen D. Studies on the mechanism of the antifibrinolytic action of tranexamic acid. Biochim Biophys Acta. 1981;673(1):75-85.
9. Wei W, Wei B. Comparison of topical and intravenous tranexamic acid on blood loss and transfusion rates in total hip arthroplasty. J Arthroplasty. 2014;29(11):2113-2116.
10. Zhang H, Chen J, Chen F, Que W. The effect of tranexamic acid on blood loss and use of blood products in total knee arthroplasty: a meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2012;20(9):1742-1752.
11. Ido K, Neo M, Asada Y, et al. Reduction of blood loss using tranexamic acid in total knee and hip arthroplasties. Arch Orthop Trauma Surg. 2000;120(9):518-520.
12. Yang ZG, Chen WP, Wu LD. Effectiveness and safety of tranexamic acid in reducing blood loss in total knee arthroplasty: a meta-analysis. J Bone Joint Surg Am. 2012;94(13):1153-1159.
13. Alshryda S, Mason J, Sarda P, et al. Topical (intra-articular) tranexamic acid reduces blood loss and transfusion rates following total hip replacement: a randomized controlled trial (TRANX-H). J Bone Joint Surg Am. 2013;95(21):1969-1974.
14. Patel JN, Spanyer JM, Smith LS, Huang J, Yakkanti MR, Malkani AL. Comparison of intravenous versus topical tranexamic acid in total knee arthroplasty: a prospective randomized study. J Arthroplasty. 2014;29(8):1528-1531.
15. Alshryda S, Sarda P, Sukeik M, Nargol A, Blenkinsopp J, Mason JM. Tranexamic in total knee replacement: a systematic review and meta-analysis. J Bone Joint Surg Br. 2011;93(12):1577-1585.
16. Good L, Peterson E, Lisander B. Tranexamic acid decreases external blood loss but not hidden blood loss in total knee replacement. Br J Anaesth. 2003;90(5):596-599.
17. Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery. 1962;51(2):224-232.
18. Eubanks JD. Antifibrinolytics in major orthopaedic surgery. J Am Acad Orthop Surg. 2010;18(3):132-138.
19. Mannucci PM. Homostatic drugs. N Engl J Med. 1998;339(4):245-253.
20. Wind TC, Barfield WR, Moskal JT. The effect of tranexamic acid on transfusion rate in primary total hip arthroplasty. J Arthroplasty. 2014;29(2):387-389.
21. Dahuja A, Dahuja G, Jaswal V, Sandhu K. A prospective study on role of tranexamic acid in reducing postoperative blood loss in total knee arthroplasty and its effect on coagulation profile. J Arthroplasty. 2014;29(4):733-735.
22. Tan J, Chen H, Liu Q, Chen C, Huang W. A meta-analysis of the effectiveness and safety of using tranexamic acid in primary unilateral total knee arthroplasty. J Surg Res. 2013;184(2):880-887.
23. Wong J, Abrishami A, El Beheiry H, et al. Topical application of tranexamic acid reduces postoperative blood loss in total knee arthroplasty: a randomized, controlled trial. J Bone Joint Surg Am. 2010;92(15):2503-2513.
24. Martin JG, Cassatt KB, Kincaid-Cinnamon KA, Westendorf DS, Garton AS, Lemke JH. Topical administration of tranexamic acid in primary total hip and total knee arthroplasty. J Arthroplasty. 2014;29(5):889-894.
25. Seo JG, Moon YW, Park SH, Kim SM, Ko KR. The comparative efficacies of intra-articular and IV tranexamic acid for reducing blood loss during total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc. 2013;21(8):1869-1874.
Total hip arthroplasty (THA) and total knee arthroplasty (TKA) can be associated with significant blood loss that in some cases requires transfusion. The incidence of transfusion ranges from 16% to 37% in patients who undergo THA and from 11% to 21% in patients who undergo TKA.1-3 Allogeneic blood transfusions have been associated with several risks (transfusion-related acute lung injury, hemolytic reactions, immunologic reactions, fluid overload, renal failure, infections), increased cost, and longer hospital length of stay (LOS).4-7 With improved patient outcomes the ultimate goal, blood-conserving strategies designed to decrease blood loss and transfusions have been adopted as a standard in successful joint replacement programs.
Tranexamic acid (TXA), an antifibrinolytic agent, has become a major component of blood conservation management after THA and TKA. TXA stabilizes clots at the surgical site by inhibiting plasminogen activation and thereby blocking fibrinolysis.8 The literature supports intravenous (IV) TXA as effective in significantly reducing blood loss and transfusion rates in elective THA and TKA.9,10 However, data on increased risk of thrombotic events with IV TXA in both THA and TKA are conflicting.11,12 Topical TXA is thought to have an advantage over IV TXA in that it provides a higher concentration of drug at the surgical site and is associated with little systemic absorption.2,13Recent prospective randomized studies have compared the efficacy and safety of IV and topical TXA in THA and TKA.9,14 However, controversy remains because relatively few studies have compared these 2 routes of administration. In addition, healthcare–associated costs have come under increased scrutiny, and the cost of these treatments should be considered. More research is needed to determine which application is most efficacious and cost-conscious and poses the least risk to patients. Therefore, we conducted a study to compare the cost, efficacy, and safety of IV and topical TXA in primary THA and TKA.
Materials and Methods
Our Institutional Review Board approved this study. Patients who were age 18 years or older, underwent primary THA or TKA, and received IV or topical TXA between August 2013 and September 2014 were considered eligible for the study. For both groups, exclusion criteria were trauma service admission, TXA hypersensitivity, pregnancy, and concomitant use of IV and topical TXA.
We collected demographic data (age, sex, weight, height, body mass index), noted all transfusions of packed red blood cells, and recorded preoperative and postoperative hemoglobin (Hgb) levels and surgical drain outputs. We also recorded any complications that occurred within 90 days after surgery: deep vein thrombosis (DVT), pulmonary embolism (PE), cardiac events, cerebrovascular events, and wound drainage. Wound drainage was defined as readmission to hospital or return to operating room for wound drainage caused by infection or hematoma. Postoperative care (disposition, LOS, follow-up) was documented. Average cost of both IV and topical TXA administration was calculated using average wholesale price.
Use of IV TXA and use of topical TXA were compared in both THA and TKA. Patients in the IV TXA group received TXA in two 10-mg/kg doses with a maximum of 1 g per dose. The first IV dose was given before the incision, and the second was given 3 hours after the first. Patients in the topical TXA group underwent direct irrigation with 3 g of TXA in 100 mL of normal saline at the surgical site after closure of the deep fascia in THA and after closure of the knee arthrotomy in TKA. The drain remained occluded for 30 minutes after surgery. The wound was irrigated with topical TXA before wound closure in the THA group and before tourniquet release in the TKA group. TXA dosing was based on institutional formulary dosing restrictions and was consistent with best practices and current literature.3,9,14,15Primary outcomes measured for each cohort and treatment arm were Hgb levels (difference between preoperative levels and lowest postoperative levels 24 hours after surgery), blood loss, transfusion rates, and cost. Secondary outcomes were LOS and complications that occurred within 90 days after surgery (DVT, PE, cardiac events, cerebrovascular events, wound drainage).
Calculated blood loss was determined with equations described by Konig and colleagues,3 Good and colleagues,16 and Nadler and colleagues.17 Total calculated blood loss was based on the difference in Hgb levels before surgery and the lowest Hgb levels 24 hours after surgery:
Blood loss (mL) = 100 mL/dL × Hgbloss/Hgbi
Hgbloss = BV × (Hgbi – Hgbe) × 10 dL/L + Hgbt
= 0.3669 × Height3 (m) + 0.03219 × Weight (kg) + 0.6041 (for men)
= 0.3561 × Height3 (m) + 0.03308 × Weight (kg) + 0.1833 (for women)
where Hgbi is the Hgb concentration (g/dL) before surgery, Hgbe is the lowest Hgb concentration (g/dL) 24 hours after surgery, Hgbt is the total amount (g) of allogeneic Hgb transfused, and BV is the estimated total body blood volume (L).17 As Hgb concentrations after blood transfusions were compared in this study, the Hgbt variable was removed from the equation. Based on Hgb decrease data in a study that compared IV and topical TXA in TKA,14 we determined that a sample size of least 140 patients (70 in each cohort) was needed in order to have 80% power to detect a difference in Hgb decrease of 0.36 g/dL in IV and topical TXA.
All data were reported with descriptive statistics. Frequencies and percentages were reported for categorical variables. Means and standard deviations were reported for continuous variables. The groups of continuous data were compared with unpaired Student t tests and 1-way analysis of variance. Comparisons among groups of categorical data were analyzed with Fisher exact tests. Statistical significance was set at P < .05.
Results
Data were collected on 291 patients (156 THA, 135 TKA). There was a significant (P = .044) sex difference in the THA group: more men in the topical TXA subgroup and more women in the IV TXA subgroup. Other patient demographics were similarly matched with respect to age, height, weight, and body mass index (Table 1).
The secondary outcomes (differences in complications and LOS) are listed in Table 3.
Discussion
TXA, an analog of the amino acid lysine, is an antifibrinolytic agent that has been used for many years to inhibit fibrin degradation.3,18 TXA works by competitively inhibiting tissue plasminogen activation, which is elevated by the trauma of surgery, and blocking plasmin binding to fibrin.3,19 The mechanism of action is not procoagulant, as TXA prevents fibrin breakdown and supports coagulation that is underway rather than increasing clot formation. These characteristics make the drug attractive for orthopedic joint surgery—TXA reduces postoperative blood loss in patients who need fibrinolysis suppressed in order to maintain homeostasis without increasing the risk of venous thromboembolism. IV TXA has been well studied, which supports its efficacy profile for reducing blood loss and transfusions; there are no reports of increased risk of thromboembolic events.20-22 Despite these studies, the risk of adverse events is still a major concern, especially in patients with medical conditions that predispose them to venothrombotic events. Topical TXA has become a viable option, especially in high-risk patients, as studies have shown 70% lower systemic absorption relative to IV TXA plasma concentration.23 Still, too few studies have compared the efficacy, safety, and cost of IV and topical TXA in both THA and TKA.
Topical TXA costs an average of $2100 per case, primarily because standard dosing is 3 g per case. Despite repeat dosing for IV TXA (first dose at incision, second dose 3 hours after first), IV TXA costs were much lower on average: $939 less for THA and $829 less for TKA. As numerous studies have outlined results similar to ours, cost-effectiveness should be considered in decisions about treatment options.
Patel and colleagues14 reported that the efficacy of topical TXA was similar to that of IV TXA and that there were no significant differences in Hgb decrease, wound drainage, or need for transfusions after TKA. Their report conflicts with our finding significant differences favoring topical TXA for Hgb change (P = .015) and reduced calculated blood loss (P = .019) in TKA. A potential reason for these differing results is that the topical TXA doses were different (2 g in the study by Patel and colleagues,14 3 g in our study). Martin and colleagues24 compared the effects of topical TXA and placebo and found a nonsignificant difference in reduced blood loss and postoperative transfusions when the drug was dosed at 2 g. Konig and colleagues3 found that topical TXA dosed at 3 g (vs placebo) could reduce blood loss and transfusions after THA and TKA. These studies support our 3-g dose protocol for topical TXA rather than the 2-g protocol used in the study by Patel and colleagues.14 Our results are congruent with those of Seo and colleagues,25 who found topical TXA superior in decreasing blood loss in TKA. Furthermore, our study is unique in that it compared costs and found topical TXA to be more expensive by almost $1000 on average.
Wei and Wei9 concluded that IV TXA 3 g and topical TXA 3 g were equally effective in reducing total blood loss, change in hematocrit, and need for transfusion after THA. In contrast, we found a significant (P = .031) difference favoring topical TXA for Hgb change. The 2 studies differed in their dosing protocols: Wei and Wei9 infused a 3-g dose, whereas we gave a maximum of two 1-g IV doses. The higher IV dose used by Wei and Wei9 could explain why they found no difference between IV and topical TXA, whereas we did find a difference. Our study was unique in that it measured Hgb change, blood loss, and cost.
Our study included an in-depth analysis of blood loss: estimated blood loss, drain outputs, calculated blood loss, and Hgb change. The equation we used for calculated blood loss is well established and has been used in multiple studies.3,16,17 To thoroughly assess the safety of TXA, we reviewed and documented complications that occurred within 90 days after surgery and that could be attributed to TXA. This study was adequately powered and exceeded the required sample size to detect a difference in one primary outcome measure, perioperative Hgb change, as calculated by the prestudy statistical power analysis.
Our study had several limitations. First, it was a retrospective chart review; documentation could have been incomplete or missing. Second, the study was not randomized and thus subject to drug selection bias. Third, patients were selected for topical TXA on the basis of perceived risk factors, such as prior or family history of DVT, PE, cardiac events, or cerebrovascular events. It was thought that, given the decrease in systemic absorption with topical TXA, these high-risk patients would be less likely to have a thromboembolic event. Their complex past medical histories may explain why the topical TXA group had more cardiac events. Furthermore, 1 orthopedic surgeon used topical TXA exclusively, and the other 3 used it selectively, according to risk factors. In addition, unlike TKA patients, not all THA patients received drains. This study was powered to measure a difference in perioperative Hgb change but may not have been powered to detect the statistically significant difference favoring topical TXA for calculated blood loss in TKA. In the THA group, a statistically significant difference was found for reduced Hgb decrease but not for estimated or calculated blood loss. This finding reinforces some of the disparities in measurements of the effects of blood conservation strategies. The study also lacked a placebo or control group. However, several other studies have found that both IV TXA and topical TXA are superior to placebo in decreasing blood loss, Hgb change, and transfusion requirements.10,12,20,22 In addition, the effects of TXA are based on estimates of blood conservation and are not without their disparities.
Conclusion
The present study found that both IV TXA and topical TXA were effective in decreasing blood loss, Hgb levels, and need for transfusion after THA and TKA. Topical TXA appears to be more effective than IV TXA in preventing Hgb decrease during THA and TKA and calculated blood loss during TKA. This increased efficacy comes with a higher cost. Thromboembolic complications were similar between groups. More studies are needed to compare the efficacy and safety profiles of topical TXA against the routine standard of IV TXA, especially in patients with perceived contraindications to IV TXA.
Am J Orthop. 2016;45(7):E439-E443. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.
Total hip arthroplasty (THA) and total knee arthroplasty (TKA) can be associated with significant blood loss that in some cases requires transfusion. The incidence of transfusion ranges from 16% to 37% in patients who undergo THA and from 11% to 21% in patients who undergo TKA.1-3 Allogeneic blood transfusions have been associated with several risks (transfusion-related acute lung injury, hemolytic reactions, immunologic reactions, fluid overload, renal failure, infections), increased cost, and longer hospital length of stay (LOS).4-7 With improved patient outcomes the ultimate goal, blood-conserving strategies designed to decrease blood loss and transfusions have been adopted as a standard in successful joint replacement programs.
Tranexamic acid (TXA), an antifibrinolytic agent, has become a major component of blood conservation management after THA and TKA. TXA stabilizes clots at the surgical site by inhibiting plasminogen activation and thereby blocking fibrinolysis.8 The literature supports intravenous (IV) TXA as effective in significantly reducing blood loss and transfusion rates in elective THA and TKA.9,10 However, data on increased risk of thrombotic events with IV TXA in both THA and TKA are conflicting.11,12 Topical TXA is thought to have an advantage over IV TXA in that it provides a higher concentration of drug at the surgical site and is associated with little systemic absorption.2,13Recent prospective randomized studies have compared the efficacy and safety of IV and topical TXA in THA and TKA.9,14 However, controversy remains because relatively few studies have compared these 2 routes of administration. In addition, healthcare–associated costs have come under increased scrutiny, and the cost of these treatments should be considered. More research is needed to determine which application is most efficacious and cost-conscious and poses the least risk to patients. Therefore, we conducted a study to compare the cost, efficacy, and safety of IV and topical TXA in primary THA and TKA.
Materials and Methods
Our Institutional Review Board approved this study. Patients who were age 18 years or older, underwent primary THA or TKA, and received IV or topical TXA between August 2013 and September 2014 were considered eligible for the study. For both groups, exclusion criteria were trauma service admission, TXA hypersensitivity, pregnancy, and concomitant use of IV and topical TXA.
We collected demographic data (age, sex, weight, height, body mass index), noted all transfusions of packed red blood cells, and recorded preoperative and postoperative hemoglobin (Hgb) levels and surgical drain outputs. We also recorded any complications that occurred within 90 days after surgery: deep vein thrombosis (DVT), pulmonary embolism (PE), cardiac events, cerebrovascular events, and wound drainage. Wound drainage was defined as readmission to hospital or return to operating room for wound drainage caused by infection or hematoma. Postoperative care (disposition, LOS, follow-up) was documented. Average cost of both IV and topical TXA administration was calculated using average wholesale price.
Use of IV TXA and use of topical TXA were compared in both THA and TKA. Patients in the IV TXA group received TXA in two 10-mg/kg doses with a maximum of 1 g per dose. The first IV dose was given before the incision, and the second was given 3 hours after the first. Patients in the topical TXA group underwent direct irrigation with 3 g of TXA in 100 mL of normal saline at the surgical site after closure of the deep fascia in THA and after closure of the knee arthrotomy in TKA. The drain remained occluded for 30 minutes after surgery. The wound was irrigated with topical TXA before wound closure in the THA group and before tourniquet release in the TKA group. TXA dosing was based on institutional formulary dosing restrictions and was consistent with best practices and current literature.3,9,14,15Primary outcomes measured for each cohort and treatment arm were Hgb levels (difference between preoperative levels and lowest postoperative levels 24 hours after surgery), blood loss, transfusion rates, and cost. Secondary outcomes were LOS and complications that occurred within 90 days after surgery (DVT, PE, cardiac events, cerebrovascular events, wound drainage).
Calculated blood loss was determined with equations described by Konig and colleagues,3 Good and colleagues,16 and Nadler and colleagues.17 Total calculated blood loss was based on the difference in Hgb levels before surgery and the lowest Hgb levels 24 hours after surgery:
Blood loss (mL) = 100 mL/dL × Hgbloss/Hgbi
Hgbloss = BV × (Hgbi – Hgbe) × 10 dL/L + Hgbt
= 0.3669 × Height3 (m) + 0.03219 × Weight (kg) + 0.6041 (for men)
= 0.3561 × Height3 (m) + 0.03308 × Weight (kg) + 0.1833 (for women)
where Hgbi is the Hgb concentration (g/dL) before surgery, Hgbe is the lowest Hgb concentration (g/dL) 24 hours after surgery, Hgbt is the total amount (g) of allogeneic Hgb transfused, and BV is the estimated total body blood volume (L).17 As Hgb concentrations after blood transfusions were compared in this study, the Hgbt variable was removed from the equation. Based on Hgb decrease data in a study that compared IV and topical TXA in TKA,14 we determined that a sample size of least 140 patients (70 in each cohort) was needed in order to have 80% power to detect a difference in Hgb decrease of 0.36 g/dL in IV and topical TXA.
All data were reported with descriptive statistics. Frequencies and percentages were reported for categorical variables. Means and standard deviations were reported for continuous variables. The groups of continuous data were compared with unpaired Student t tests and 1-way analysis of variance. Comparisons among groups of categorical data were analyzed with Fisher exact tests. Statistical significance was set at P < .05.
Results
Data were collected on 291 patients (156 THA, 135 TKA). There was a significant (P = .044) sex difference in the THA group: more men in the topical TXA subgroup and more women in the IV TXA subgroup. Other patient demographics were similarly matched with respect to age, height, weight, and body mass index (Table 1).
The secondary outcomes (differences in complications and LOS) are listed in Table 3.
Discussion
TXA, an analog of the amino acid lysine, is an antifibrinolytic agent that has been used for many years to inhibit fibrin degradation.3,18 TXA works by competitively inhibiting tissue plasminogen activation, which is elevated by the trauma of surgery, and blocking plasmin binding to fibrin.3,19 The mechanism of action is not procoagulant, as TXA prevents fibrin breakdown and supports coagulation that is underway rather than increasing clot formation. These characteristics make the drug attractive for orthopedic joint surgery—TXA reduces postoperative blood loss in patients who need fibrinolysis suppressed in order to maintain homeostasis without increasing the risk of venous thromboembolism. IV TXA has been well studied, which supports its efficacy profile for reducing blood loss and transfusions; there are no reports of increased risk of thromboembolic events.20-22 Despite these studies, the risk of adverse events is still a major concern, especially in patients with medical conditions that predispose them to venothrombotic events. Topical TXA has become a viable option, especially in high-risk patients, as studies have shown 70% lower systemic absorption relative to IV TXA plasma concentration.23 Still, too few studies have compared the efficacy, safety, and cost of IV and topical TXA in both THA and TKA.
Topical TXA costs an average of $2100 per case, primarily because standard dosing is 3 g per case. Despite repeat dosing for IV TXA (first dose at incision, second dose 3 hours after first), IV TXA costs were much lower on average: $939 less for THA and $829 less for TKA. As numerous studies have outlined results similar to ours, cost-effectiveness should be considered in decisions about treatment options.
Patel and colleagues14 reported that the efficacy of topical TXA was similar to that of IV TXA and that there were no significant differences in Hgb decrease, wound drainage, or need for transfusions after TKA. Their report conflicts with our finding significant differences favoring topical TXA for Hgb change (P = .015) and reduced calculated blood loss (P = .019) in TKA. A potential reason for these differing results is that the topical TXA doses were different (2 g in the study by Patel and colleagues,14 3 g in our study). Martin and colleagues24 compared the effects of topical TXA and placebo and found a nonsignificant difference in reduced blood loss and postoperative transfusions when the drug was dosed at 2 g. Konig and colleagues3 found that topical TXA dosed at 3 g (vs placebo) could reduce blood loss and transfusions after THA and TKA. These studies support our 3-g dose protocol for topical TXA rather than the 2-g protocol used in the study by Patel and colleagues.14 Our results are congruent with those of Seo and colleagues,25 who found topical TXA superior in decreasing blood loss in TKA. Furthermore, our study is unique in that it compared costs and found topical TXA to be more expensive by almost $1000 on average.
Wei and Wei9 concluded that IV TXA 3 g and topical TXA 3 g were equally effective in reducing total blood loss, change in hematocrit, and need for transfusion after THA. In contrast, we found a significant (P = .031) difference favoring topical TXA for Hgb change. The 2 studies differed in their dosing protocols: Wei and Wei9 infused a 3-g dose, whereas we gave a maximum of two 1-g IV doses. The higher IV dose used by Wei and Wei9 could explain why they found no difference between IV and topical TXA, whereas we did find a difference. Our study was unique in that it measured Hgb change, blood loss, and cost.
Our study included an in-depth analysis of blood loss: estimated blood loss, drain outputs, calculated blood loss, and Hgb change. The equation we used for calculated blood loss is well established and has been used in multiple studies.3,16,17 To thoroughly assess the safety of TXA, we reviewed and documented complications that occurred within 90 days after surgery and that could be attributed to TXA. This study was adequately powered and exceeded the required sample size to detect a difference in one primary outcome measure, perioperative Hgb change, as calculated by the prestudy statistical power analysis.
Our study had several limitations. First, it was a retrospective chart review; documentation could have been incomplete or missing. Second, the study was not randomized and thus subject to drug selection bias. Third, patients were selected for topical TXA on the basis of perceived risk factors, such as prior or family history of DVT, PE, cardiac events, or cerebrovascular events. It was thought that, given the decrease in systemic absorption with topical TXA, these high-risk patients would be less likely to have a thromboembolic event. Their complex past medical histories may explain why the topical TXA group had more cardiac events. Furthermore, 1 orthopedic surgeon used topical TXA exclusively, and the other 3 used it selectively, according to risk factors. In addition, unlike TKA patients, not all THA patients received drains. This study was powered to measure a difference in perioperative Hgb change but may not have been powered to detect the statistically significant difference favoring topical TXA for calculated blood loss in TKA. In the THA group, a statistically significant difference was found for reduced Hgb decrease but not for estimated or calculated blood loss. This finding reinforces some of the disparities in measurements of the effects of blood conservation strategies. The study also lacked a placebo or control group. However, several other studies have found that both IV TXA and topical TXA are superior to placebo in decreasing blood loss, Hgb change, and transfusion requirements.10,12,20,22 In addition, the effects of TXA are based on estimates of blood conservation and are not without their disparities.
Conclusion
The present study found that both IV TXA and topical TXA were effective in decreasing blood loss, Hgb levels, and need for transfusion after THA and TKA. Topical TXA appears to be more effective than IV TXA in preventing Hgb decrease during THA and TKA and calculated blood loss during TKA. This increased efficacy comes with a higher cost. Thromboembolic complications were similar between groups. More studies are needed to compare the efficacy and safety profiles of topical TXA against the routine standard of IV TXA, especially in patients with perceived contraindications to IV TXA.
Am J Orthop. 2016;45(7):E439-E443. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.
1. Bierbaum BE, Callaghan JJ, Galante JO, Rubash HE, Tooms RE, Welch RB. An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg Am. 1999;81(1):2-10.
2. Yue C, Kang P, Yang P, Xie J, Pei F. Topical application of tranexamic acid in primary total hip arthroplasty: a randomized double-blind controlled trial. J Arthroplasty. 2014;29(12):2452-2456.
3. Konig G, Hamlin BR, Waters JH. Topical tranexamic acid reduces blood loss and transfusion rates in total hip and total knee arthroplasty. J Arthroplasty. 2013;28(9):1473-1476.
4. Stokes ME, Ye X, Shah M, et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res. 2011;11:135.
5. Lemos MJ, Healy WL. Blood transfusion in orthopaedic operations. J Bone Joint Surg Am. 1996;78(8):1260-1270.
6. Vamvakas EC, Blajchman MA. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood. 2009;113(15):3406-3417.
7. Kumar A. Perioperative management of anemia: limits of blood transfusion and alternatives to it. Cleve Clin J Med. 2009;76(suppl 4):S112-S118.
8. Hoylaerts M, Lijnen HR, Collen D. Studies on the mechanism of the antifibrinolytic action of tranexamic acid. Biochim Biophys Acta. 1981;673(1):75-85.
9. Wei W, Wei B. Comparison of topical and intravenous tranexamic acid on blood loss and transfusion rates in total hip arthroplasty. J Arthroplasty. 2014;29(11):2113-2116.
10. Zhang H, Chen J, Chen F, Que W. The effect of tranexamic acid on blood loss and use of blood products in total knee arthroplasty: a meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2012;20(9):1742-1752.
11. Ido K, Neo M, Asada Y, et al. Reduction of blood loss using tranexamic acid in total knee and hip arthroplasties. Arch Orthop Trauma Surg. 2000;120(9):518-520.
12. Yang ZG, Chen WP, Wu LD. Effectiveness and safety of tranexamic acid in reducing blood loss in total knee arthroplasty: a meta-analysis. J Bone Joint Surg Am. 2012;94(13):1153-1159.
13. Alshryda S, Mason J, Sarda P, et al. Topical (intra-articular) tranexamic acid reduces blood loss and transfusion rates following total hip replacement: a randomized controlled trial (TRANX-H). J Bone Joint Surg Am. 2013;95(21):1969-1974.
14. Patel JN, Spanyer JM, Smith LS, Huang J, Yakkanti MR, Malkani AL. Comparison of intravenous versus topical tranexamic acid in total knee arthroplasty: a prospective randomized study. J Arthroplasty. 2014;29(8):1528-1531.
15. Alshryda S, Sarda P, Sukeik M, Nargol A, Blenkinsopp J, Mason JM. Tranexamic in total knee replacement: a systematic review and meta-analysis. J Bone Joint Surg Br. 2011;93(12):1577-1585.
16. Good L, Peterson E, Lisander B. Tranexamic acid decreases external blood loss but not hidden blood loss in total knee replacement. Br J Anaesth. 2003;90(5):596-599.
17. Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery. 1962;51(2):224-232.
18. Eubanks JD. Antifibrinolytics in major orthopaedic surgery. J Am Acad Orthop Surg. 2010;18(3):132-138.
19. Mannucci PM. Homostatic drugs. N Engl J Med. 1998;339(4):245-253.
20. Wind TC, Barfield WR, Moskal JT. The effect of tranexamic acid on transfusion rate in primary total hip arthroplasty. J Arthroplasty. 2014;29(2):387-389.
21. Dahuja A, Dahuja G, Jaswal V, Sandhu K. A prospective study on role of tranexamic acid in reducing postoperative blood loss in total knee arthroplasty and its effect on coagulation profile. J Arthroplasty. 2014;29(4):733-735.
22. Tan J, Chen H, Liu Q, Chen C, Huang W. A meta-analysis of the effectiveness and safety of using tranexamic acid in primary unilateral total knee arthroplasty. J Surg Res. 2013;184(2):880-887.
23. Wong J, Abrishami A, El Beheiry H, et al. Topical application of tranexamic acid reduces postoperative blood loss in total knee arthroplasty: a randomized, controlled trial. J Bone Joint Surg Am. 2010;92(15):2503-2513.
24. Martin JG, Cassatt KB, Kincaid-Cinnamon KA, Westendorf DS, Garton AS, Lemke JH. Topical administration of tranexamic acid in primary total hip and total knee arthroplasty. J Arthroplasty. 2014;29(5):889-894.
25. Seo JG, Moon YW, Park SH, Kim SM, Ko KR. The comparative efficacies of intra-articular and IV tranexamic acid for reducing blood loss during total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc. 2013;21(8):1869-1874.
1. Bierbaum BE, Callaghan JJ, Galante JO, Rubash HE, Tooms RE, Welch RB. An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg Am. 1999;81(1):2-10.
2. Yue C, Kang P, Yang P, Xie J, Pei F. Topical application of tranexamic acid in primary total hip arthroplasty: a randomized double-blind controlled trial. J Arthroplasty. 2014;29(12):2452-2456.
3. Konig G, Hamlin BR, Waters JH. Topical tranexamic acid reduces blood loss and transfusion rates in total hip and total knee arthroplasty. J Arthroplasty. 2013;28(9):1473-1476.
4. Stokes ME, Ye X, Shah M, et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res. 2011;11:135.
5. Lemos MJ, Healy WL. Blood transfusion in orthopaedic operations. J Bone Joint Surg Am. 1996;78(8):1260-1270.
6. Vamvakas EC, Blajchman MA. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood. 2009;113(15):3406-3417.
7. Kumar A. Perioperative management of anemia: limits of blood transfusion and alternatives to it. Cleve Clin J Med. 2009;76(suppl 4):S112-S118.
8. Hoylaerts M, Lijnen HR, Collen D. Studies on the mechanism of the antifibrinolytic action of tranexamic acid. Biochim Biophys Acta. 1981;673(1):75-85.
9. Wei W, Wei B. Comparison of topical and intravenous tranexamic acid on blood loss and transfusion rates in total hip arthroplasty. J Arthroplasty. 2014;29(11):2113-2116.
10. Zhang H, Chen J, Chen F, Que W. The effect of tranexamic acid on blood loss and use of blood products in total knee arthroplasty: a meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2012;20(9):1742-1752.
11. Ido K, Neo M, Asada Y, et al. Reduction of blood loss using tranexamic acid in total knee and hip arthroplasties. Arch Orthop Trauma Surg. 2000;120(9):518-520.
12. Yang ZG, Chen WP, Wu LD. Effectiveness and safety of tranexamic acid in reducing blood loss in total knee arthroplasty: a meta-analysis. J Bone Joint Surg Am. 2012;94(13):1153-1159.
13. Alshryda S, Mason J, Sarda P, et al. Topical (intra-articular) tranexamic acid reduces blood loss and transfusion rates following total hip replacement: a randomized controlled trial (TRANX-H). J Bone Joint Surg Am. 2013;95(21):1969-1974.
14. Patel JN, Spanyer JM, Smith LS, Huang J, Yakkanti MR, Malkani AL. Comparison of intravenous versus topical tranexamic acid in total knee arthroplasty: a prospective randomized study. J Arthroplasty. 2014;29(8):1528-1531.
15. Alshryda S, Sarda P, Sukeik M, Nargol A, Blenkinsopp J, Mason JM. Tranexamic in total knee replacement: a systematic review and meta-analysis. J Bone Joint Surg Br. 2011;93(12):1577-1585.
16. Good L, Peterson E, Lisander B. Tranexamic acid decreases external blood loss but not hidden blood loss in total knee replacement. Br J Anaesth. 2003;90(5):596-599.
17. Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery. 1962;51(2):224-232.
18. Eubanks JD. Antifibrinolytics in major orthopaedic surgery. J Am Acad Orthop Surg. 2010;18(3):132-138.
19. Mannucci PM. Homostatic drugs. N Engl J Med. 1998;339(4):245-253.
20. Wind TC, Barfield WR, Moskal JT. The effect of tranexamic acid on transfusion rate in primary total hip arthroplasty. J Arthroplasty. 2014;29(2):387-389.
21. Dahuja A, Dahuja G, Jaswal V, Sandhu K. A prospective study on role of tranexamic acid in reducing postoperative blood loss in total knee arthroplasty and its effect on coagulation profile. J Arthroplasty. 2014;29(4):733-735.
22. Tan J, Chen H, Liu Q, Chen C, Huang W. A meta-analysis of the effectiveness and safety of using tranexamic acid in primary unilateral total knee arthroplasty. J Surg Res. 2013;184(2):880-887.
23. Wong J, Abrishami A, El Beheiry H, et al. Topical application of tranexamic acid reduces postoperative blood loss in total knee arthroplasty: a randomized, controlled trial. J Bone Joint Surg Am. 2010;92(15):2503-2513.
24. Martin JG, Cassatt KB, Kincaid-Cinnamon KA, Westendorf DS, Garton AS, Lemke JH. Topical administration of tranexamic acid in primary total hip and total knee arthroplasty. J Arthroplasty. 2014;29(5):889-894.
25. Seo JG, Moon YW, Park SH, Kim SM, Ko KR. The comparative efficacies of intra-articular and IV tranexamic acid for reducing blood loss during total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc. 2013;21(8):1869-1874.
Kratom: A New Product in an Expanding Substance Abuse Market
According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.1 There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opiates, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most health care providers (HCPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.2,3
In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of the “dark Internet” websites and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite these websites’ purported raison d’être, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer and colleagues of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patient’s digital habits, the researchers demonstrated that the majority of subjects used these websites and as a result either increased their drug use or learned about (and tried) new substances!4
One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opiate withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and is increasingly popular in the U.S. and in the United Kingdom.2,5,6 In the U.S., this poses a problem for HCPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.2 Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.
Although considered a “substance of concern” without any approved medical use by the U.S. Drug Enforcement Agency (DEA
To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined websites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about U.S. $13).5 This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.2,3,6-8 In fact, Krypton, a product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least 9 deaths.7
This article presents a case of kratom abuse and will outline a brief history, the pharmacologic characteristics, clinical presentation of kratom abuse, and conclude with an overview of the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the U.S., a basic working knowledge of the drug is quickly becoming a must for federal HCPs.
Case Presentation
At his employer’s request, a 33-year-old married man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disc resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he thought that he was abusing his opiate medication, and it was discontinued. The patient was transferred to the local hospital and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.
On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline. Initial point-of-care admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s additional sequelae had passed, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.
Background
Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia (eFigure).2,3 The leaves contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-l
In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.5,8 Presently, kratom’s legal status in the U.S. continues to be nebulous: It has not been officially scheduled by the DEA, and it is easily obtained.
Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.2,3,5,6
Pharmacology and Clinical Presentation
More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the 2 major compounds are mitragynine and 7-hydroxymitragynine.
Mitragynine
Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including μ, δ, and κ opioid receptors, leading to its opioid-like ef
7-Hydroxymitragynine
7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.2
Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.2
Intoxication and Withdrawal
Due to its increasing worldwide popularity, it is now imperative for HCPs to be aware of the clinical presentation of kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from prodrug websites like Erowid or SageWisdom.2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.
Kratom seems to have dose-dependent effects. At low doses (1 g-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.
At moderate-to-high doses (5 g-15 g of raw crushed leaves), it is believed that the μ opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.2 As such, if an individual is intoxicated, he or she should be managed symptomatically with judicious use of benzodiazepines and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.9,10
The medical management of an acute kratom overdose (typically requiring ingestion of > 15 g of crushed leaves) begins with addressing airway blockage, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including point-of-care glucose, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, etc).11 If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.9,10
The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong μ agonism.2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid detoxification.
The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, α-2 agonists, and antidiarrheal agents.5,9,10
Kratom Toxicity
A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to HCPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:
- Fastidious medication reconciliation with drug-interaction check;
- Exhaustive substance abuse history;
- Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
- Electrocardiogram;
- Thyroid function testing;
- Hepatic function testing; and
- Comprehensive neurologic and mental status exams.
In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and permanent psychosis.3-7 Additionally, a 2008 study by Kittirattanapaiboon and colleagues correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥ 14,000 individuals included in the study sample) with statistically significant higher suicide risk.12
Detection
Because kratom is a relatively new compound in the U.S., medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and 2 metabolites of mitragynine in urine.7 Le and colleagues were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours.13 Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the study patient’s urine because a urine test was not done until hospital day 5.
Conclusion
When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden in this highly intelligent individual—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.
Kratom is an emerging drug of abuse in the Western World. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the U.S. and multiple other Western countries, kratom is easily accessible and is difficult to detect. Health care providers need to be aware of kratom, and during their evaluations, question patients about kratom and other legal highs.
1. United Nations Office of Drug and Crime. World Drug Report 2014. https://www.unodc.org/documents/wdr2014/World_Drug_Report_2014_web.pdf. Published June 2014. Accessed September 26, 2016.
2. Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc. 2012;112(12):792-799.
3. U.S. Drug Enforcement Administration, Office of Diversion Control. Kratom (Mitragyna speciosa korth). http://www.deadiversion.usdoj.gov/drug _chem_info/kratom.pdf. Published January 2013. Accessed September 26, 2016.
4. Boyer EW, Shannon M, Hibberd PL. The Internet and psychoactive substance use among innovative drug users. Pediatrics. 2005;115(2):302-305.
5. Yusoff NH, Suhaimi FW, Vadivelu RK, et al. Abuse potential and adverse cognitive effects of mitragynine (kratom). Addict Biol. 2016;21(1):98-110.
6. Schmidt MM, Sharma A, Schifano F, Feinmann C. “Legal highs” on the net-evaluation of UK-based websites, products and product information. Forensic Sci Int. 2011;206(1-3):92-97.
7. Kronstrand R, Roman M, Thelander G, Eriksson A. Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton. J Anal Toxicol. 2011;35(4):242-247.
8. Holler JM, Vorce SP, McDonough-Bender PC, Magluilo J Jr, Solomon CJ, Levine B. A drug toxicity death involving propylhexedrine and mitragynine. J Anal Toxicol. 2011;35(1):54-59.
9. Rosenbaum CD, Carreiro SP, Babu KM. Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines. J Med Toxicol. 2012;8(1):15-32.
10. Rech MA, Donahey E, Cappiello Dziedzic JM, Oh L, Greenhalgh E. New drugs of abuse. Pharmacotherapy. 2015;35(2):189-197.
11. Silvilotti MLA. Initial management of the critically ill adult with an unknown overdose. http://www.uptodate.com/contents/initial-management-of-the -critically-ill-adult-with-an-unknown-overdose. Updated August 27, 2015. Accessed September 26, 2016.
12. Kittirattanapaiboon P, Suttajit S, Junsirimongkol B, Likhitsathian S, Srisurapanont M. Suicide risk among Thai illicit drug users with and without mental/alcohol use disorders. Neuropsychiatr Dis Treat. 2014;10:453-458.
13. Le D, Goggin MM, Janis GC. Analysis of mitragynine and metabolites in human urine for detecting the use of the psychoactive plant kratom. J Anal Toxicol. 2012;36(9):616-625.
According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.1 There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opiates, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most health care providers (HCPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.2,3
In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of the “dark Internet” websites and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite these websites’ purported raison d’être, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer and colleagues of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patient’s digital habits, the researchers demonstrated that the majority of subjects used these websites and as a result either increased their drug use or learned about (and tried) new substances!4
One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opiate withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and is increasingly popular in the U.S. and in the United Kingdom.2,5,6 In the U.S., this poses a problem for HCPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.2 Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.
Although considered a “substance of concern” without any approved medical use by the U.S. Drug Enforcement Agency (DEA
To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined websites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about U.S. $13).5 This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.2,3,6-8 In fact, Krypton, a product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least 9 deaths.7
This article presents a case of kratom abuse and will outline a brief history, the pharmacologic characteristics, clinical presentation of kratom abuse, and conclude with an overview of the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the U.S., a basic working knowledge of the drug is quickly becoming a must for federal HCPs.
Case Presentation
At his employer’s request, a 33-year-old married man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disc resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he thought that he was abusing his opiate medication, and it was discontinued. The patient was transferred to the local hospital and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.
On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline. Initial point-of-care admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s additional sequelae had passed, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.
Background
Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia (eFigure).2,3 The leaves contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-l
In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.5,8 Presently, kratom’s legal status in the U.S. continues to be nebulous: It has not been officially scheduled by the DEA, and it is easily obtained.
Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.2,3,5,6
Pharmacology and Clinical Presentation
More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the 2 major compounds are mitragynine and 7-hydroxymitragynine.
Mitragynine
Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including μ, δ, and κ opioid receptors, leading to its opioid-like ef
7-Hydroxymitragynine
7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.2
Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.2
Intoxication and Withdrawal
Due to its increasing worldwide popularity, it is now imperative for HCPs to be aware of the clinical presentation of kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from prodrug websites like Erowid or SageWisdom.2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.
Kratom seems to have dose-dependent effects. At low doses (1 g-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.
At moderate-to-high doses (5 g-15 g of raw crushed leaves), it is believed that the μ opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.2 As such, if an individual is intoxicated, he or she should be managed symptomatically with judicious use of benzodiazepines and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.9,10
The medical management of an acute kratom overdose (typically requiring ingestion of > 15 g of crushed leaves) begins with addressing airway blockage, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including point-of-care glucose, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, etc).11 If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.9,10
The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong μ agonism.2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid detoxification.
The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, α-2 agonists, and antidiarrheal agents.5,9,10
Kratom Toxicity
A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to HCPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:
- Fastidious medication reconciliation with drug-interaction check;
- Exhaustive substance abuse history;
- Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
- Electrocardiogram;
- Thyroid function testing;
- Hepatic function testing; and
- Comprehensive neurologic and mental status exams.
In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and permanent psychosis.3-7 Additionally, a 2008 study by Kittirattanapaiboon and colleagues correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥ 14,000 individuals included in the study sample) with statistically significant higher suicide risk.12
Detection
Because kratom is a relatively new compound in the U.S., medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and 2 metabolites of mitragynine in urine.7 Le and colleagues were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours.13 Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the study patient’s urine because a urine test was not done until hospital day 5.
Conclusion
When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden in this highly intelligent individual—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.
Kratom is an emerging drug of abuse in the Western World. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the U.S. and multiple other Western countries, kratom is easily accessible and is difficult to detect. Health care providers need to be aware of kratom, and during their evaluations, question patients about kratom and other legal highs.
According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.1 There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opiates, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most health care providers (HCPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.2,3
In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of the “dark Internet” websites and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite these websites’ purported raison d’être, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer and colleagues of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patient’s digital habits, the researchers demonstrated that the majority of subjects used these websites and as a result either increased their drug use or learned about (and tried) new substances!4
One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opiate withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and is increasingly popular in the U.S. and in the United Kingdom.2,5,6 In the U.S., this poses a problem for HCPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.2 Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.
Although considered a “substance of concern” without any approved medical use by the U.S. Drug Enforcement Agency (DEA
To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined websites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about U.S. $13).5 This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.2,3,6-8 In fact, Krypton, a product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least 9 deaths.7
This article presents a case of kratom abuse and will outline a brief history, the pharmacologic characteristics, clinical presentation of kratom abuse, and conclude with an overview of the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the U.S., a basic working knowledge of the drug is quickly becoming a must for federal HCPs.
Case Presentation
At his employer’s request, a 33-year-old married man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disc resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he thought that he was abusing his opiate medication, and it was discontinued. The patient was transferred to the local hospital and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.
On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline. Initial point-of-care admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s additional sequelae had passed, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.
Background
Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia (eFigure).2,3 The leaves contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-l
In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.5,8 Presently, kratom’s legal status in the U.S. continues to be nebulous: It has not been officially scheduled by the DEA, and it is easily obtained.
Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.2,3,5,6
Pharmacology and Clinical Presentation
More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the 2 major compounds are mitragynine and 7-hydroxymitragynine.
Mitragynine
Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including μ, δ, and κ opioid receptors, leading to its opioid-like ef
7-Hydroxymitragynine
7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.2
Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.2
Intoxication and Withdrawal
Due to its increasing worldwide popularity, it is now imperative for HCPs to be aware of the clinical presentation of kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from prodrug websites like Erowid or SageWisdom.2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.
Kratom seems to have dose-dependent effects. At low doses (1 g-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.
At moderate-to-high doses (5 g-15 g of raw crushed leaves), it is believed that the μ opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.2 As such, if an individual is intoxicated, he or she should be managed symptomatically with judicious use of benzodiazepines and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.9,10
The medical management of an acute kratom overdose (typically requiring ingestion of > 15 g of crushed leaves) begins with addressing airway blockage, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including point-of-care glucose, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, etc).11 If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.9,10
The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong μ agonism.2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid detoxification.
The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, α-2 agonists, and antidiarrheal agents.5,9,10
Kratom Toxicity
A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to HCPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:
- Fastidious medication reconciliation with drug-interaction check;
- Exhaustive substance abuse history;
- Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
- Electrocardiogram;
- Thyroid function testing;
- Hepatic function testing; and
- Comprehensive neurologic and mental status exams.
In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and permanent psychosis.3-7 Additionally, a 2008 study by Kittirattanapaiboon and colleagues correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥ 14,000 individuals included in the study sample) with statistically significant higher suicide risk.12
Detection
Because kratom is a relatively new compound in the U.S., medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and 2 metabolites of mitragynine in urine.7 Le and colleagues were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours.13 Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the study patient’s urine because a urine test was not done until hospital day 5.
Conclusion
When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden in this highly intelligent individual—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.
Kratom is an emerging drug of abuse in the Western World. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the U.S. and multiple other Western countries, kratom is easily accessible and is difficult to detect. Health care providers need to be aware of kratom, and during their evaluations, question patients about kratom and other legal highs.
1. United Nations Office of Drug and Crime. World Drug Report 2014. https://www.unodc.org/documents/wdr2014/World_Drug_Report_2014_web.pdf. Published June 2014. Accessed September 26, 2016.
2. Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc. 2012;112(12):792-799.
3. U.S. Drug Enforcement Administration, Office of Diversion Control. Kratom (Mitragyna speciosa korth). http://www.deadiversion.usdoj.gov/drug _chem_info/kratom.pdf. Published January 2013. Accessed September 26, 2016.
4. Boyer EW, Shannon M, Hibberd PL. The Internet and psychoactive substance use among innovative drug users. Pediatrics. 2005;115(2):302-305.
5. Yusoff NH, Suhaimi FW, Vadivelu RK, et al. Abuse potential and adverse cognitive effects of mitragynine (kratom). Addict Biol. 2016;21(1):98-110.
6. Schmidt MM, Sharma A, Schifano F, Feinmann C. “Legal highs” on the net-evaluation of UK-based websites, products and product information. Forensic Sci Int. 2011;206(1-3):92-97.
7. Kronstrand R, Roman M, Thelander G, Eriksson A. Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton. J Anal Toxicol. 2011;35(4):242-247.
8. Holler JM, Vorce SP, McDonough-Bender PC, Magluilo J Jr, Solomon CJ, Levine B. A drug toxicity death involving propylhexedrine and mitragynine. J Anal Toxicol. 2011;35(1):54-59.
9. Rosenbaum CD, Carreiro SP, Babu KM. Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines. J Med Toxicol. 2012;8(1):15-32.
10. Rech MA, Donahey E, Cappiello Dziedzic JM, Oh L, Greenhalgh E. New drugs of abuse. Pharmacotherapy. 2015;35(2):189-197.
11. Silvilotti MLA. Initial management of the critically ill adult with an unknown overdose. http://www.uptodate.com/contents/initial-management-of-the -critically-ill-adult-with-an-unknown-overdose. Updated August 27, 2015. Accessed September 26, 2016.
12. Kittirattanapaiboon P, Suttajit S, Junsirimongkol B, Likhitsathian S, Srisurapanont M. Suicide risk among Thai illicit drug users with and without mental/alcohol use disorders. Neuropsychiatr Dis Treat. 2014;10:453-458.
13. Le D, Goggin MM, Janis GC. Analysis of mitragynine and metabolites in human urine for detecting the use of the psychoactive plant kratom. J Anal Toxicol. 2012;36(9):616-625.
1. United Nations Office of Drug and Crime. World Drug Report 2014. https://www.unodc.org/documents/wdr2014/World_Drug_Report_2014_web.pdf. Published June 2014. Accessed September 26, 2016.
2. Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc. 2012;112(12):792-799.
3. U.S. Drug Enforcement Administration, Office of Diversion Control. Kratom (Mitragyna speciosa korth). http://www.deadiversion.usdoj.gov/drug _chem_info/kratom.pdf. Published January 2013. Accessed September 26, 2016.
4. Boyer EW, Shannon M, Hibberd PL. The Internet and psychoactive substance use among innovative drug users. Pediatrics. 2005;115(2):302-305.
5. Yusoff NH, Suhaimi FW, Vadivelu RK, et al. Abuse potential and adverse cognitive effects of mitragynine (kratom). Addict Biol. 2016;21(1):98-110.
6. Schmidt MM, Sharma A, Schifano F, Feinmann C. “Legal highs” on the net-evaluation of UK-based websites, products and product information. Forensic Sci Int. 2011;206(1-3):92-97.
7. Kronstrand R, Roman M, Thelander G, Eriksson A. Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton. J Anal Toxicol. 2011;35(4):242-247.
8. Holler JM, Vorce SP, McDonough-Bender PC, Magluilo J Jr, Solomon CJ, Levine B. A drug toxicity death involving propylhexedrine and mitragynine. J Anal Toxicol. 2011;35(1):54-59.
9. Rosenbaum CD, Carreiro SP, Babu KM. Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines. J Med Toxicol. 2012;8(1):15-32.
10. Rech MA, Donahey E, Cappiello Dziedzic JM, Oh L, Greenhalgh E. New drugs of abuse. Pharmacotherapy. 2015;35(2):189-197.
11. Silvilotti MLA. Initial management of the critically ill adult with an unknown overdose. http://www.uptodate.com/contents/initial-management-of-the -critically-ill-adult-with-an-unknown-overdose. Updated August 27, 2015. Accessed September 26, 2016.
12. Kittirattanapaiboon P, Suttajit S, Junsirimongkol B, Likhitsathian S, Srisurapanont M. Suicide risk among Thai illicit drug users with and without mental/alcohol use disorders. Neuropsychiatr Dis Treat. 2014;10:453-458.
13. Le D, Goggin MM, Janis GC. Analysis of mitragynine and metabolites in human urine for detecting the use of the psychoactive plant kratom. J Anal Toxicol. 2012;36(9):616-625.
Hospitalists Should Endorse Their Team Members
Editor’s note: “Everything We Say and Do” is an informational series developed by SHM’s Patient Experience Committee to provide readers with thoughtful and actionable communication tactics that have great potential to positively impact patients’ experience of care. Each article will focus on how the contributor applies one or more of the “key communication” tactics in practice to maintain provider accountability for “everything we say and do that affects our patients’ thoughts, feelings, and well-being.”
View a chart outlining key communication tactics
What I Say and Do
At every opportunity, I position and endorse my colleagues who are or will be participating in my patient’s care by describing their roles and expressing my confidence in their abilities.
Why I Do It
It is vital that our patients feel assured they are being cared for by a high-functioning team of experts. During any given hospital stay, our patients will meet consulting physicians, nurses, therapists, case managers … The list goes on and on. Each person plays a vital part in patients’ care. But it can be difficult for patients to understand every person’s role and to feel assured that each person is highly skilled and aligned with the care plan.
As hospitalists, we are in a unique position to provide a foundation of assuredness and confidence that is a cornerstone of patient experience before our teammates meet patients. When we miss this opportunity, our patients perceive us as a sea of white coats passing in and out of their rooms rather than a cohesive team with their best interests at heart.
How I Do It
Let’s take the example of an elderly patient admitted for a hip fracture after a fall. Alongside the hospitalist will be the orthopedic surgeon, nurse, physical therapist, and case manager, all working toward an optimal outcome. In each case, the hospitalist can choose to provide no information about these team members or to position them for a positive first impression.
Here are the steps to take when positioning colleagues with patients:
- Identify team members and explain their roles.
- Endorse colleagues by expressing honest confidence in their expertise and ability.
- Describe how communication between you and your team members will work.
- Assure the patient that during handoff, your colleagues will be up-to-date and aligned with the plan.
- Tell your patients they are part of a team dedicated to a safe and effective hospitalization.
Mark Shapiro, MD, is medical director for hospital medicine at St. Joseph Health Medical Group in Santa Rosa, Calif., and producer and host of Explore the Space podcast (explorethespaceshow.com).
Editor’s note: “Everything We Say and Do” is an informational series developed by SHM’s Patient Experience Committee to provide readers with thoughtful and actionable communication tactics that have great potential to positively impact patients’ experience of care. Each article will focus on how the contributor applies one or more of the “key communication” tactics in practice to maintain provider accountability for “everything we say and do that affects our patients’ thoughts, feelings, and well-being.”
View a chart outlining key communication tactics
What I Say and Do
At every opportunity, I position and endorse my colleagues who are or will be participating in my patient’s care by describing their roles and expressing my confidence in their abilities.
Why I Do It
It is vital that our patients feel assured they are being cared for by a high-functioning team of experts. During any given hospital stay, our patients will meet consulting physicians, nurses, therapists, case managers … The list goes on and on. Each person plays a vital part in patients’ care. But it can be difficult for patients to understand every person’s role and to feel assured that each person is highly skilled and aligned with the care plan.
As hospitalists, we are in a unique position to provide a foundation of assuredness and confidence that is a cornerstone of patient experience before our teammates meet patients. When we miss this opportunity, our patients perceive us as a sea of white coats passing in and out of their rooms rather than a cohesive team with their best interests at heart.
How I Do It
Let’s take the example of an elderly patient admitted for a hip fracture after a fall. Alongside the hospitalist will be the orthopedic surgeon, nurse, physical therapist, and case manager, all working toward an optimal outcome. In each case, the hospitalist can choose to provide no information about these team members or to position them for a positive first impression.
Here are the steps to take when positioning colleagues with patients:
- Identify team members and explain their roles.
- Endorse colleagues by expressing honest confidence in their expertise and ability.
- Describe how communication between you and your team members will work.
- Assure the patient that during handoff, your colleagues will be up-to-date and aligned with the plan.
- Tell your patients they are part of a team dedicated to a safe and effective hospitalization.
Mark Shapiro, MD, is medical director for hospital medicine at St. Joseph Health Medical Group in Santa Rosa, Calif., and producer and host of Explore the Space podcast (explorethespaceshow.com).
Editor’s note: “Everything We Say and Do” is an informational series developed by SHM’s Patient Experience Committee to provide readers with thoughtful and actionable communication tactics that have great potential to positively impact patients’ experience of care. Each article will focus on how the contributor applies one or more of the “key communication” tactics in practice to maintain provider accountability for “everything we say and do that affects our patients’ thoughts, feelings, and well-being.”
View a chart outlining key communication tactics
What I Say and Do
At every opportunity, I position and endorse my colleagues who are or will be participating in my patient’s care by describing their roles and expressing my confidence in their abilities.
Why I Do It
It is vital that our patients feel assured they are being cared for by a high-functioning team of experts. During any given hospital stay, our patients will meet consulting physicians, nurses, therapists, case managers … The list goes on and on. Each person plays a vital part in patients’ care. But it can be difficult for patients to understand every person’s role and to feel assured that each person is highly skilled and aligned with the care plan.
As hospitalists, we are in a unique position to provide a foundation of assuredness and confidence that is a cornerstone of patient experience before our teammates meet patients. When we miss this opportunity, our patients perceive us as a sea of white coats passing in and out of their rooms rather than a cohesive team with their best interests at heart.
How I Do It
Let’s take the example of an elderly patient admitted for a hip fracture after a fall. Alongside the hospitalist will be the orthopedic surgeon, nurse, physical therapist, and case manager, all working toward an optimal outcome. In each case, the hospitalist can choose to provide no information about these team members or to position them for a positive first impression.
Here are the steps to take when positioning colleagues with patients:
- Identify team members and explain their roles.
- Endorse colleagues by expressing honest confidence in their expertise and ability.
- Describe how communication between you and your team members will work.
- Assure the patient that during handoff, your colleagues will be up-to-date and aligned with the plan.
- Tell your patients they are part of a team dedicated to a safe and effective hospitalization.
Mark Shapiro, MD, is medical director for hospital medicine at St. Joseph Health Medical Group in Santa Rosa, Calif., and producer and host of Explore the Space podcast (explorethespaceshow.com).
Non-Hodgkin Lymphoma Death Rates Continue to Fall
The 5-year relative survival rate for non-Hodgkin lymphoma (NHL) climbed to 72.7% and is as high as 82.6% for localized NHL, according to the most recent SEER data. The number of new cases remains high at 19.1 per 100,000 people (all races) per year; however the number of deaths is relatively low at 5.7 deaths per 100,000 people (all races) per year. Death rates have been falling on average 2.4% each year from 2004 to 2013.
While the new cases represent 4.3% of all new cancer diagnoses, NHL deaths represent 3.4% of all cancer deaths. Based on 2011-2013 SEER data, about 2.1% of men and women will receive a NHL diagnosis at some point during their lifetime.
Patient diagnoses by stage:
- 28% are diagnosed at the local stage
- 15% are diagnosed with spread to regional lymph nodes
- 50% are diagnosed after distant cancer has metastasized
- 8% unknown/unstaged
As of 2013, there were an estimated 569,536 people living with NHL in the U.S.
Using statistical models for analysis, rates for new non-Hodgkin lymphoma cases have not changed significantly over the past 10 years.
The 5-year relative survival rate for non-Hodgkin lymphoma (NHL) climbed to 72.7% and is as high as 82.6% for localized NHL, according to the most recent SEER data. The number of new cases remains high at 19.1 per 100,000 people (all races) per year; however the number of deaths is relatively low at 5.7 deaths per 100,000 people (all races) per year. Death rates have been falling on average 2.4% each year from 2004 to 2013.
While the new cases represent 4.3% of all new cancer diagnoses, NHL deaths represent 3.4% of all cancer deaths. Based on 2011-2013 SEER data, about 2.1% of men and women will receive a NHL diagnosis at some point during their lifetime.
Patient diagnoses by stage:
- 28% are diagnosed at the local stage
- 15% are diagnosed with spread to regional lymph nodes
- 50% are diagnosed after distant cancer has metastasized
- 8% unknown/unstaged
As of 2013, there were an estimated 569,536 people living with NHL in the U.S.
Using statistical models for analysis, rates for new non-Hodgkin lymphoma cases have not changed significantly over the past 10 years.
The 5-year relative survival rate for non-Hodgkin lymphoma (NHL) climbed to 72.7% and is as high as 82.6% for localized NHL, according to the most recent SEER data. The number of new cases remains high at 19.1 per 100,000 people (all races) per year; however the number of deaths is relatively low at 5.7 deaths per 100,000 people (all races) per year. Death rates have been falling on average 2.4% each year from 2004 to 2013.
While the new cases represent 4.3% of all new cancer diagnoses, NHL deaths represent 3.4% of all cancer deaths. Based on 2011-2013 SEER data, about 2.1% of men and women will receive a NHL diagnosis at some point during their lifetime.
Patient diagnoses by stage:
- 28% are diagnosed at the local stage
- 15% are diagnosed with spread to regional lymph nodes
- 50% are diagnosed after distant cancer has metastasized
- 8% unknown/unstaged
As of 2013, there were an estimated 569,536 people living with NHL in the U.S.
Using statistical models for analysis, rates for new non-Hodgkin lymphoma cases have not changed significantly over the past 10 years.
EC grants ixazomib conditional approval to treat MM
The European Commission (EC) has granted conditional marketing authorization for ixazomib (NinlaroTM) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
This decision makes ixazomib the first oral proteasome inhibitor approved to treat MM in the European Economic Area.
“With the approval of Ninlaro by the European Commission, physicians across the region will have the option to prescribe an all-oral triplet regimen to treat patients with multiple myeloma who have received at least 1 prior therapy,” said Philippe Moreau, MD, of the University Hospital of Nantes in France.
Conditional marketing authorization represents an expedited path for approval. The EC grants this type of authorization before pivotal registration studies are completed.
Conditional marketing authorization is granted to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.
The conditional authorization for ixazomib means the company developing the drug, Takeda Pharmaceutical Company Limited, is required to provide post-approval updates on safety and efficacy analyses from ongoing studies to demonstrate the long-term effects of ixazomib.
Phase 3 trial
The EC’s decision to grant ixazomib conditional marketing authorization is based on results from the phase 3 TOURMALINE-MM1 trial, which were presented at the 2015 ASH Annual Meeting.
The trial included 722 patients with relapsed or refractory MM. The patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).
Baseline patient characteristics were similar between the treatment arms. Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines of therapy.
Seventy-eight percent of patients responded to IRd, and 72% responded to Rd (P=0.035). The rates of complete response were 12% and 7%, respectively (P=0.019).
At a median follow-up of about 15 months, the median progression-free survival was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).
At a median follow-up of about 23 months, the median overall survival had not been reached in either treatment arm. Follow-up analyses for overall survival are planned for 2017.
The incidence of adverse events (AEs) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.
Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%). 
The European Commission (EC) has granted conditional marketing authorization for ixazomib (NinlaroTM) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
This decision makes ixazomib the first oral proteasome inhibitor approved to treat MM in the European Economic Area.
“With the approval of Ninlaro by the European Commission, physicians across the region will have the option to prescribe an all-oral triplet regimen to treat patients with multiple myeloma who have received at least 1 prior therapy,” said Philippe Moreau, MD, of the University Hospital of Nantes in France.
Conditional marketing authorization represents an expedited path for approval. The EC grants this type of authorization before pivotal registration studies are completed.
Conditional marketing authorization is granted to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.
The conditional authorization for ixazomib means the company developing the drug, Takeda Pharmaceutical Company Limited, is required to provide post-approval updates on safety and efficacy analyses from ongoing studies to demonstrate the long-term effects of ixazomib.
Phase 3 trial
The EC’s decision to grant ixazomib conditional marketing authorization is based on results from the phase 3 TOURMALINE-MM1 trial, which were presented at the 2015 ASH Annual Meeting.
The trial included 722 patients with relapsed or refractory MM. The patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).
Baseline patient characteristics were similar between the treatment arms. Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines of therapy.
Seventy-eight percent of patients responded to IRd, and 72% responded to Rd (P=0.035). The rates of complete response were 12% and 7%, respectively (P=0.019).
At a median follow-up of about 15 months, the median progression-free survival was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).
At a median follow-up of about 23 months, the median overall survival had not been reached in either treatment arm. Follow-up analyses for overall survival are planned for 2017.
The incidence of adverse events (AEs) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.
Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).
The European Commission (EC) has granted conditional marketing authorization for ixazomib (NinlaroTM) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
This decision makes ixazomib the first oral proteasome inhibitor approved to treat MM in the European Economic Area.
“With the approval of Ninlaro by the European Commission, physicians across the region will have the option to prescribe an all-oral triplet regimen to treat patients with multiple myeloma who have received at least 1 prior therapy,” said Philippe Moreau, MD, of the University Hospital of Nantes in France.
Conditional marketing authorization represents an expedited path for approval. The EC grants this type of authorization before pivotal registration studies are completed.
Conditional marketing authorization is granted to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.
The conditional authorization for ixazomib means the company developing the drug, Takeda Pharmaceutical Company Limited, is required to provide post-approval updates on safety and efficacy analyses from ongoing studies to demonstrate the long-term effects of ixazomib.
Phase 3 trial
The EC’s decision to grant ixazomib conditional marketing authorization is based on results from the phase 3 TOURMALINE-MM1 trial, which were presented at the 2015 ASH Annual Meeting.
The trial included 722 patients with relapsed or refractory MM. The patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).
Baseline patient characteristics were similar between the treatment arms. Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines of therapy.
Seventy-eight percent of patients responded to IRd, and 72% responded to Rd (P=0.035). The rates of complete response were 12% and 7%, respectively (P=0.019).
At a median follow-up of about 15 months, the median progression-free survival was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).
At a median follow-up of about 23 months, the median overall survival had not been reached in either treatment arm. Follow-up analyses for overall survival are planned for 2017.
The incidence of adverse events (AEs) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.
Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).
Decitabine produces responses in high-risk MDS, AML
receiving chemotherapy
Photo by Rhoda Baer
Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.
All patients in this study who had TP53 mutations responded to decitabine.
Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.
“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.
For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.
Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m2/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.
To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.
Response
Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.
Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.
There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.
Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.
“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.
“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”
Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)
Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.
“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.
“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”
Survival and next steps
The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.
“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”
The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).
The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).
“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.
“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”
receiving chemotherapy
Photo by Rhoda Baer
Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.
All patients in this study who had TP53 mutations responded to decitabine.
Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.
“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.
For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.
Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m2/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.
To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.
Response
Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.
Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.
There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.
Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.
“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.
“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”
Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)
Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.
“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.
“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”
Survival and next steps
The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.
“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”
The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).
The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).
“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.
“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”
receiving chemotherapy
Photo by Rhoda Baer
Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.
All patients in this study who had TP53 mutations responded to decitabine.
Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.
“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.
For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.
Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m2/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.
To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.
Response
Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.
Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.
There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.
Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.
“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.
“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”
Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)
Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.
“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.
“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”
Survival and next steps
The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.
“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”
The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).
The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).
“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.
“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”
Tazemetostat receives fast track designation for DLBCL
The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.
Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.
Tazemetostat is being developed by Epizyme, Inc.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat trials
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.
Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.
In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.
In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.
The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.
Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.
Tazemetostat is being developed by Epizyme, Inc.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat trials
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.
Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.
In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.
In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.
The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.
Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.
Tazemetostat is being developed by Epizyme, Inc.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat trials
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.
Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.
In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.
In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.
Increased death rate with platelets for aspirin/clopidogrel GI bleed
Patients with normal platelet counts who have a GI bleed while on antiplatelets were almost six times more likely to die in the hospital if they had a platelet transfusion in a retrospective cohort study from the Yale University in New Haven, Conn.
Ten of the 14 deaths in the 204 transfused patients – versus none of the 3 deaths in the 204 nontransfused patients - were due to bleeding, so it’s possible that the mortality difference was simply because patients with worse bleeding were more likely to get transfused. “On the other hand, the adjusted [odds ratios] for mortality (4.5-6.8 with different sensitivity analyses) [were] large, increasing the likelihood of a cause-and-effect relationship,” said investigators led by gastroenterologist Liam Zakko, MD, now at the Mayo Clinic in Rochester, Minn. (Clin Gastroenterol Hepatol. 2016 Jul 25. doi: 10.1016/j.cgh.2016.07.017).
Current guidelines suggest platelet transfusions are an option for antiplatelet patients with serious GI bleeds, but the Yale team found that they did not reduce rebleeding. “The observation of increased mortality without documentation of clinical benefit suggests a very cautious approach to the use of platelet transfusion. ... We do not support the use of platelet transfusions in patients with GI [bleeds] who are taking antiplatelet agents,” the investigators wrote.
Subjects in the two groups were matched for sex, age, and GI bleed location, and all had platelet counts above 100 × 109/L. Almost everyone was on aspirin for cardiovascular protection, and 30% were on also on clopidogrel.
Just over half in both groups had upper GI bleeds, and about 40% in each group had colonic bleeds. Transfused patients had more-severe bleeding, with overall lower blood pressure and lower hemoglobin; a larger proportion was admitted to the ICU.
On univariate analyses, platelet patients had more cardiovascular events (23% vs. 13%) while in the hospital. They were also more likely to stay in the hospital for more than 4 days (47% vs. 33%) and more likely to die while there (7% vs. 1%). On multivariable analysis, only the greater risk for death during admission remained statistically significant (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was not significant.
Four patients in the platelet group died from cardiovascular causes. One patient in the control group had a fatal cardiovascular event.
Although counterintuitive, the authors said that it’s possible that platelet transfusions might actually increase the risk of severe and fatal GI bleeding. “Mechanisms by which platelet transfusion would increase mortality or [GI bleeding]–related mortality are not clear,” but “platelet transfusions are reported to be proinflammatory and alter recipient immunity,” they said.
At least for now, “the most prudent way to manage patients on antiplatelet agents with [GI bleeding] is to follow current evidence-based recommendations,” including early endoscopy, endoscopic hemostatic therapy for high-risk lesions, and intensive proton pump inhibitor therapy in patients with ulcers and high-risk endoscopic features.
“Although not based on high-quality evidence, we believe that hemostatic techniques that do not cause significant tissue damage (e.g., clips rather than thermal devices or sclerosants) should be used in patients on antiplatelet agents, especially if patients are expected to remain on these agents in the future,” they said.
The mean age in the study was 74 years, and about two-thirds of the subjects were men.
The authors had no disclosures.
The management of patients with gastrointestinal bleeding on antithrombotic drugs is a major challenge for gastroenterologists. Unfortunately, the use of aspirin alone has been shown to increase the risk of GI bleed twofold, and the addition of a thienopyridine additionally increases the risk of bleeding twofold. Furthermore, there is no available agent to reverse antiplatelet affects of these drugs, which irreversibly block platelet function for the life of the platelet (8-10 days). Current recommendations for the management of severe GI bleeding in patients receiving antithrombotic therapy include platelet transfusion, including those with a normal platelet count. However, this comes with a price as reversal of platelet function may increase the rate of cardiovascular events.
Zakko et al. performed a retrospective case-control study evaluating the role of platelet transfusion in patients presenting with GI bleeding. Patients were matched by age, sex, and the location of the GI bleed. Most patients included in the study were on low-dose aspirin and almost a third of the patients were taking both aspirin and a thienopyridine. Patients receiving platelet transfusions appeared to have more severe GI bleeding compared with matched controls, as patients receiving transfusion were more likely to have been hypotensive, tachycardic, have a low hemoglobin level, and require treatment in the intensive care unit (72% vs. 28%, P less than .0001). Patients receiving platelet transfusions were also more likely than matched controls to have recurrent GI bleeding as well as major cardiovascular adverse events, including myocardial infarction and inpatient death. After adjusting for patient characteristics, patients receiving platelet transfusions were more likely to have an increased risk of death (adjusted OR, 5.57; 95% CI, 1.52-27.1). The authors conclude that “the use of platelet transfusions in patients with GI bleeding who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality.”
Currently, there is no convincing evidence to support platelet transfusion in patients with bleeding on aspirin and/or a thienopyridine. Because the majority of the deaths were due to GI bleeding and not cardiovascular events, the observed increase in adverse events in patients receiving platelet transfusions likely reflects more severe GI bleeding in patients receiving platelet transfusions than in controls. We should avoid platelet transfusions and focus our management on achieving adequate resuscitation, use of proton pump inhibitors for patients with high-risk ulcers, and early endoscopy with endoscopic therapy for high-risk lesions.
John R. Saltzman, MD, AGAF, is director of endoscopy, Brigham and Women’s Hospital, professor of medicine, Harvard Medical School, Boston. He has no conflicts of interest.
The management of patients with gastrointestinal bleeding on antithrombotic drugs is a major challenge for gastroenterologists. Unfortunately, the use of aspirin alone has been shown to increase the risk of GI bleed twofold, and the addition of a thienopyridine additionally increases the risk of bleeding twofold. Furthermore, there is no available agent to reverse antiplatelet affects of these drugs, which irreversibly block platelet function for the life of the platelet (8-10 days). Current recommendations for the management of severe GI bleeding in patients receiving antithrombotic therapy include platelet transfusion, including those with a normal platelet count. However, this comes with a price as reversal of platelet function may increase the rate of cardiovascular events.
Zakko et al. performed a retrospective case-control study evaluating the role of platelet transfusion in patients presenting with GI bleeding. Patients were matched by age, sex, and the location of the GI bleed. Most patients included in the study were on low-dose aspirin and almost a third of the patients were taking both aspirin and a thienopyridine. Patients receiving platelet transfusions appeared to have more severe GI bleeding compared with matched controls, as patients receiving transfusion were more likely to have been hypotensive, tachycardic, have a low hemoglobin level, and require treatment in the intensive care unit (72% vs. 28%, P less than .0001). Patients receiving platelet transfusions were also more likely than matched controls to have recurrent GI bleeding as well as major cardiovascular adverse events, including myocardial infarction and inpatient death. After adjusting for patient characteristics, patients receiving platelet transfusions were more likely to have an increased risk of death (adjusted OR, 5.57; 95% CI, 1.52-27.1). The authors conclude that “the use of platelet transfusions in patients with GI bleeding who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality.”
Currently, there is no convincing evidence to support platelet transfusion in patients with bleeding on aspirin and/or a thienopyridine. Because the majority of the deaths were due to GI bleeding and not cardiovascular events, the observed increase in adverse events in patients receiving platelet transfusions likely reflects more severe GI bleeding in patients receiving platelet transfusions than in controls. We should avoid platelet transfusions and focus our management on achieving adequate resuscitation, use of proton pump inhibitors for patients with high-risk ulcers, and early endoscopy with endoscopic therapy for high-risk lesions.
John R. Saltzman, MD, AGAF, is director of endoscopy, Brigham and Women’s Hospital, professor of medicine, Harvard Medical School, Boston. He has no conflicts of interest.
The management of patients with gastrointestinal bleeding on antithrombotic drugs is a major challenge for gastroenterologists. Unfortunately, the use of aspirin alone has been shown to increase the risk of GI bleed twofold, and the addition of a thienopyridine additionally increases the risk of bleeding twofold. Furthermore, there is no available agent to reverse antiplatelet affects of these drugs, which irreversibly block platelet function for the life of the platelet (8-10 days). Current recommendations for the management of severe GI bleeding in patients receiving antithrombotic therapy include platelet transfusion, including those with a normal platelet count. However, this comes with a price as reversal of platelet function may increase the rate of cardiovascular events.
Zakko et al. performed a retrospective case-control study evaluating the role of platelet transfusion in patients presenting with GI bleeding. Patients were matched by age, sex, and the location of the GI bleed. Most patients included in the study were on low-dose aspirin and almost a third of the patients were taking both aspirin and a thienopyridine. Patients receiving platelet transfusions appeared to have more severe GI bleeding compared with matched controls, as patients receiving transfusion were more likely to have been hypotensive, tachycardic, have a low hemoglobin level, and require treatment in the intensive care unit (72% vs. 28%, P less than .0001). Patients receiving platelet transfusions were also more likely than matched controls to have recurrent GI bleeding as well as major cardiovascular adverse events, including myocardial infarction and inpatient death. After adjusting for patient characteristics, patients receiving platelet transfusions were more likely to have an increased risk of death (adjusted OR, 5.57; 95% CI, 1.52-27.1). The authors conclude that “the use of platelet transfusions in patients with GI bleeding who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality.”
Currently, there is no convincing evidence to support platelet transfusion in patients with bleeding on aspirin and/or a thienopyridine. Because the majority of the deaths were due to GI bleeding and not cardiovascular events, the observed increase in adverse events in patients receiving platelet transfusions likely reflects more severe GI bleeding in patients receiving platelet transfusions than in controls. We should avoid platelet transfusions and focus our management on achieving adequate resuscitation, use of proton pump inhibitors for patients with high-risk ulcers, and early endoscopy with endoscopic therapy for high-risk lesions.
John R. Saltzman, MD, AGAF, is director of endoscopy, Brigham and Women’s Hospital, professor of medicine, Harvard Medical School, Boston. He has no conflicts of interest.
Patients with normal platelet counts who have a GI bleed while on antiplatelets were almost six times more likely to die in the hospital if they had a platelet transfusion in a retrospective cohort study from the Yale University in New Haven, Conn.
Ten of the 14 deaths in the 204 transfused patients – versus none of the 3 deaths in the 204 nontransfused patients - were due to bleeding, so it’s possible that the mortality difference was simply because patients with worse bleeding were more likely to get transfused. “On the other hand, the adjusted [odds ratios] for mortality (4.5-6.8 with different sensitivity analyses) [were] large, increasing the likelihood of a cause-and-effect relationship,” said investigators led by gastroenterologist Liam Zakko, MD, now at the Mayo Clinic in Rochester, Minn. (Clin Gastroenterol Hepatol. 2016 Jul 25. doi: 10.1016/j.cgh.2016.07.017).
Current guidelines suggest platelet transfusions are an option for antiplatelet patients with serious GI bleeds, but the Yale team found that they did not reduce rebleeding. “The observation of increased mortality without documentation of clinical benefit suggests a very cautious approach to the use of platelet transfusion. ... We do not support the use of platelet transfusions in patients with GI [bleeds] who are taking antiplatelet agents,” the investigators wrote.
Subjects in the two groups were matched for sex, age, and GI bleed location, and all had platelet counts above 100 × 109/L. Almost everyone was on aspirin for cardiovascular protection, and 30% were on also on clopidogrel.
Just over half in both groups had upper GI bleeds, and about 40% in each group had colonic bleeds. Transfused patients had more-severe bleeding, with overall lower blood pressure and lower hemoglobin; a larger proportion was admitted to the ICU.
On univariate analyses, platelet patients had more cardiovascular events (23% vs. 13%) while in the hospital. They were also more likely to stay in the hospital for more than 4 days (47% vs. 33%) and more likely to die while there (7% vs. 1%). On multivariable analysis, only the greater risk for death during admission remained statistically significant (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was not significant.
Four patients in the platelet group died from cardiovascular causes. One patient in the control group had a fatal cardiovascular event.
Although counterintuitive, the authors said that it’s possible that platelet transfusions might actually increase the risk of severe and fatal GI bleeding. “Mechanisms by which platelet transfusion would increase mortality or [GI bleeding]–related mortality are not clear,” but “platelet transfusions are reported to be proinflammatory and alter recipient immunity,” they said.
At least for now, “the most prudent way to manage patients on antiplatelet agents with [GI bleeding] is to follow current evidence-based recommendations,” including early endoscopy, endoscopic hemostatic therapy for high-risk lesions, and intensive proton pump inhibitor therapy in patients with ulcers and high-risk endoscopic features.
“Although not based on high-quality evidence, we believe that hemostatic techniques that do not cause significant tissue damage (e.g., clips rather than thermal devices or sclerosants) should be used in patients on antiplatelet agents, especially if patients are expected to remain on these agents in the future,” they said.
The mean age in the study was 74 years, and about two-thirds of the subjects were men.
The authors had no disclosures.
Patients with normal platelet counts who have a GI bleed while on antiplatelets were almost six times more likely to die in the hospital if they had a platelet transfusion in a retrospective cohort study from the Yale University in New Haven, Conn.
Ten of the 14 deaths in the 204 transfused patients – versus none of the 3 deaths in the 204 nontransfused patients - were due to bleeding, so it’s possible that the mortality difference was simply because patients with worse bleeding were more likely to get transfused. “On the other hand, the adjusted [odds ratios] for mortality (4.5-6.8 with different sensitivity analyses) [were] large, increasing the likelihood of a cause-and-effect relationship,” said investigators led by gastroenterologist Liam Zakko, MD, now at the Mayo Clinic in Rochester, Minn. (Clin Gastroenterol Hepatol. 2016 Jul 25. doi: 10.1016/j.cgh.2016.07.017).
Current guidelines suggest platelet transfusions are an option for antiplatelet patients with serious GI bleeds, but the Yale team found that they did not reduce rebleeding. “The observation of increased mortality without documentation of clinical benefit suggests a very cautious approach to the use of platelet transfusion. ... We do not support the use of platelet transfusions in patients with GI [bleeds] who are taking antiplatelet agents,” the investigators wrote.
Subjects in the two groups were matched for sex, age, and GI bleed location, and all had platelet counts above 100 × 109/L. Almost everyone was on aspirin for cardiovascular protection, and 30% were on also on clopidogrel.
Just over half in both groups had upper GI bleeds, and about 40% in each group had colonic bleeds. Transfused patients had more-severe bleeding, with overall lower blood pressure and lower hemoglobin; a larger proportion was admitted to the ICU.
On univariate analyses, platelet patients had more cardiovascular events (23% vs. 13%) while in the hospital. They were also more likely to stay in the hospital for more than 4 days (47% vs. 33%) and more likely to die while there (7% vs. 1%). On multivariable analysis, only the greater risk for death during admission remained statistically significant (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was not significant.
Four patients in the platelet group died from cardiovascular causes. One patient in the control group had a fatal cardiovascular event.
Although counterintuitive, the authors said that it’s possible that platelet transfusions might actually increase the risk of severe and fatal GI bleeding. “Mechanisms by which platelet transfusion would increase mortality or [GI bleeding]–related mortality are not clear,” but “platelet transfusions are reported to be proinflammatory and alter recipient immunity,” they said.
At least for now, “the most prudent way to manage patients on antiplatelet agents with [GI bleeding] is to follow current evidence-based recommendations,” including early endoscopy, endoscopic hemostatic therapy for high-risk lesions, and intensive proton pump inhibitor therapy in patients with ulcers and high-risk endoscopic features.
“Although not based on high-quality evidence, we believe that hemostatic techniques that do not cause significant tissue damage (e.g., clips rather than thermal devices or sclerosants) should be used in patients on antiplatelet agents, especially if patients are expected to remain on these agents in the future,” they said.
The mean age in the study was 74 years, and about two-thirds of the subjects were men.
The authors had no disclosures.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point:
Major finding: Compared with those not transfused, the risk for death during admission remained statistically significant on multivariate analysis (OR, 5.57; 95% CI, 1.52-27.1).
Data source: Retrospective cohort study of 408 GI bleed patients
Disclosures: The authors had no disclosures.
SPG Stimulation May Enhance Delivery of Drugs to the Brain
BALTIMORE—Stimulation of the sphenopalatine ganglion (SPG) may be a safe and effective method of temporarily disrupting the blood–brain barrier to deliver therapeutics to the brain. In an animal model of stroke, SPG stimulation enhances the delivery of mesenchymal stem cells and improves functional outcomes, according to research presented at the 141st Annual Meeting of the American Neurological Association. The technique does not entail unwanted systemic effects and potentially could be applied in the treatment of other neurologic disorders.
Although it would be undesirable to deliver bone-marrow stem cells to the human brain, SPG stimulation could aid the delivery of neural stem cells, viral vectors, antibody infusions, and gene therapies, said Lorraine Iacovitti, PhD, Director of the Jefferson Stem Cell and Regenerative Neuroscience Center at Thomas Jefferson University in Philadelphia. She and her colleagues plan to investigate the mechanisms responsible for the response to SPG stimulation. In addition, they will examine various stimulation frequencies and determine the size of therapies that can be delivered to the brain. 
Disruption of the Blood–Brain Barrier
Modifying the blood–brain barrier has been a longstanding goal of medicine. Achieving this goal would “improve treatments for many neurologic diseases and disorders, particularly if you could combine it with a focused endovascular delivery system so that these reagents get to the appropriate regions,” said Dr. Iacovitti. In 2004, Yarnitsky et al found that stimulating the SPG caused a transient, reversible increase in blood–brain barrier permeability in animals. The technique enabled Evans blue to penetrate nearly the entire side of the brain that received stimulation.
Michael Lang, MD, a fifth-year neurosurgical resident, led Dr. Iacovitti’s group in a study of SPG stimulation in rats with middle cerebral artery (MCA) occlusion. The researchers previously had found that injection of exogenous bone-marrow mesenchymal stem cells reduced infarct size, improved behavioral deficits, and decreased proinflammatory factors in this model of stroke. Although some stem cells reached the brain, most collected in the lungs, the kidneys, and the liver. Dr. Iacovitti’s group hypothesized that SPG stimulation would increase mesenchymal stem cell engraftment following intra-arterial delivery.
SPG Stimulation in a Stroke Model
The investigators studied three groups of rats. One group received MCA occlusion. The second group received MCA occlusion and an intra-arterial infusion of mesenchymal stem cells at one day post stroke. The third group underwent MCA occlusion, intra-arterial infusion of mesenchymal stem cells, and SPG stimulation at one day post stroke. The stimulation frequency was 10 Hz, and the potential was 5 V. Stimulation continuously alternated between 90-s on and 60-s off for a total of 20 minutes.
In the absence of SPG stimulation, few, if any, stem cells reached the parenchyma. The cells did reach the parenchyma, however, in rats that received SPG stimulation. In addition, SPG stimulation was associated with an improvement in functional outcome. At day 7 and at day 14, the researchers observed a difference in function between animals that received mesenchymal stem cells alone and those that received mesenchymal stem cells plus SPG stimulation. At day 14, the Modified Neurologic Severity score was approximately 50% lower in rats that received stem cells and SPG stimulation, compared with untreated rats.
Electron microscopy revealed that most tight junctions in the rats’ brains appeared normal after SPG stimulation, although tight junction discontinuity was common. The effect was similar to that of a mannitol infusion, said Dr. Iacovitti. “It is possible that stem cells are moving out of circulation into the brain in a fashion similar to what you would see after tumor-necrosis-factor-alpha-stimulated inflammation, where you would get immune cells to move out of the blood vessels and into the damaged brain area through a process of diapedesis.” Unlike mannitol administration, which causes dangerous systemic side effects, SPG stimulation has no observed adverse side effects.
“The combination of endovascular selectivity with SPG stimulation is potentially an extremely powerful tool to deliver [therapies] across the blood–brain barrier into the brain,” she continued. “We have just started to look at getting viruses across…. This work has really just begun.”
Dr. Iacovitti’s research was funded by grants awarded by the NIH, the Joseph and Marie Field Family Foundation, and the Mary E. Groff Charitable Trust.
—Erik Greb
BALTIMORE—Stimulation of the sphenopalatine ganglion (SPG) may be a safe and effective method of temporarily disrupting the blood–brain barrier to deliver therapeutics to the brain. In an animal model of stroke, SPG stimulation enhances the delivery of mesenchymal stem cells and improves functional outcomes, according to research presented at the 141st Annual Meeting of the American Neurological Association. The technique does not entail unwanted systemic effects and potentially could be applied in the treatment of other neurologic disorders.
Although it would be undesirable to deliver bone-marrow stem cells to the human brain, SPG stimulation could aid the delivery of neural stem cells, viral vectors, antibody infusions, and gene therapies, said Lorraine Iacovitti, PhD, Director of the Jefferson Stem Cell and Regenerative Neuroscience Center at Thomas Jefferson University in Philadelphia. She and her colleagues plan to investigate the mechanisms responsible for the response to SPG stimulation. In addition, they will examine various stimulation frequencies and determine the size of therapies that can be delivered to the brain.
Disruption of the Blood–Brain Barrier
Modifying the blood–brain barrier has been a longstanding goal of medicine. Achieving this goal would “improve treatments for many neurologic diseases and disorders, particularly if you could combine it with a focused endovascular delivery system so that these reagents get to the appropriate regions,” said Dr. Iacovitti. In 2004, Yarnitsky et al found that stimulating the SPG caused a transient, reversible increase in blood–brain barrier permeability in animals. The technique enabled Evans blue to penetrate nearly the entire side of the brain that received stimulation.
Michael Lang, MD, a fifth-year neurosurgical resident, led Dr. Iacovitti’s group in a study of SPG stimulation in rats with middle cerebral artery (MCA) occlusion. The researchers previously had found that injection of exogenous bone-marrow mesenchymal stem cells reduced infarct size, improved behavioral deficits, and decreased proinflammatory factors in this model of stroke. Although some stem cells reached the brain, most collected in the lungs, the kidneys, and the liver. Dr. Iacovitti’s group hypothesized that SPG stimulation would increase mesenchymal stem cell engraftment following intra-arterial delivery.
SPG Stimulation in a Stroke Model
The investigators studied three groups of rats. One group received MCA occlusion. The second group received MCA occlusion and an intra-arterial infusion of mesenchymal stem cells at one day post stroke. The third group underwent MCA occlusion, intra-arterial infusion of mesenchymal stem cells, and SPG stimulation at one day post stroke. The stimulation frequency was 10 Hz, and the potential was 5 V. Stimulation continuously alternated between 90-s on and 60-s off for a total of 20 minutes.
In the absence of SPG stimulation, few, if any, stem cells reached the parenchyma. The cells did reach the parenchyma, however, in rats that received SPG stimulation. In addition, SPG stimulation was associated with an improvement in functional outcome. At day 7 and at day 14, the researchers observed a difference in function between animals that received mesenchymal stem cells alone and those that received mesenchymal stem cells plus SPG stimulation. At day 14, the Modified Neurologic Severity score was approximately 50% lower in rats that received stem cells and SPG stimulation, compared with untreated rats.
Electron microscopy revealed that most tight junctions in the rats’ brains appeared normal after SPG stimulation, although tight junction discontinuity was common. The effect was similar to that of a mannitol infusion, said Dr. Iacovitti. “It is possible that stem cells are moving out of circulation into the brain in a fashion similar to what you would see after tumor-necrosis-factor-alpha-stimulated inflammation, where you would get immune cells to move out of the blood vessels and into the damaged brain area through a process of diapedesis.” Unlike mannitol administration, which causes dangerous systemic side effects, SPG stimulation has no observed adverse side effects.
“The combination of endovascular selectivity with SPG stimulation is potentially an extremely powerful tool to deliver [therapies] across the blood–brain barrier into the brain,” she continued. “We have just started to look at getting viruses across…. This work has really just begun.”
Dr. Iacovitti’s research was funded by grants awarded by the NIH, the Joseph and Marie Field Family Foundation, and the Mary E. Groff Charitable Trust.
—Erik Greb
BALTIMORE—Stimulation of the sphenopalatine ganglion (SPG) may be a safe and effective method of temporarily disrupting the blood–brain barrier to deliver therapeutics to the brain. In an animal model of stroke, SPG stimulation enhances the delivery of mesenchymal stem cells and improves functional outcomes, according to research presented at the 141st Annual Meeting of the American Neurological Association. The technique does not entail unwanted systemic effects and potentially could be applied in the treatment of other neurologic disorders.
Although it would be undesirable to deliver bone-marrow stem cells to the human brain, SPG stimulation could aid the delivery of neural stem cells, viral vectors, antibody infusions, and gene therapies, said Lorraine Iacovitti, PhD, Director of the Jefferson Stem Cell and Regenerative Neuroscience Center at Thomas Jefferson University in Philadelphia. She and her colleagues plan to investigate the mechanisms responsible for the response to SPG stimulation. In addition, they will examine various stimulation frequencies and determine the size of therapies that can be delivered to the brain.
Disruption of the Blood–Brain Barrier
Modifying the blood–brain barrier has been a longstanding goal of medicine. Achieving this goal would “improve treatments for many neurologic diseases and disorders, particularly if you could combine it with a focused endovascular delivery system so that these reagents get to the appropriate regions,” said Dr. Iacovitti. In 2004, Yarnitsky et al found that stimulating the SPG caused a transient, reversible increase in blood–brain barrier permeability in animals. The technique enabled Evans blue to penetrate nearly the entire side of the brain that received stimulation.
Michael Lang, MD, a fifth-year neurosurgical resident, led Dr. Iacovitti’s group in a study of SPG stimulation in rats with middle cerebral artery (MCA) occlusion. The researchers previously had found that injection of exogenous bone-marrow mesenchymal stem cells reduced infarct size, improved behavioral deficits, and decreased proinflammatory factors in this model of stroke. Although some stem cells reached the brain, most collected in the lungs, the kidneys, and the liver. Dr. Iacovitti’s group hypothesized that SPG stimulation would increase mesenchymal stem cell engraftment following intra-arterial delivery.
SPG Stimulation in a Stroke Model
The investigators studied three groups of rats. One group received MCA occlusion. The second group received MCA occlusion and an intra-arterial infusion of mesenchymal stem cells at one day post stroke. The third group underwent MCA occlusion, intra-arterial infusion of mesenchymal stem cells, and SPG stimulation at one day post stroke. The stimulation frequency was 10 Hz, and the potential was 5 V. Stimulation continuously alternated between 90-s on and 60-s off for a total of 20 minutes.
In the absence of SPG stimulation, few, if any, stem cells reached the parenchyma. The cells did reach the parenchyma, however, in rats that received SPG stimulation. In addition, SPG stimulation was associated with an improvement in functional outcome. At day 7 and at day 14, the researchers observed a difference in function between animals that received mesenchymal stem cells alone and those that received mesenchymal stem cells plus SPG stimulation. At day 14, the Modified Neurologic Severity score was approximately 50% lower in rats that received stem cells and SPG stimulation, compared with untreated rats.
Electron microscopy revealed that most tight junctions in the rats’ brains appeared normal after SPG stimulation, although tight junction discontinuity was common. The effect was similar to that of a mannitol infusion, said Dr. Iacovitti. “It is possible that stem cells are moving out of circulation into the brain in a fashion similar to what you would see after tumor-necrosis-factor-alpha-stimulated inflammation, where you would get immune cells to move out of the blood vessels and into the damaged brain area through a process of diapedesis.” Unlike mannitol administration, which causes dangerous systemic side effects, SPG stimulation has no observed adverse side effects.
“The combination of endovascular selectivity with SPG stimulation is potentially an extremely powerful tool to deliver [therapies] across the blood–brain barrier into the brain,” she continued. “We have just started to look at getting viruses across…. This work has really just begun.”
Dr. Iacovitti’s research was funded by grants awarded by the NIH, the Joseph and Marie Field Family Foundation, and the Mary E. Groff Charitable Trust.
—Erik Greb
