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Potential Impact of USPS Mail Delivery Delays on Colorectal Cancer Screening Programs
Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States.1 In 2022, there were an estimated 151,030 new CRC cases and 52,580 deaths.1 Options for CRC screening of patients at average risk include stool tests (annual fecal immunochemical test [FIT], annual guaiac-based fecal occult blood test, or stool FIT-DNA test every 1 to 3 years), colonoscopies every 10 years, flexible sigmoidoscopies every 5 years (or every 10 years with annual FIT), and computed tomography (CT) colonography every 5 years.2 Many health care systems use annual FIT for patients at average risk. Compared with guaiac-based fecal occult blood testing, FIT does not require dietary or medication modifications and yields greater sensitivity and patient participation.3
The COVID-19 pandemic and staffing issues have caused a scheduling backlog for screening, diagnostic, and surveillance endoscopies at some medical centers. As a result, FIT has become the primary means of CRC screening at these institutions. FIT kits for home use are typically distributed to eligible patients at an office visit or by mail, and patients are then instructed to mail the kits back to the laboratory. For the test to be as sensitive as possible, FIT kit manufacturers advise laboratory analysis within 14 to 15 days of collection, if stored at ambient temperature, and to reject the sample if it does not meet testing criteria for stability. Delayed FIT sample analysis has been associated with higher false-negative rates because of hemoglobin degradation.4 FIT sample exposure to high ambient temperatures also has been linked to decreased sensitivity for detecting CRC.5
US Postal Service (USPS) mail delivery delays have plagued many areas of the country. A variety of factors, including the COVID-19 pandemic, understaffing, changes in USPS policies, closure of post offices, and changes in mail delivery standards, may also be contributory causes. According to the USPS website, delivery standard for first-class mail is 1 to 5 days, but this is not guaranteed.6
The Jesse Brown Veterans Affairs Medical Center (JBVAMC) laboratory in Chicago has reported receiving FIT kit envelopes in batches by the USPS, with some prepaid first-class business reply envelopes delivered up to 60 days after the time of sample collection. Polymedco, a company that assists US Department of Veterans Affairs (VA) medical centers with logistics of FIT programs for CRC screening, reports that USPS batching of FIT kits leading to delayed delivery has been a periodic problem for medical centers around the country. Polymedco staff remind USPS staff about 4 points when they encounter this issue: Mailers are first-class mail; mailers contain a human biologic specimen that has limited viability; the biological sample used for detecting cancer is time sensitive; and delays in delivery by holding/batching kits could impact morbidity and mortality. Reviewing these key points with local USPS staff usually helps, however, batching and delayed delivery of the FIT kits can sometimes recur with USPS staffing turnover.
Tracking and identifying when a patient receives the FIT kit is difficult. Patients are instructed to write the date of collection on the kit, so the receiving laboratory knows whether the sample can be reliably analyzed. When patients are notified about delayed delivery of their sample, a staff member asks if they postponed dropping the kit in the mail. Most patients report mailing the sample within 1 to 2 days of collection. Tracking and dating each step of FIT kit events is not feasible with a mass mailing campaign. In our experience, most patients write the date of collection on the kit. If a collection date is not provided, the laboratory will call the patient to confirm a date. Cheng and colleagues reviewed the causes for FIT specimen rejection in a laboratory analyzing specimens for VA patients and found that 14% of submitted samples were rejected because the specimen was received > 14 days after collection, and 6% because the patient did not record the collection date. With a series of interventions aimed at reminding patients and improving laboratory procedures, rates of rejection for these 2 causes were reduced to < 4%.7 USPS delays were not identified as a factor or tracked in this study.
It is unclear why the USPS sometimes holds FIT kits at their facilities and then delivers large bins of them at the same time. Because FIT kits should be analyzed within 14 to 15 days of sample collection to assure reliable results, mail delivery delays can result in increased sample rejection. Based on the JBVAMC experience, up to 30% of submitted samples might need to be discarded when batched delivery takes place. In these cases, patients need to be contacted, informed of the problem, and asked to submit new kits. Understandably, patients are reluctant to repeat this type of testing, and we are concerned this could lead to reduced rates of CRC screening in affected communities.
As an alternative to discarding delayed samples, laboratories could report the results of delayed FIT kits with an added comment that “negative test results may be less reliable due to delayed processing,” but this approach would raise quality and medicolegal concerns. Clinicians have reached out to local USPS supervisory personnel with mixed results. Sometimes batching and delayed deliveries stop for a few months, only to resume without warning. Dropping off the sample directly at the laboratory is not a realistic option for most patients. Some patients can be convinced to submit another sample, some elect to switch to other CRC screening strategies, while others, unfortunately, decline further screening efforts.
Laboratory staff can be overwhelmed with having to process hundreds of samples in a short time frame, especially because there is no way of knowing when USPS will make a batched delivery. Laboratory capacities can limit staff at some facilities to performing analysis of only 10 tests at a time. The FIT kits should be delivered on a rolling basis and without delay so that the samples can be reliably analyzed with a predictable workload for the laboratory personnel and without unexpected surges.
When health care facilities identify delayed mail delivery of FIT kits via USPS, laboratories should first ensure that the correct postage rates are used on the prepaid envelopes and that their USPS accounts are properly funded, so that insufficient funds are not contributing to delayed deliveries. Stakeholders should then reach out to local USPS supervisory staff and request that the practice of batching the delivery of FIT kits be stopped. Educating USPS supervisory staff about concerns related to decreased test reliability associated with delayed mail delivery can be a persuasive argument. Adding additional language to the preprinted envelopes, such as “time sensitive,” may also be helpful. Unfortunately, the JBVAMC experience has been that the problem initially gets better after contacting the USPS, only to unexpectedly resurface months later. This cycle has been repeated several times in the past 2 years at JBVAMC.
All clinicians involved in CRC screening and treatment at institutions that use FIT kits need to be aware of the impact that local USPS delays can have on the reliability of these results. Health care systems should be prepared to implement mitigation strategies if they encounter significant delays with mail delivery. If delays cannot be reliably resolved by working with the local USPS staff, consider involving national USPS oversight bodies. And if the problems persist despite an attempt to work with the USPS, some institutions might find it feasible to offer drop boxes at their clinics and instruct patients to drop off FIT kits immediately following collection, in lieu of mailing them. Switching to private carriers is not a cost-effective alternative for most health care systems, and some may exclude rural areas. Depending on the local availability and capacity of endoscopists, some clinicians might prioritize referring patients for screening colonoscopies or screening flexible sigmoidoscopies, and might deemphasize FIT kits as a preferred option for CRC screening. CT colonography is an alternative screening method that is not as widely offered, nor as widely accepted at this time.
Conclusions
CRC screening is an essential part of preventive medicine, and the percentage of eligible patients screened is a well-established quality metric in primary care settings. Health care systems, clinicians, and laboratories must be vigilant to ensure that USPS delays in delivering FIT kits do not negatively impact their CRC screening programs. Facilities should actively monitor for delays in the return of FIT kits.
Despite the widespread use of mail-order pharmacies and the use of mail to communicate notifications about test results and follow-up appointments, unreliable or delayed mail delivery traditionally has not been considered a social determinant of health.8 This article highlights the impact delayed mail delivery can have on health outcomes. Disadvantaged communities in inner cities and rural areas have been disproportionately affected by the worsening performance of the USPS over the past few years.9 This represents an underappreciated public health concern in need of a sustainable solution.
1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. doi:10.3322/caac.21708
2. Centers for Disease Control and Prevention. Colorectal cancer screening tests. Updated February 23, 2023. Accessed March 14, 2024. https://www.cdc.gov/cancer/colorectal/basic_info/screening/tests.htm
3. van Rossum LG, van Rijn AF, Laheij RJ, et al. Random comparison of guaiac and immunochemical fecal occult blood tests for colorectal cancer in a screening population. Gastroenterology. 2008;135(1):82-90. doi:10.1053/j.gastro.2008.03.040
4. van Rossum LG, van Rijn AF, van Oijen MG, et al. False negative fecal occult blood tests due to delayed sample return in colorectal cancer screening. Int J Cancer. 2009;125(4):746-750. doi:10.1002/ijc.24458
5. Doubeni CA, Jensen CD, Fedewa SA, et al. Fecal immunochemical test (FIT) for colon cancer screening: variable performance with ambient temperature. J Am Board Fam Med. 2016;29(6):672-681. doi:10.3122/jabfm.2016.06.160060
6. United States Postal Service. Shipping and mailing with USPS. Accessed March 14, 2024. https://www.usps.com/ship
7. Cheng C, Ganz DA, Chang ET, Huynh A, De Peralta S. Reducing rejected fecal immunochemical tests received in the laboratory for colorectal cancer screening. J Healthc Qual. 2019;41(2):75-82.doi:10.1097/JHQ.0000000000000181
8. Hussaini SMQ, Alexander GC. The United States Postal Service: an essential public health agency? J Gen Intern Med. 2020;35(12):3699-3701. doi:10.1007/s11606-020-06275-2
9. Hampton DJ. Colorado mountain towns are plagued by post office delays as residents wait weeks for medication and retirement checks. NBC News. February 25, 2023. Accessed March 14, 2024. https://www.nbcnews.com/news/us-news/colo-mountain-towns-are-plagued-post-office-delays-residents-wait-week-rcna72085
Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States.1 In 2022, there were an estimated 151,030 new CRC cases and 52,580 deaths.1 Options for CRC screening of patients at average risk include stool tests (annual fecal immunochemical test [FIT], annual guaiac-based fecal occult blood test, or stool FIT-DNA test every 1 to 3 years), colonoscopies every 10 years, flexible sigmoidoscopies every 5 years (or every 10 years with annual FIT), and computed tomography (CT) colonography every 5 years.2 Many health care systems use annual FIT for patients at average risk. Compared with guaiac-based fecal occult blood testing, FIT does not require dietary or medication modifications and yields greater sensitivity and patient participation.3
The COVID-19 pandemic and staffing issues have caused a scheduling backlog for screening, diagnostic, and surveillance endoscopies at some medical centers. As a result, FIT has become the primary means of CRC screening at these institutions. FIT kits for home use are typically distributed to eligible patients at an office visit or by mail, and patients are then instructed to mail the kits back to the laboratory. For the test to be as sensitive as possible, FIT kit manufacturers advise laboratory analysis within 14 to 15 days of collection, if stored at ambient temperature, and to reject the sample if it does not meet testing criteria for stability. Delayed FIT sample analysis has been associated with higher false-negative rates because of hemoglobin degradation.4 FIT sample exposure to high ambient temperatures also has been linked to decreased sensitivity for detecting CRC.5
US Postal Service (USPS) mail delivery delays have plagued many areas of the country. A variety of factors, including the COVID-19 pandemic, understaffing, changes in USPS policies, closure of post offices, and changes in mail delivery standards, may also be contributory causes. According to the USPS website, delivery standard for first-class mail is 1 to 5 days, but this is not guaranteed.6
The Jesse Brown Veterans Affairs Medical Center (JBVAMC) laboratory in Chicago has reported receiving FIT kit envelopes in batches by the USPS, with some prepaid first-class business reply envelopes delivered up to 60 days after the time of sample collection. Polymedco, a company that assists US Department of Veterans Affairs (VA) medical centers with logistics of FIT programs for CRC screening, reports that USPS batching of FIT kits leading to delayed delivery has been a periodic problem for medical centers around the country. Polymedco staff remind USPS staff about 4 points when they encounter this issue: Mailers are first-class mail; mailers contain a human biologic specimen that has limited viability; the biological sample used for detecting cancer is time sensitive; and delays in delivery by holding/batching kits could impact morbidity and mortality. Reviewing these key points with local USPS staff usually helps, however, batching and delayed delivery of the FIT kits can sometimes recur with USPS staffing turnover.
Tracking and identifying when a patient receives the FIT kit is difficult. Patients are instructed to write the date of collection on the kit, so the receiving laboratory knows whether the sample can be reliably analyzed. When patients are notified about delayed delivery of their sample, a staff member asks if they postponed dropping the kit in the mail. Most patients report mailing the sample within 1 to 2 days of collection. Tracking and dating each step of FIT kit events is not feasible with a mass mailing campaign. In our experience, most patients write the date of collection on the kit. If a collection date is not provided, the laboratory will call the patient to confirm a date. Cheng and colleagues reviewed the causes for FIT specimen rejection in a laboratory analyzing specimens for VA patients and found that 14% of submitted samples were rejected because the specimen was received > 14 days after collection, and 6% because the patient did not record the collection date. With a series of interventions aimed at reminding patients and improving laboratory procedures, rates of rejection for these 2 causes were reduced to < 4%.7 USPS delays were not identified as a factor or tracked in this study.
It is unclear why the USPS sometimes holds FIT kits at their facilities and then delivers large bins of them at the same time. Because FIT kits should be analyzed within 14 to 15 days of sample collection to assure reliable results, mail delivery delays can result in increased sample rejection. Based on the JBVAMC experience, up to 30% of submitted samples might need to be discarded when batched delivery takes place. In these cases, patients need to be contacted, informed of the problem, and asked to submit new kits. Understandably, patients are reluctant to repeat this type of testing, and we are concerned this could lead to reduced rates of CRC screening in affected communities.
As an alternative to discarding delayed samples, laboratories could report the results of delayed FIT kits with an added comment that “negative test results may be less reliable due to delayed processing,” but this approach would raise quality and medicolegal concerns. Clinicians have reached out to local USPS supervisory personnel with mixed results. Sometimes batching and delayed deliveries stop for a few months, only to resume without warning. Dropping off the sample directly at the laboratory is not a realistic option for most patients. Some patients can be convinced to submit another sample, some elect to switch to other CRC screening strategies, while others, unfortunately, decline further screening efforts.
Laboratory staff can be overwhelmed with having to process hundreds of samples in a short time frame, especially because there is no way of knowing when USPS will make a batched delivery. Laboratory capacities can limit staff at some facilities to performing analysis of only 10 tests at a time. The FIT kits should be delivered on a rolling basis and without delay so that the samples can be reliably analyzed with a predictable workload for the laboratory personnel and without unexpected surges.
When health care facilities identify delayed mail delivery of FIT kits via USPS, laboratories should first ensure that the correct postage rates are used on the prepaid envelopes and that their USPS accounts are properly funded, so that insufficient funds are not contributing to delayed deliveries. Stakeholders should then reach out to local USPS supervisory staff and request that the practice of batching the delivery of FIT kits be stopped. Educating USPS supervisory staff about concerns related to decreased test reliability associated with delayed mail delivery can be a persuasive argument. Adding additional language to the preprinted envelopes, such as “time sensitive,” may also be helpful. Unfortunately, the JBVAMC experience has been that the problem initially gets better after contacting the USPS, only to unexpectedly resurface months later. This cycle has been repeated several times in the past 2 years at JBVAMC.
All clinicians involved in CRC screening and treatment at institutions that use FIT kits need to be aware of the impact that local USPS delays can have on the reliability of these results. Health care systems should be prepared to implement mitigation strategies if they encounter significant delays with mail delivery. If delays cannot be reliably resolved by working with the local USPS staff, consider involving national USPS oversight bodies. And if the problems persist despite an attempt to work with the USPS, some institutions might find it feasible to offer drop boxes at their clinics and instruct patients to drop off FIT kits immediately following collection, in lieu of mailing them. Switching to private carriers is not a cost-effective alternative for most health care systems, and some may exclude rural areas. Depending on the local availability and capacity of endoscopists, some clinicians might prioritize referring patients for screening colonoscopies or screening flexible sigmoidoscopies, and might deemphasize FIT kits as a preferred option for CRC screening. CT colonography is an alternative screening method that is not as widely offered, nor as widely accepted at this time.
Conclusions
CRC screening is an essential part of preventive medicine, and the percentage of eligible patients screened is a well-established quality metric in primary care settings. Health care systems, clinicians, and laboratories must be vigilant to ensure that USPS delays in delivering FIT kits do not negatively impact their CRC screening programs. Facilities should actively monitor for delays in the return of FIT kits.
Despite the widespread use of mail-order pharmacies and the use of mail to communicate notifications about test results and follow-up appointments, unreliable or delayed mail delivery traditionally has not been considered a social determinant of health.8 This article highlights the impact delayed mail delivery can have on health outcomes. Disadvantaged communities in inner cities and rural areas have been disproportionately affected by the worsening performance of the USPS over the past few years.9 This represents an underappreciated public health concern in need of a sustainable solution.
Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States.1 In 2022, there were an estimated 151,030 new CRC cases and 52,580 deaths.1 Options for CRC screening of patients at average risk include stool tests (annual fecal immunochemical test [FIT], annual guaiac-based fecal occult blood test, or stool FIT-DNA test every 1 to 3 years), colonoscopies every 10 years, flexible sigmoidoscopies every 5 years (or every 10 years with annual FIT), and computed tomography (CT) colonography every 5 years.2 Many health care systems use annual FIT for patients at average risk. Compared with guaiac-based fecal occult blood testing, FIT does not require dietary or medication modifications and yields greater sensitivity and patient participation.3
The COVID-19 pandemic and staffing issues have caused a scheduling backlog for screening, diagnostic, and surveillance endoscopies at some medical centers. As a result, FIT has become the primary means of CRC screening at these institutions. FIT kits for home use are typically distributed to eligible patients at an office visit or by mail, and patients are then instructed to mail the kits back to the laboratory. For the test to be as sensitive as possible, FIT kit manufacturers advise laboratory analysis within 14 to 15 days of collection, if stored at ambient temperature, and to reject the sample if it does not meet testing criteria for stability. Delayed FIT sample analysis has been associated with higher false-negative rates because of hemoglobin degradation.4 FIT sample exposure to high ambient temperatures also has been linked to decreased sensitivity for detecting CRC.5
US Postal Service (USPS) mail delivery delays have plagued many areas of the country. A variety of factors, including the COVID-19 pandemic, understaffing, changes in USPS policies, closure of post offices, and changes in mail delivery standards, may also be contributory causes. According to the USPS website, delivery standard for first-class mail is 1 to 5 days, but this is not guaranteed.6
The Jesse Brown Veterans Affairs Medical Center (JBVAMC) laboratory in Chicago has reported receiving FIT kit envelopes in batches by the USPS, with some prepaid first-class business reply envelopes delivered up to 60 days after the time of sample collection. Polymedco, a company that assists US Department of Veterans Affairs (VA) medical centers with logistics of FIT programs for CRC screening, reports that USPS batching of FIT kits leading to delayed delivery has been a periodic problem for medical centers around the country. Polymedco staff remind USPS staff about 4 points when they encounter this issue: Mailers are first-class mail; mailers contain a human biologic specimen that has limited viability; the biological sample used for detecting cancer is time sensitive; and delays in delivery by holding/batching kits could impact morbidity and mortality. Reviewing these key points with local USPS staff usually helps, however, batching and delayed delivery of the FIT kits can sometimes recur with USPS staffing turnover.
Tracking and identifying when a patient receives the FIT kit is difficult. Patients are instructed to write the date of collection on the kit, so the receiving laboratory knows whether the sample can be reliably analyzed. When patients are notified about delayed delivery of their sample, a staff member asks if they postponed dropping the kit in the mail. Most patients report mailing the sample within 1 to 2 days of collection. Tracking and dating each step of FIT kit events is not feasible with a mass mailing campaign. In our experience, most patients write the date of collection on the kit. If a collection date is not provided, the laboratory will call the patient to confirm a date. Cheng and colleagues reviewed the causes for FIT specimen rejection in a laboratory analyzing specimens for VA patients and found that 14% of submitted samples were rejected because the specimen was received > 14 days after collection, and 6% because the patient did not record the collection date. With a series of interventions aimed at reminding patients and improving laboratory procedures, rates of rejection for these 2 causes were reduced to < 4%.7 USPS delays were not identified as a factor or tracked in this study.
It is unclear why the USPS sometimes holds FIT kits at their facilities and then delivers large bins of them at the same time. Because FIT kits should be analyzed within 14 to 15 days of sample collection to assure reliable results, mail delivery delays can result in increased sample rejection. Based on the JBVAMC experience, up to 30% of submitted samples might need to be discarded when batched delivery takes place. In these cases, patients need to be contacted, informed of the problem, and asked to submit new kits. Understandably, patients are reluctant to repeat this type of testing, and we are concerned this could lead to reduced rates of CRC screening in affected communities.
As an alternative to discarding delayed samples, laboratories could report the results of delayed FIT kits with an added comment that “negative test results may be less reliable due to delayed processing,” but this approach would raise quality and medicolegal concerns. Clinicians have reached out to local USPS supervisory personnel with mixed results. Sometimes batching and delayed deliveries stop for a few months, only to resume without warning. Dropping off the sample directly at the laboratory is not a realistic option for most patients. Some patients can be convinced to submit another sample, some elect to switch to other CRC screening strategies, while others, unfortunately, decline further screening efforts.
Laboratory staff can be overwhelmed with having to process hundreds of samples in a short time frame, especially because there is no way of knowing when USPS will make a batched delivery. Laboratory capacities can limit staff at some facilities to performing analysis of only 10 tests at a time. The FIT kits should be delivered on a rolling basis and without delay so that the samples can be reliably analyzed with a predictable workload for the laboratory personnel and without unexpected surges.
When health care facilities identify delayed mail delivery of FIT kits via USPS, laboratories should first ensure that the correct postage rates are used on the prepaid envelopes and that their USPS accounts are properly funded, so that insufficient funds are not contributing to delayed deliveries. Stakeholders should then reach out to local USPS supervisory staff and request that the practice of batching the delivery of FIT kits be stopped. Educating USPS supervisory staff about concerns related to decreased test reliability associated with delayed mail delivery can be a persuasive argument. Adding additional language to the preprinted envelopes, such as “time sensitive,” may also be helpful. Unfortunately, the JBVAMC experience has been that the problem initially gets better after contacting the USPS, only to unexpectedly resurface months later. This cycle has been repeated several times in the past 2 years at JBVAMC.
All clinicians involved in CRC screening and treatment at institutions that use FIT kits need to be aware of the impact that local USPS delays can have on the reliability of these results. Health care systems should be prepared to implement mitigation strategies if they encounter significant delays with mail delivery. If delays cannot be reliably resolved by working with the local USPS staff, consider involving national USPS oversight bodies. And if the problems persist despite an attempt to work with the USPS, some institutions might find it feasible to offer drop boxes at their clinics and instruct patients to drop off FIT kits immediately following collection, in lieu of mailing them. Switching to private carriers is not a cost-effective alternative for most health care systems, and some may exclude rural areas. Depending on the local availability and capacity of endoscopists, some clinicians might prioritize referring patients for screening colonoscopies or screening flexible sigmoidoscopies, and might deemphasize FIT kits as a preferred option for CRC screening. CT colonography is an alternative screening method that is not as widely offered, nor as widely accepted at this time.
Conclusions
CRC screening is an essential part of preventive medicine, and the percentage of eligible patients screened is a well-established quality metric in primary care settings. Health care systems, clinicians, and laboratories must be vigilant to ensure that USPS delays in delivering FIT kits do not negatively impact their CRC screening programs. Facilities should actively monitor for delays in the return of FIT kits.
Despite the widespread use of mail-order pharmacies and the use of mail to communicate notifications about test results and follow-up appointments, unreliable or delayed mail delivery traditionally has not been considered a social determinant of health.8 This article highlights the impact delayed mail delivery can have on health outcomes. Disadvantaged communities in inner cities and rural areas have been disproportionately affected by the worsening performance of the USPS over the past few years.9 This represents an underappreciated public health concern in need of a sustainable solution.
1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. doi:10.3322/caac.21708
2. Centers for Disease Control and Prevention. Colorectal cancer screening tests. Updated February 23, 2023. Accessed March 14, 2024. https://www.cdc.gov/cancer/colorectal/basic_info/screening/tests.htm
3. van Rossum LG, van Rijn AF, Laheij RJ, et al. Random comparison of guaiac and immunochemical fecal occult blood tests for colorectal cancer in a screening population. Gastroenterology. 2008;135(1):82-90. doi:10.1053/j.gastro.2008.03.040
4. van Rossum LG, van Rijn AF, van Oijen MG, et al. False negative fecal occult blood tests due to delayed sample return in colorectal cancer screening. Int J Cancer. 2009;125(4):746-750. doi:10.1002/ijc.24458
5. Doubeni CA, Jensen CD, Fedewa SA, et al. Fecal immunochemical test (FIT) for colon cancer screening: variable performance with ambient temperature. J Am Board Fam Med. 2016;29(6):672-681. doi:10.3122/jabfm.2016.06.160060
6. United States Postal Service. Shipping and mailing with USPS. Accessed March 14, 2024. https://www.usps.com/ship
7. Cheng C, Ganz DA, Chang ET, Huynh A, De Peralta S. Reducing rejected fecal immunochemical tests received in the laboratory for colorectal cancer screening. J Healthc Qual. 2019;41(2):75-82.doi:10.1097/JHQ.0000000000000181
8. Hussaini SMQ, Alexander GC. The United States Postal Service: an essential public health agency? J Gen Intern Med. 2020;35(12):3699-3701. doi:10.1007/s11606-020-06275-2
9. Hampton DJ. Colorado mountain towns are plagued by post office delays as residents wait weeks for medication and retirement checks. NBC News. February 25, 2023. Accessed March 14, 2024. https://www.nbcnews.com/news/us-news/colo-mountain-towns-are-plagued-post-office-delays-residents-wait-week-rcna72085
1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. doi:10.3322/caac.21708
2. Centers for Disease Control and Prevention. Colorectal cancer screening tests. Updated February 23, 2023. Accessed March 14, 2024. https://www.cdc.gov/cancer/colorectal/basic_info/screening/tests.htm
3. van Rossum LG, van Rijn AF, Laheij RJ, et al. Random comparison of guaiac and immunochemical fecal occult blood tests for colorectal cancer in a screening population. Gastroenterology. 2008;135(1):82-90. doi:10.1053/j.gastro.2008.03.040
4. van Rossum LG, van Rijn AF, van Oijen MG, et al. False negative fecal occult blood tests due to delayed sample return in colorectal cancer screening. Int J Cancer. 2009;125(4):746-750. doi:10.1002/ijc.24458
5. Doubeni CA, Jensen CD, Fedewa SA, et al. Fecal immunochemical test (FIT) for colon cancer screening: variable performance with ambient temperature. J Am Board Fam Med. 2016;29(6):672-681. doi:10.3122/jabfm.2016.06.160060
6. United States Postal Service. Shipping and mailing with USPS. Accessed March 14, 2024. https://www.usps.com/ship
7. Cheng C, Ganz DA, Chang ET, Huynh A, De Peralta S. Reducing rejected fecal immunochemical tests received in the laboratory for colorectal cancer screening. J Healthc Qual. 2019;41(2):75-82.doi:10.1097/JHQ.0000000000000181
8. Hussaini SMQ, Alexander GC. The United States Postal Service: an essential public health agency? J Gen Intern Med. 2020;35(12):3699-3701. doi:10.1007/s11606-020-06275-2
9. Hampton DJ. Colorado mountain towns are plagued by post office delays as residents wait weeks for medication and retirement checks. NBC News. February 25, 2023. Accessed March 14, 2024. https://www.nbcnews.com/news/us-news/colo-mountain-towns-are-plagued-post-office-delays-residents-wait-week-rcna72085
Management of Rodenticide Poisoning Associated with Synthetic Cannabinoids
Between March 7, 2018, and May 9, 2018, at least 164 people in Illinois were sickened by synthetic cannabinoids laced with rodenticides. The Illinois Department of Public Health has reported 4 deaths connected with the use of synthetic cannabinoids (sold under names such as Spice, K2, Legal Weed, etc).1 Synthetic cannabinoids are mind-altering chemicals that are sprayed on dried plant material and often sold at convenience stores. Some users have reported smoking these substances because they are generally not detected by standard urine toxicology tests.
Recreational use of synthetic cannabinoids can lead to serious and, at times, deadly complications. Chemicals found in rat poison have contaminated batches of synthetic cannabinoids, leading to coagulopathy and severe bleeding. Affected patients have reported hemoptysis, hematuria, severe epistaxis, bleeding gums, conjunctival hemorrhages, and gastrointestinal bleeding. The following case is of a patient who presented to an emergency department (ED) with severe coagulopathy and cardiotoxicity after using an adulterated synthetic cannabinoid product.
Case Presentation
A 65-year-old man presented to the ED reporting hematochezia, hematuria, and hemoptysis. He reported that these symptoms began about 1 day after he had smoked a synthetic cannabinoid called K2. The patient stated that some of his friends who used the same product were experiencing similar symptoms. He reported mild generalized abdominal pain but reported no chest pain, dyspnea, headache, fevers, chills, or dysuria.
The patient’s past medical history included hypertension, dyslipidemia, chronic lower back pain, and vitamin D deficiency. His past surgical history was notable for an exploratory laparotomy after a stab wound to the abdomen. The patient reported taking the following medications: morphine SA 30 mg bid, meloxicam 15 mg daily, amitriptyline 100 mg qhs, amlodipine 5 mg daily, hydrocodone/acetaminophen 5/325 mg q12h prn, atorvastatin 20 mg qhs, omeprazole 20 mg qam, senna 187 mg daily prn, psyllium 1 packet dissolved in water daily prn, and cholecalciferol 1,000 IU daily.
The patient’s temperature was 98o F, blood pressure, 144/80 mm Hg; pulse, 131 beats per minute; respiratory rate, 18 breaths per minute; and O2 saturation, 98% (ambient air). A physical examination revealed no acute distress; he was coughing up blood; clear lungs; heart sounds were tachycardic and irregularly irregular; soft, nondistended, mild generalized tenderness in the abdomen with no guarding and no rebound. The pertinent laboratory tests were international normalized ratio (INR), > 20; prothrombin time, > 150 seconds; prothrombin thromboplastin time, 157 seconds; hemoglobin, 13.3 g/dL; platelet count, 195 k/uL; white blood count, 11.3 k/uL; creatinine, 0.57mg/dL; potassium, 3.8 mmol/L, D-dimertest, 0.87 ug/mL fibrinogen equivalent units; fibrinogen level, 624 mg/dL; troponin, < 0.04 ng/mL; lactic acid, 1.3 mmol/L; total bilirubin, 0.8 mg/dL; alanine aminotransferase, 22 U/L, aspartate aminotransferase, 22 U/L; alkaline phosphatase, 89 U/L; urinalysis with > 50 red blood cells/high power field; large blood, negative leukocyte esterase, negative nitrite. The patient’s urine toxicology was negative for cannabinoids, methadone, amphetamines, cocaine, and benzodiazepines; but was positive for opiates. An anticoagulant poisoning panel also was ordered.
An electrocardiogram (ECG) and imaging studies were ordered. The ECG showed atrial fibrillation (AF) with rapid ventricular response (Figure 1). A chest X-ray indicated bibasilar consolidations that were worse on the right side. A noncontrast computed tomography (CT) of the head did not show intracranial bleeding. An abdomen/pelvis CT showed bilateral diffuse patchy peribronchovascular ground-glass opacities in the lung bases that could represent pulmonary hemorrhage, but no peritoneal or retroperitoneal bleeding.
Treatment
In the ED, the case was discussed with the Illinois Poison Control Center. The patient was diagnosed with coagulopathy likely due to anticoagulant poisoning. He was immediately treated with 10 mg of IV vitamin K, a fixed dose of 2,000 units of 4-factor prothrombin complex concentrate, and 4 units of fresh frozen plasma. His INR improved to 1.42 within several hours. He received 5 mg of IV metoprolol for uncontrolled AF and was admitted to the intensive care unit (ICU) for further care.
In the ICU the patient was started on oral vitamin K 50 mg tid for ongoing treatment of coagulopathy due to concern for possible rodenticide poisoning associated with very long half-life. This dose was then decreased to 50 mg bid. He was given IV fluid resuscitation with normal saline and started on rate control for AF with oral metoprolol. His heart rate improved. An echocardiogram showed new cardiomyopathy with an ejection fraction of 25% to 30%. Given basilar infiltrates and 1 episode of low-grade fever, he was started on ceftriaxone for possible community-acquired pneumonia. The patient was started on cholestyramine to help with washout of the possible rodenticide. No endoscopic interventions were performed.
The patient was transferred to an inpatient telemetry floor 24 hours after admission to the ICU once his tachycardia and bleeding improved. He did not require transfusion of packed red blood cells. In the ICU his INR had ranged between 1.62 and 2.46 (down from > 20 in the ED). His hemoglobin dropped from 13.3 g/dL on admission to 12 g/dL on transfer from the ICU, before stabilizing around 11 g/dL on the floor. The patient’s heart rate required better control, so metoprolol was increased to a total daily dose of 200 mg on the telemetry floor. Oral digoxin was then added after a digoxin load for additional rate control, as the patient remained tachycardic. Twice a day the patient continued to take 50 mg vitamin K. Cholestyramine and ceftriaxone were initially continued, but when the INR started increasing again, the cholestyramine was stopped to allow for an increase to more frequent 3-times daily vitamin 50 mg K administration (cholestyramine can interfere with vitamin K absorption). According to the toxicology service, there was only weak evidence to support use of cholestyramine in this setting.
Given his ongoing mild hemoptysis, the patient received first 1 unit, and then another 4 units of FFP when the INR increased to 3.96 despite oral vitamin K. After FFP, the INR decreased to 1.93 and subsequently to 1.52. A CT of the chest showed patchy ground-glass densities throughout the lungs, predominantly at the lung bases and to a lesser extent in the upper lobes. The findings were felt to represent pulmonary hemorrhage given the patient’s history of hemoptysis (Figure 2). 
The patient’s heart rate control improved, and he remained hemodynamically stable. A thyroid function test was within normal limits. Lisinopril was added to metoprolol and digoxin given his newly diagnosed cardiomyopathy. The patient was observed for a total of 4 days on the inpatient floor and discharged after his INR stabilized around 1.5 on twice daily 50 mg vitamin K. The patient’s hematuria and hematochezia completely resolved, and hemoptysis was much improved at the time of discharge. His hemoglobin remained stable. The anticoagulant poisoning panel came back positive for
The patient has remained in AF at all follow-up visits. The INR normalized by 6 weeks after hospital discharge, and the dose of vitamin K slowly was tapered with close monitoring of the INR. Vitamin K was tapered for about 6 months after his initial presentation, and the patient was started on a direct oral anticoagulant (DOAC) for anticoagulation when the INR remained stable off vitamin K. He subsequently underwent a transesophageal echocardiogram followed by an attempt at direct current (DC) cardioversion; however, he did not remain in sinus rhythm, and is being continued on anticoagulation and rate control for his AF.
Discussion
Users generally smoke synthetic cannabinoids, which produce cannabis-like effects. However, atypical intoxication effects with worse complications often occur.2 These products typically contain dried shredded plant material that is soaked in or sprayed with several synthetic cannabinoids, varying in dosage and combination.3 Synthetic cannabinoids have been associated with serious adverse effects (AEs), including drowsiness, light-headedness, and fast or irregular heartbeat.4 More severe clinical features such as psychosis, delirium, cardiotoxicity, seizures, rhabdomyolysis, acute kidney injury, hyperthermia, myocardial ischemia, ischemic strokes, and death have also been noted.4
It is not known how some batches of synthetic cannabinoids came to be contaminated with rat poison or how commonly such an adulteration is found across the country. Several different guidelines provide pathways for the treatment of acute bleeding in the setting of coagulopathy due to vitamin K antagonists.5,6 Each guideline divides the indications for reversal into either severity of bleeding or the criticality of the bleeding based on location.5,6 All guidelines recommend the use of vitamin K (either oral or IV) followed by FFP or 4-factor prothrombin complex concentrate (PCC) for more severe bleeding.5,6 However, recommendations regarding the use of PCC vary in dosing for vitamin K antagonists (in contrast to treatment of coagulopathy due to DOACs). Recent studies and guidelines suggest that fixed-dose (rather than weight-based dose) PCC is effective for the reversal of coagulopathy due to vitamin K antagonists.6,7 Using fixed rather than weight-based dosing decreases cost and may decrease the possibility of thrombotic AEs.7 In this patient, a fixed-dose of 2,000 units of PCC was given based on data that were extrapolated from warfarin reversal using PCC.7
The vitamin K antagonists that adulterated this patient’s synthetic cannabinoid were difenacoum and brodifacoum, which are 4-hydroxycoumarin derivatives. These are second-generation long-acting anticoagulant rodenticides (LAARs) that are about 100 times more potent than warfarin.8 As the name implies, LAARs have a longer duration of action in the body of any organism that ingests the poison, which is due to the highly lipophilic groups that have been added to the warfarin molecule to combat resistance in rodents.9
As a result of the deposition in the tissues, there have been reports of the duration of action of brodifacoum ranging from 51 days to 9 months after ingestion, with the latter caused by an intentional overdose in a human.9-12 Reports suggest that coagulopathy is not likely to occur when the serum brodifacoum concentration is < 10 ng/mL.13,14 Animal models show difenacoum has a tissue half-life of about 62 days.15 Reports of difenacoum poisoning in humans have shown variable lengths of treatment, ranging from 30 to 47 days.16-18 The length of treatment for either brodifacoum or difenacoum will depend on the amount of poison exposure.
The long duration of action and treatment duration may lead to problems with drug procurement, especially in the early phase of treatment in which IV vitamin K is used. The supply of IV vitamin K recently has been limited for at least some manufacturers. According to the American Society of Health System Pharmacists Current Drug Shortage List, the increased demand is thought to be due to increased use of synthetic inhaled cannabinoids laced with anticoagulant.19 IV vitamin K products are available from suppliers such as Amphastar (Rancho Cucamonga, CA) and Hospira (Lake Forest, IL).
The American College of Chest Physicians recommends IV vitamin K administration in patients with major bleeding secondary to vitamin K antagonists.20 The oral route is thought to be more effective than a subcutaneous route in the treatment of nonbleeding patients with rodenticide-associated coagulopathy. Due to erratic and unpredictable absorption, the subcutaneous route of administration has fallen out of favor. Oral vitamin K products were not affected by the recent shortage. However, large doses of oral vitamin K can be costly. Due to the long half-life of LAAR, many patients are discharged with a prescription for oral vitamin K. Although vitamin K is found in most over-the-counter (OTC) multivitamins, the strength is insufficient. Most OTC formulations are ≤ 100 μg, whereas the prescription strength is 5 mg, but patients being treated for rodenticide poisoning require much larger doses.
Commercial insurance carriers and Medicare Part D usually do not cover vitamins and minerals unless it is for a medically accepted indication or is an indication supported by citation in either the American Hospital Formulary System, United States Pharmacopeia drug information book, or an electronic information resource that is supported by evidence such as Micromedex.21 For a patient without insurance coverage being treated with high-dose vitamin K therapy for rodenticide poisoning outside of a federal health care system, the cost could be as high as $500 to $1,000 per day, depending on the dose of vitamin K needed to maintain an acceptable INR.
Conclusion
In addition to bleeding as a result of coagulopathy, this patient presented with new onset of AF with rapid ventricular response and a newly diagnosed cardiomyopathy. Although the patient had other cardiovascular risk factors, such as hypertension, dyslipidemia, and a remote history of cocaine use, it is likely that the use of the synthetic cannabinoids contributed to the development and/or worsening of this arrhythmia and cardiomyopathy. The patient remained in AF 6 weeks after hospital discharge with a controlled ventricular rate on metoprolol and digoxin. An interval echocardiogram 6 weeks after hospital discharge showed a recovered ejection fraction. In cases of tachycardia-induced cardiomyopathy, the ejection fraction often recovers with control of the tachycardia. The patient was weaned off vitamin K about 6 months after his initial presentation and started on a DOAC for anticoagulation. He subsequently underwent a transesophageal echocardiogram followed by an attempt at DC cardioversion; however, he did not remain in sinus rhythm and is being continued on anticoagulation and rate control for his AF.
Although unclear how synthetic cannabinoids became adulterated with a potent vitamin K antagonist, health care practitioners should consider this if a patient presents with unexplained coagulopathy and widespread bleeding. Fixed-dose PCC should be considered as an alternative to weight-based dosing in these cases. Physicians and pharmacy personnel should anticipate a need for long-term high doses of vitamin K in order to begin work early to obtain sufficient supplies to treat presenting patients.
1. Illinois Department of Public Health. Synthetic cannabinoids. http://dph.illinois.gov/topics-services/prevention-wellness/medical-cannabis/synthetic-cannabinoids. Updated May 30, 2018. Accessed April 8, 2019.
2. Tournebize J, Gibaja V, Kahn JP. Acute effects of synthetic cannabinoids: update 2015. Subst Abus. 2017;38(3):344-366.
3. United Nations Office on Drugs and Crime. Global SMART update. https://www.unodc.org/documents/scientific/Global_SMART_Update_13_web.pdf. Published March 2015. Accessed April 8, 2019.
4. Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R, “Zombie” outbreak caused by the synthetic cannabinoid AMB-FUBINACA in New York. N Engl J Med. 2017;376(3):235-242.
5. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067.
6. Cushman M, Lim W, Zakai NA. 2011 Clinical Practice guide on anticoagulant dosing and management of anticoagulant-associated bleeding complications in adults. http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Ref/525.aspx. Published 2011. Accessed April 8, 2019.
7. Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med. 2015;33(9):1213-1218.
8. Bachmann KA, Sullivan TJ. Dispositional and pharmacodynamic characteristics of brodifacoum in warfarin-sensitive rats. Pharmacology. 1983;27(5):281-288.
9. Lipton RA, Klass EM. Human ingestion of ‘superwarfarin’ rodenticide resulting in a prolonged anticoagulant effect. JAMA. 1984;252(21):3004-3005.
10. Chong LL, Chau WK, Ho CH. A case of ‘superwarfarin’ poisoning. Scand J Haematol. 1986;36(3):314-331.
11. Jones EC, Growe GH, Naiman SC. Prolonged anticoagulation in rat poisoning. JAMA. 1984;252(21):3005-3007.
12. Babcock J, Hartman K, Pedersen A, Murphy M, Alving B. Rodenticide-induced coagulopathy in a young child. A case of Munchausen syndrome by proxy. Am J Pediatr Hematol Oncol. 1993;15(1):126-130.
13. Hollinger BR, Pastoor TP. Case management and plasma half-life in a case of brodifacoum poisoning. Arch Intern Med. 1993;153(16):1925-1928.
14. Bruno GR, Howland MA, McMeeking A, Hoffman RS. Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med. 2000;36(3):262-267.
15. Vandenbrouke V, Bousquet-Meloua A, De Backer P, Croubels S. Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration. J Vet Pharmacol Ther. 2008;31(5):437-445.
16. Barlow AM, Gay AL, Park BK. Difenacoum (Neosorexa) poisoning. Br Med J (Clin Res Ed). 1982;285(6341):541.
17. Katona B, Wason S. Superwarfarin poisoning. J Emerg Med. 1989;7(6):627-631.
18. Butcher GP, Shearer MJ, MacNicoll AD, Kelly MJ, Ind PW. Difenacoum poisoning as a cause of haematuria. Hum Exp Toxicol. 1992;11(6):553-554.
19. American Society of Health System Pharmacists. Current drug shortages. Vitamin K (phytonadione) injection. https://www.ashp.org/drug-shortages/current-shortages/Drug-Shortage-Detail.aspx?id=100. Updated July 5, 2018. Accessed April 8, 2019.
20. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e152S-e184S.
21. Centers for Medicare and Medicaid Services. Part D Excluded Drugs. https://www.medicareadvocacy.org/old-site/News/Archives/PartD_ExcludedDrugsByState.htm. Accessed on August 23, 2018.
Between March 7, 2018, and May 9, 2018, at least 164 people in Illinois were sickened by synthetic cannabinoids laced with rodenticides. The Illinois Department of Public Health has reported 4 deaths connected with the use of synthetic cannabinoids (sold under names such as Spice, K2, Legal Weed, etc).1 Synthetic cannabinoids are mind-altering chemicals that are sprayed on dried plant material and often sold at convenience stores. Some users have reported smoking these substances because they are generally not detected by standard urine toxicology tests.
Recreational use of synthetic cannabinoids can lead to serious and, at times, deadly complications. Chemicals found in rat poison have contaminated batches of synthetic cannabinoids, leading to coagulopathy and severe bleeding. Affected patients have reported hemoptysis, hematuria, severe epistaxis, bleeding gums, conjunctival hemorrhages, and gastrointestinal bleeding. The following case is of a patient who presented to an emergency department (ED) with severe coagulopathy and cardiotoxicity after using an adulterated synthetic cannabinoid product.
Case Presentation
A 65-year-old man presented to the ED reporting hematochezia, hematuria, and hemoptysis. He reported that these symptoms began about 1 day after he had smoked a synthetic cannabinoid called K2. The patient stated that some of his friends who used the same product were experiencing similar symptoms. He reported mild generalized abdominal pain but reported no chest pain, dyspnea, headache, fevers, chills, or dysuria.
The patient’s past medical history included hypertension, dyslipidemia, chronic lower back pain, and vitamin D deficiency. His past surgical history was notable for an exploratory laparotomy after a stab wound to the abdomen. The patient reported taking the following medications: morphine SA 30 mg bid, meloxicam 15 mg daily, amitriptyline 100 mg qhs, amlodipine 5 mg daily, hydrocodone/acetaminophen 5/325 mg q12h prn, atorvastatin 20 mg qhs, omeprazole 20 mg qam, senna 187 mg daily prn, psyllium 1 packet dissolved in water daily prn, and cholecalciferol 1,000 IU daily.
The patient’s temperature was 98o F, blood pressure, 144/80 mm Hg; pulse, 131 beats per minute; respiratory rate, 18 breaths per minute; and O2 saturation, 98% (ambient air). A physical examination revealed no acute distress; he was coughing up blood; clear lungs; heart sounds were tachycardic and irregularly irregular; soft, nondistended, mild generalized tenderness in the abdomen with no guarding and no rebound. The pertinent laboratory tests were international normalized ratio (INR), > 20; prothrombin time, > 150 seconds; prothrombin thromboplastin time, 157 seconds; hemoglobin, 13.3 g/dL; platelet count, 195 k/uL; white blood count, 11.3 k/uL; creatinine, 0.57mg/dL; potassium, 3.8 mmol/L, D-dimertest, 0.87 ug/mL fibrinogen equivalent units; fibrinogen level, 624 mg/dL; troponin, < 0.04 ng/mL; lactic acid, 1.3 mmol/L; total bilirubin, 0.8 mg/dL; alanine aminotransferase, 22 U/L, aspartate aminotransferase, 22 U/L; alkaline phosphatase, 89 U/L; urinalysis with > 50 red blood cells/high power field; large blood, negative leukocyte esterase, negative nitrite. The patient’s urine toxicology was negative for cannabinoids, methadone, amphetamines, cocaine, and benzodiazepines; but was positive for opiates. An anticoagulant poisoning panel also was ordered.
An electrocardiogram (ECG) and imaging studies were ordered. The ECG showed atrial fibrillation (AF) with rapid ventricular response (Figure 1). A chest X-ray indicated bibasilar consolidations that were worse on the right side. A noncontrast computed tomography (CT) of the head did not show intracranial bleeding. An abdomen/pelvis CT showed bilateral diffuse patchy peribronchovascular ground-glass opacities in the lung bases that could represent pulmonary hemorrhage, but no peritoneal or retroperitoneal bleeding.
Treatment
In the ED, the case was discussed with the Illinois Poison Control Center. The patient was diagnosed with coagulopathy likely due to anticoagulant poisoning. He was immediately treated with 10 mg of IV vitamin K, a fixed dose of 2,000 units of 4-factor prothrombin complex concentrate, and 4 units of fresh frozen plasma. His INR improved to 1.42 within several hours. He received 5 mg of IV metoprolol for uncontrolled AF and was admitted to the intensive care unit (ICU) for further care.
In the ICU the patient was started on oral vitamin K 50 mg tid for ongoing treatment of coagulopathy due to concern for possible rodenticide poisoning associated with very long half-life. This dose was then decreased to 50 mg bid. He was given IV fluid resuscitation with normal saline and started on rate control for AF with oral metoprolol. His heart rate improved. An echocardiogram showed new cardiomyopathy with an ejection fraction of 25% to 30%. Given basilar infiltrates and 1 episode of low-grade fever, he was started on ceftriaxone for possible community-acquired pneumonia. The patient was started on cholestyramine to help with washout of the possible rodenticide. No endoscopic interventions were performed.
The patient was transferred to an inpatient telemetry floor 24 hours after admission to the ICU once his tachycardia and bleeding improved. He did not require transfusion of packed red blood cells. In the ICU his INR had ranged between 1.62 and 2.46 (down from > 20 in the ED). His hemoglobin dropped from 13.3 g/dL on admission to 12 g/dL on transfer from the ICU, before stabilizing around 11 g/dL on the floor. The patient’s heart rate required better control, so metoprolol was increased to a total daily dose of 200 mg on the telemetry floor. Oral digoxin was then added after a digoxin load for additional rate control, as the patient remained tachycardic. Twice a day the patient continued to take 50 mg vitamin K. Cholestyramine and ceftriaxone were initially continued, but when the INR started increasing again, the cholestyramine was stopped to allow for an increase to more frequent 3-times daily vitamin 50 mg K administration (cholestyramine can interfere with vitamin K absorption). According to the toxicology service, there was only weak evidence to support use of cholestyramine in this setting.
Given his ongoing mild hemoptysis, the patient received first 1 unit, and then another 4 units of FFP when the INR increased to 3.96 despite oral vitamin K. After FFP, the INR decreased to 1.93 and subsequently to 1.52. A CT of the chest showed patchy ground-glass densities throughout the lungs, predominantly at the lung bases and to a lesser extent in the upper lobes. The findings were felt to represent pulmonary hemorrhage given the patient’s history of hemoptysis (Figure 2).
The patient’s heart rate control improved, and he remained hemodynamically stable. A thyroid function test was within normal limits. Lisinopril was added to metoprolol and digoxin given his newly diagnosed cardiomyopathy. The patient was observed for a total of 4 days on the inpatient floor and discharged after his INR stabilized around 1.5 on twice daily 50 mg vitamin K. The patient’s hematuria and hematochezia completely resolved, and hemoptysis was much improved at the time of discharge. His hemoglobin remained stable. The anticoagulant poisoning panel came back positive for
The patient has remained in AF at all follow-up visits. The INR normalized by 6 weeks after hospital discharge, and the dose of vitamin K slowly was tapered with close monitoring of the INR. Vitamin K was tapered for about 6 months after his initial presentation, and the patient was started on a direct oral anticoagulant (DOAC) for anticoagulation when the INR remained stable off vitamin K. He subsequently underwent a transesophageal echocardiogram followed by an attempt at direct current (DC) cardioversion; however, he did not remain in sinus rhythm, and is being continued on anticoagulation and rate control for his AF.
Discussion
Users generally smoke synthetic cannabinoids, which produce cannabis-like effects. However, atypical intoxication effects with worse complications often occur.2 These products typically contain dried shredded plant material that is soaked in or sprayed with several synthetic cannabinoids, varying in dosage and combination.3 Synthetic cannabinoids have been associated with serious adverse effects (AEs), including drowsiness, light-headedness, and fast or irregular heartbeat.4 More severe clinical features such as psychosis, delirium, cardiotoxicity, seizures, rhabdomyolysis, acute kidney injury, hyperthermia, myocardial ischemia, ischemic strokes, and death have also been noted.4
It is not known how some batches of synthetic cannabinoids came to be contaminated with rat poison or how commonly such an adulteration is found across the country. Several different guidelines provide pathways for the treatment of acute bleeding in the setting of coagulopathy due to vitamin K antagonists.5,6 Each guideline divides the indications for reversal into either severity of bleeding or the criticality of the bleeding based on location.5,6 All guidelines recommend the use of vitamin K (either oral or IV) followed by FFP or 4-factor prothrombin complex concentrate (PCC) for more severe bleeding.5,6 However, recommendations regarding the use of PCC vary in dosing for vitamin K antagonists (in contrast to treatment of coagulopathy due to DOACs). Recent studies and guidelines suggest that fixed-dose (rather than weight-based dose) PCC is effective for the reversal of coagulopathy due to vitamin K antagonists.6,7 Using fixed rather than weight-based dosing decreases cost and may decrease the possibility of thrombotic AEs.7 In this patient, a fixed-dose of 2,000 units of PCC was given based on data that were extrapolated from warfarin reversal using PCC.7
The vitamin K antagonists that adulterated this patient’s synthetic cannabinoid were difenacoum and brodifacoum, which are 4-hydroxycoumarin derivatives. These are second-generation long-acting anticoagulant rodenticides (LAARs) that are about 100 times more potent than warfarin.8 As the name implies, LAARs have a longer duration of action in the body of any organism that ingests the poison, which is due to the highly lipophilic groups that have been added to the warfarin molecule to combat resistance in rodents.9
As a result of the deposition in the tissues, there have been reports of the duration of action of brodifacoum ranging from 51 days to 9 months after ingestion, with the latter caused by an intentional overdose in a human.9-12 Reports suggest that coagulopathy is not likely to occur when the serum brodifacoum concentration is < 10 ng/mL.13,14 Animal models show difenacoum has a tissue half-life of about 62 days.15 Reports of difenacoum poisoning in humans have shown variable lengths of treatment, ranging from 30 to 47 days.16-18 The length of treatment for either brodifacoum or difenacoum will depend on the amount of poison exposure.
The long duration of action and treatment duration may lead to problems with drug procurement, especially in the early phase of treatment in which IV vitamin K is used. The supply of IV vitamin K recently has been limited for at least some manufacturers. According to the American Society of Health System Pharmacists Current Drug Shortage List, the increased demand is thought to be due to increased use of synthetic inhaled cannabinoids laced with anticoagulant.19 IV vitamin K products are available from suppliers such as Amphastar (Rancho Cucamonga, CA) and Hospira (Lake Forest, IL).
The American College of Chest Physicians recommends IV vitamin K administration in patients with major bleeding secondary to vitamin K antagonists.20 The oral route is thought to be more effective than a subcutaneous route in the treatment of nonbleeding patients with rodenticide-associated coagulopathy. Due to erratic and unpredictable absorption, the subcutaneous route of administration has fallen out of favor. Oral vitamin K products were not affected by the recent shortage. However, large doses of oral vitamin K can be costly. Due to the long half-life of LAAR, many patients are discharged with a prescription for oral vitamin K. Although vitamin K is found in most over-the-counter (OTC) multivitamins, the strength is insufficient. Most OTC formulations are ≤ 100 μg, whereas the prescription strength is 5 mg, but patients being treated for rodenticide poisoning require much larger doses.
Commercial insurance carriers and Medicare Part D usually do not cover vitamins and minerals unless it is for a medically accepted indication or is an indication supported by citation in either the American Hospital Formulary System, United States Pharmacopeia drug information book, or an electronic information resource that is supported by evidence such as Micromedex.21 For a patient without insurance coverage being treated with high-dose vitamin K therapy for rodenticide poisoning outside of a federal health care system, the cost could be as high as $500 to $1,000 per day, depending on the dose of vitamin K needed to maintain an acceptable INR.
Conclusion
In addition to bleeding as a result of coagulopathy, this patient presented with new onset of AF with rapid ventricular response and a newly diagnosed cardiomyopathy. Although the patient had other cardiovascular risk factors, such as hypertension, dyslipidemia, and a remote history of cocaine use, it is likely that the use of the synthetic cannabinoids contributed to the development and/or worsening of this arrhythmia and cardiomyopathy. The patient remained in AF 6 weeks after hospital discharge with a controlled ventricular rate on metoprolol and digoxin. An interval echocardiogram 6 weeks after hospital discharge showed a recovered ejection fraction. In cases of tachycardia-induced cardiomyopathy, the ejection fraction often recovers with control of the tachycardia. The patient was weaned off vitamin K about 6 months after his initial presentation and started on a DOAC for anticoagulation. He subsequently underwent a transesophageal echocardiogram followed by an attempt at DC cardioversion; however, he did not remain in sinus rhythm and is being continued on anticoagulation and rate control for his AF.
Although unclear how synthetic cannabinoids became adulterated with a potent vitamin K antagonist, health care practitioners should consider this if a patient presents with unexplained coagulopathy and widespread bleeding. Fixed-dose PCC should be considered as an alternative to weight-based dosing in these cases. Physicians and pharmacy personnel should anticipate a need for long-term high doses of vitamin K in order to begin work early to obtain sufficient supplies to treat presenting patients.
Between March 7, 2018, and May 9, 2018, at least 164 people in Illinois were sickened by synthetic cannabinoids laced with rodenticides. The Illinois Department of Public Health has reported 4 deaths connected with the use of synthetic cannabinoids (sold under names such as Spice, K2, Legal Weed, etc).1 Synthetic cannabinoids are mind-altering chemicals that are sprayed on dried plant material and often sold at convenience stores. Some users have reported smoking these substances because they are generally not detected by standard urine toxicology tests.
Recreational use of synthetic cannabinoids can lead to serious and, at times, deadly complications. Chemicals found in rat poison have contaminated batches of synthetic cannabinoids, leading to coagulopathy and severe bleeding. Affected patients have reported hemoptysis, hematuria, severe epistaxis, bleeding gums, conjunctival hemorrhages, and gastrointestinal bleeding. The following case is of a patient who presented to an emergency department (ED) with severe coagulopathy and cardiotoxicity after using an adulterated synthetic cannabinoid product.
Case Presentation
A 65-year-old man presented to the ED reporting hematochezia, hematuria, and hemoptysis. He reported that these symptoms began about 1 day after he had smoked a synthetic cannabinoid called K2. The patient stated that some of his friends who used the same product were experiencing similar symptoms. He reported mild generalized abdominal pain but reported no chest pain, dyspnea, headache, fevers, chills, or dysuria.
The patient’s past medical history included hypertension, dyslipidemia, chronic lower back pain, and vitamin D deficiency. His past surgical history was notable for an exploratory laparotomy after a stab wound to the abdomen. The patient reported taking the following medications: morphine SA 30 mg bid, meloxicam 15 mg daily, amitriptyline 100 mg qhs, amlodipine 5 mg daily, hydrocodone/acetaminophen 5/325 mg q12h prn, atorvastatin 20 mg qhs, omeprazole 20 mg qam, senna 187 mg daily prn, psyllium 1 packet dissolved in water daily prn, and cholecalciferol 1,000 IU daily.
The patient’s temperature was 98o F, blood pressure, 144/80 mm Hg; pulse, 131 beats per minute; respiratory rate, 18 breaths per minute; and O2 saturation, 98% (ambient air). A physical examination revealed no acute distress; he was coughing up blood; clear lungs; heart sounds were tachycardic and irregularly irregular; soft, nondistended, mild generalized tenderness in the abdomen with no guarding and no rebound. The pertinent laboratory tests were international normalized ratio (INR), > 20; prothrombin time, > 150 seconds; prothrombin thromboplastin time, 157 seconds; hemoglobin, 13.3 g/dL; platelet count, 195 k/uL; white blood count, 11.3 k/uL; creatinine, 0.57mg/dL; potassium, 3.8 mmol/L, D-dimertest, 0.87 ug/mL fibrinogen equivalent units; fibrinogen level, 624 mg/dL; troponin, < 0.04 ng/mL; lactic acid, 1.3 mmol/L; total bilirubin, 0.8 mg/dL; alanine aminotransferase, 22 U/L, aspartate aminotransferase, 22 U/L; alkaline phosphatase, 89 U/L; urinalysis with > 50 red blood cells/high power field; large blood, negative leukocyte esterase, negative nitrite. The patient’s urine toxicology was negative for cannabinoids, methadone, amphetamines, cocaine, and benzodiazepines; but was positive for opiates. An anticoagulant poisoning panel also was ordered.
An electrocardiogram (ECG) and imaging studies were ordered. The ECG showed atrial fibrillation (AF) with rapid ventricular response (Figure 1). A chest X-ray indicated bibasilar consolidations that were worse on the right side. A noncontrast computed tomography (CT) of the head did not show intracranial bleeding. An abdomen/pelvis CT showed bilateral diffuse patchy peribronchovascular ground-glass opacities in the lung bases that could represent pulmonary hemorrhage, but no peritoneal or retroperitoneal bleeding.
Treatment
In the ED, the case was discussed with the Illinois Poison Control Center. The patient was diagnosed with coagulopathy likely due to anticoagulant poisoning. He was immediately treated with 10 mg of IV vitamin K, a fixed dose of 2,000 units of 4-factor prothrombin complex concentrate, and 4 units of fresh frozen plasma. His INR improved to 1.42 within several hours. He received 5 mg of IV metoprolol for uncontrolled AF and was admitted to the intensive care unit (ICU) for further care.
In the ICU the patient was started on oral vitamin K 50 mg tid for ongoing treatment of coagulopathy due to concern for possible rodenticide poisoning associated with very long half-life. This dose was then decreased to 50 mg bid. He was given IV fluid resuscitation with normal saline and started on rate control for AF with oral metoprolol. His heart rate improved. An echocardiogram showed new cardiomyopathy with an ejection fraction of 25% to 30%. Given basilar infiltrates and 1 episode of low-grade fever, he was started on ceftriaxone for possible community-acquired pneumonia. The patient was started on cholestyramine to help with washout of the possible rodenticide. No endoscopic interventions were performed.
The patient was transferred to an inpatient telemetry floor 24 hours after admission to the ICU once his tachycardia and bleeding improved. He did not require transfusion of packed red blood cells. In the ICU his INR had ranged between 1.62 and 2.46 (down from > 20 in the ED). His hemoglobin dropped from 13.3 g/dL on admission to 12 g/dL on transfer from the ICU, before stabilizing around 11 g/dL on the floor. The patient’s heart rate required better control, so metoprolol was increased to a total daily dose of 200 mg on the telemetry floor. Oral digoxin was then added after a digoxin load for additional rate control, as the patient remained tachycardic. Twice a day the patient continued to take 50 mg vitamin K. Cholestyramine and ceftriaxone were initially continued, but when the INR started increasing again, the cholestyramine was stopped to allow for an increase to more frequent 3-times daily vitamin 50 mg K administration (cholestyramine can interfere with vitamin K absorption). According to the toxicology service, there was only weak evidence to support use of cholestyramine in this setting.
Given his ongoing mild hemoptysis, the patient received first 1 unit, and then another 4 units of FFP when the INR increased to 3.96 despite oral vitamin K. After FFP, the INR decreased to 1.93 and subsequently to 1.52. A CT of the chest showed patchy ground-glass densities throughout the lungs, predominantly at the lung bases and to a lesser extent in the upper lobes. The findings were felt to represent pulmonary hemorrhage given the patient’s history of hemoptysis (Figure 2).
The patient’s heart rate control improved, and he remained hemodynamically stable. A thyroid function test was within normal limits. Lisinopril was added to metoprolol and digoxin given his newly diagnosed cardiomyopathy. The patient was observed for a total of 4 days on the inpatient floor and discharged after his INR stabilized around 1.5 on twice daily 50 mg vitamin K. The patient’s hematuria and hematochezia completely resolved, and hemoptysis was much improved at the time of discharge. His hemoglobin remained stable. The anticoagulant poisoning panel came back positive for
The patient has remained in AF at all follow-up visits. The INR normalized by 6 weeks after hospital discharge, and the dose of vitamin K slowly was tapered with close monitoring of the INR. Vitamin K was tapered for about 6 months after his initial presentation, and the patient was started on a direct oral anticoagulant (DOAC) for anticoagulation when the INR remained stable off vitamin K. He subsequently underwent a transesophageal echocardiogram followed by an attempt at direct current (DC) cardioversion; however, he did not remain in sinus rhythm, and is being continued on anticoagulation and rate control for his AF.
Discussion
Users generally smoke synthetic cannabinoids, which produce cannabis-like effects. However, atypical intoxication effects with worse complications often occur.2 These products typically contain dried shredded plant material that is soaked in or sprayed with several synthetic cannabinoids, varying in dosage and combination.3 Synthetic cannabinoids have been associated with serious adverse effects (AEs), including drowsiness, light-headedness, and fast or irregular heartbeat.4 More severe clinical features such as psychosis, delirium, cardiotoxicity, seizures, rhabdomyolysis, acute kidney injury, hyperthermia, myocardial ischemia, ischemic strokes, and death have also been noted.4
It is not known how some batches of synthetic cannabinoids came to be contaminated with rat poison or how commonly such an adulteration is found across the country. Several different guidelines provide pathways for the treatment of acute bleeding in the setting of coagulopathy due to vitamin K antagonists.5,6 Each guideline divides the indications for reversal into either severity of bleeding or the criticality of the bleeding based on location.5,6 All guidelines recommend the use of vitamin K (either oral or IV) followed by FFP or 4-factor prothrombin complex concentrate (PCC) for more severe bleeding.5,6 However, recommendations regarding the use of PCC vary in dosing for vitamin K antagonists (in contrast to treatment of coagulopathy due to DOACs). Recent studies and guidelines suggest that fixed-dose (rather than weight-based dose) PCC is effective for the reversal of coagulopathy due to vitamin K antagonists.6,7 Using fixed rather than weight-based dosing decreases cost and may decrease the possibility of thrombotic AEs.7 In this patient, a fixed-dose of 2,000 units of PCC was given based on data that were extrapolated from warfarin reversal using PCC.7
The vitamin K antagonists that adulterated this patient’s synthetic cannabinoid were difenacoum and brodifacoum, which are 4-hydroxycoumarin derivatives. These are second-generation long-acting anticoagulant rodenticides (LAARs) that are about 100 times more potent than warfarin.8 As the name implies, LAARs have a longer duration of action in the body of any organism that ingests the poison, which is due to the highly lipophilic groups that have been added to the warfarin molecule to combat resistance in rodents.9
As a result of the deposition in the tissues, there have been reports of the duration of action of brodifacoum ranging from 51 days to 9 months after ingestion, with the latter caused by an intentional overdose in a human.9-12 Reports suggest that coagulopathy is not likely to occur when the serum brodifacoum concentration is < 10 ng/mL.13,14 Animal models show difenacoum has a tissue half-life of about 62 days.15 Reports of difenacoum poisoning in humans have shown variable lengths of treatment, ranging from 30 to 47 days.16-18 The length of treatment for either brodifacoum or difenacoum will depend on the amount of poison exposure.
The long duration of action and treatment duration may lead to problems with drug procurement, especially in the early phase of treatment in which IV vitamin K is used. The supply of IV vitamin K recently has been limited for at least some manufacturers. According to the American Society of Health System Pharmacists Current Drug Shortage List, the increased demand is thought to be due to increased use of synthetic inhaled cannabinoids laced with anticoagulant.19 IV vitamin K products are available from suppliers such as Amphastar (Rancho Cucamonga, CA) and Hospira (Lake Forest, IL).
The American College of Chest Physicians recommends IV vitamin K administration in patients with major bleeding secondary to vitamin K antagonists.20 The oral route is thought to be more effective than a subcutaneous route in the treatment of nonbleeding patients with rodenticide-associated coagulopathy. Due to erratic and unpredictable absorption, the subcutaneous route of administration has fallen out of favor. Oral vitamin K products were not affected by the recent shortage. However, large doses of oral vitamin K can be costly. Due to the long half-life of LAAR, many patients are discharged with a prescription for oral vitamin K. Although vitamin K is found in most over-the-counter (OTC) multivitamins, the strength is insufficient. Most OTC formulations are ≤ 100 μg, whereas the prescription strength is 5 mg, but patients being treated for rodenticide poisoning require much larger doses.
Commercial insurance carriers and Medicare Part D usually do not cover vitamins and minerals unless it is for a medically accepted indication or is an indication supported by citation in either the American Hospital Formulary System, United States Pharmacopeia drug information book, or an electronic information resource that is supported by evidence such as Micromedex.21 For a patient without insurance coverage being treated with high-dose vitamin K therapy for rodenticide poisoning outside of a federal health care system, the cost could be as high as $500 to $1,000 per day, depending on the dose of vitamin K needed to maintain an acceptable INR.
Conclusion
In addition to bleeding as a result of coagulopathy, this patient presented with new onset of AF with rapid ventricular response and a newly diagnosed cardiomyopathy. Although the patient had other cardiovascular risk factors, such as hypertension, dyslipidemia, and a remote history of cocaine use, it is likely that the use of the synthetic cannabinoids contributed to the development and/or worsening of this arrhythmia and cardiomyopathy. The patient remained in AF 6 weeks after hospital discharge with a controlled ventricular rate on metoprolol and digoxin. An interval echocardiogram 6 weeks after hospital discharge showed a recovered ejection fraction. In cases of tachycardia-induced cardiomyopathy, the ejection fraction often recovers with control of the tachycardia. The patient was weaned off vitamin K about 6 months after his initial presentation and started on a DOAC for anticoagulation. He subsequently underwent a transesophageal echocardiogram followed by an attempt at DC cardioversion; however, he did not remain in sinus rhythm and is being continued on anticoagulation and rate control for his AF.
Although unclear how synthetic cannabinoids became adulterated with a potent vitamin K antagonist, health care practitioners should consider this if a patient presents with unexplained coagulopathy and widespread bleeding. Fixed-dose PCC should be considered as an alternative to weight-based dosing in these cases. Physicians and pharmacy personnel should anticipate a need for long-term high doses of vitamin K in order to begin work early to obtain sufficient supplies to treat presenting patients.
1. Illinois Department of Public Health. Synthetic cannabinoids. http://dph.illinois.gov/topics-services/prevention-wellness/medical-cannabis/synthetic-cannabinoids. Updated May 30, 2018. Accessed April 8, 2019.
2. Tournebize J, Gibaja V, Kahn JP. Acute effects of synthetic cannabinoids: update 2015. Subst Abus. 2017;38(3):344-366.
3. United Nations Office on Drugs and Crime. Global SMART update. https://www.unodc.org/documents/scientific/Global_SMART_Update_13_web.pdf. Published March 2015. Accessed April 8, 2019.
4. Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R, “Zombie” outbreak caused by the synthetic cannabinoid AMB-FUBINACA in New York. N Engl J Med. 2017;376(3):235-242.
5. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067.
6. Cushman M, Lim W, Zakai NA. 2011 Clinical Practice guide on anticoagulant dosing and management of anticoagulant-associated bleeding complications in adults. http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Ref/525.aspx. Published 2011. Accessed April 8, 2019.
7. Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med. 2015;33(9):1213-1218.
8. Bachmann KA, Sullivan TJ. Dispositional and pharmacodynamic characteristics of brodifacoum in warfarin-sensitive rats. Pharmacology. 1983;27(5):281-288.
9. Lipton RA, Klass EM. Human ingestion of ‘superwarfarin’ rodenticide resulting in a prolonged anticoagulant effect. JAMA. 1984;252(21):3004-3005.
10. Chong LL, Chau WK, Ho CH. A case of ‘superwarfarin’ poisoning. Scand J Haematol. 1986;36(3):314-331.
11. Jones EC, Growe GH, Naiman SC. Prolonged anticoagulation in rat poisoning. JAMA. 1984;252(21):3005-3007.
12. Babcock J, Hartman K, Pedersen A, Murphy M, Alving B. Rodenticide-induced coagulopathy in a young child. A case of Munchausen syndrome by proxy. Am J Pediatr Hematol Oncol. 1993;15(1):126-130.
13. Hollinger BR, Pastoor TP. Case management and plasma half-life in a case of brodifacoum poisoning. Arch Intern Med. 1993;153(16):1925-1928.
14. Bruno GR, Howland MA, McMeeking A, Hoffman RS. Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med. 2000;36(3):262-267.
15. Vandenbrouke V, Bousquet-Meloua A, De Backer P, Croubels S. Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration. J Vet Pharmacol Ther. 2008;31(5):437-445.
16. Barlow AM, Gay AL, Park BK. Difenacoum (Neosorexa) poisoning. Br Med J (Clin Res Ed). 1982;285(6341):541.
17. Katona B, Wason S. Superwarfarin poisoning. J Emerg Med. 1989;7(6):627-631.
18. Butcher GP, Shearer MJ, MacNicoll AD, Kelly MJ, Ind PW. Difenacoum poisoning as a cause of haematuria. Hum Exp Toxicol. 1992;11(6):553-554.
19. American Society of Health System Pharmacists. Current drug shortages. Vitamin K (phytonadione) injection. https://www.ashp.org/drug-shortages/current-shortages/Drug-Shortage-Detail.aspx?id=100. Updated July 5, 2018. Accessed April 8, 2019.
20. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e152S-e184S.
21. Centers for Medicare and Medicaid Services. Part D Excluded Drugs. https://www.medicareadvocacy.org/old-site/News/Archives/PartD_ExcludedDrugsByState.htm. Accessed on August 23, 2018.
1. Illinois Department of Public Health. Synthetic cannabinoids. http://dph.illinois.gov/topics-services/prevention-wellness/medical-cannabis/synthetic-cannabinoids. Updated May 30, 2018. Accessed April 8, 2019.
2. Tournebize J, Gibaja V, Kahn JP. Acute effects of synthetic cannabinoids: update 2015. Subst Abus. 2017;38(3):344-366.
3. United Nations Office on Drugs and Crime. Global SMART update. https://www.unodc.org/documents/scientific/Global_SMART_Update_13_web.pdf. Published March 2015. Accessed April 8, 2019.
4. Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R, “Zombie” outbreak caused by the synthetic cannabinoid AMB-FUBINACA in New York. N Engl J Med. 2017;376(3):235-242.
5. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067.
6. Cushman M, Lim W, Zakai NA. 2011 Clinical Practice guide on anticoagulant dosing and management of anticoagulant-associated bleeding complications in adults. http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Ref/525.aspx. Published 2011. Accessed April 8, 2019.
7. Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med. 2015;33(9):1213-1218.
8. Bachmann KA, Sullivan TJ. Dispositional and pharmacodynamic characteristics of brodifacoum in warfarin-sensitive rats. Pharmacology. 1983;27(5):281-288.
9. Lipton RA, Klass EM. Human ingestion of ‘superwarfarin’ rodenticide resulting in a prolonged anticoagulant effect. JAMA. 1984;252(21):3004-3005.
10. Chong LL, Chau WK, Ho CH. A case of ‘superwarfarin’ poisoning. Scand J Haematol. 1986;36(3):314-331.
11. Jones EC, Growe GH, Naiman SC. Prolonged anticoagulation in rat poisoning. JAMA. 1984;252(21):3005-3007.
12. Babcock J, Hartman K, Pedersen A, Murphy M, Alving B. Rodenticide-induced coagulopathy in a young child. A case of Munchausen syndrome by proxy. Am J Pediatr Hematol Oncol. 1993;15(1):126-130.
13. Hollinger BR, Pastoor TP. Case management and plasma half-life in a case of brodifacoum poisoning. Arch Intern Med. 1993;153(16):1925-1928.
14. Bruno GR, Howland MA, McMeeking A, Hoffman RS. Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med. 2000;36(3):262-267.
15. Vandenbrouke V, Bousquet-Meloua A, De Backer P, Croubels S. Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration. J Vet Pharmacol Ther. 2008;31(5):437-445.
16. Barlow AM, Gay AL, Park BK. Difenacoum (Neosorexa) poisoning. Br Med J (Clin Res Ed). 1982;285(6341):541.
17. Katona B, Wason S. Superwarfarin poisoning. J Emerg Med. 1989;7(6):627-631.
18. Butcher GP, Shearer MJ, MacNicoll AD, Kelly MJ, Ind PW. Difenacoum poisoning as a cause of haematuria. Hum Exp Toxicol. 1992;11(6):553-554.
19. American Society of Health System Pharmacists. Current drug shortages. Vitamin K (phytonadione) injection. https://www.ashp.org/drug-shortages/current-shortages/Drug-Shortage-Detail.aspx?id=100. Updated July 5, 2018. Accessed April 8, 2019.
20. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e152S-e184S.
21. Centers for Medicare and Medicaid Services. Part D Excluded Drugs. https://www.medicareadvocacy.org/old-site/News/Archives/PartD_ExcludedDrugsByState.htm. Accessed on August 23, 2018.