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Poor Hypertension Control and Longer Transport Times Are Associated with Worse Outcome in Drip-and-Ship Stroke Patients
ARTICLE IN PRESS
Poor Hypertension Control and Longer Transport Times Are Associated with Worse Outcome in Drip-and-Ship Stroke Patients Thomas V. Kodankandath, MD, Jane Shaji, BA, Nina Kohn, MBA, MA, Rohan Arora, MBBS, Elliott Salamon, DO, Richard B. Libman, MD, and Jeffrey M. Katz, MD
Background: The “drip-and-ship” paradigm is an important treatment modality for acute ischemic stroke (AIS) patients who do not have immediate access to a comprehensive stroke center (CSC). Intravenous thrombolysis is initiated at a primary stroke center followed by expeditious transfer to a CSC. We sought to determine factors associated with poor outcomes in drip-and-ship AIS patients transferred to a CSC. Methods: This study is a retrospective analysis of 130 consecutive dripand-ship patients transferred by ambulance to a single CSC between July 2012 and June 2014. Multiple patient and transport factors were analyzed. Transport blood pressure (BP) control was considered inadequate if the systolic BP was greater than 180 mmHg and/or diastolic BP was greater than 105 mmHg upon CSC arrival. Poor patient outcome was defined as discharge to hospice or expiry, a discharge modified Rankin Scale (mRS) score higher than 2, or symptomatic intracerebral hemorrhage (ICH). Results: There was a significant association between inadequate BP control upon CSC arrival and in-hospital mortality or discharge to hospice (P < .0007). Arrival BP was not associated with the risk of post-thrombolysis symptomatic ICH. Longer transport time was significantly associated with a poorer mRS score at discharge (P < .0174) and death (P < .0351). Conclusions: Post-thrombolysis BP guideline violations and longer transport times during drip-and-ship transfers were significantly associated with poor outcome. Guidelines for strict transport BP management and alternative modes of transfer for longer-distance transports may be warranted. Key Words: Ischemic stroke—drip and ship—endovascular therapy—thrombolysis—acute therapy. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction Stroke is a major health concern in the United States, affecting more than 795,000 people each year.1 On average, From the Department of Neurology, North Shore University Hospital, Manhasset, New York. Received March 4, 2016; revision received April 6, 2016; accepted April 13, 2016. Address correspondence to Jeffrey M. Katz, MD, Department of Neurology, NSUH, 300 Community Drive, 9 Tower, Manhasset, NY, 11030. E-mail: [email protected] 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.04.013
every 4 minutes a person dies from a stroke, making it the fifth leading cause of death.2 The current mainstay treatment for acute ischemic stroke (AIS) is the administration of intravenous recombinant tissue plasminogen activator (IV-rtPA) within a 3.0- to 4.5-hour window from the last known well time. IV-rtPA was first approved by the Food and Drug Administration in 1996 for the treatment of AIS.3,4 However, IV-rtPA still has a low frequency of use due to the narrow time frame for administration and the concern for hemorrhagic complications. For patients with large-vessel occlusions, endovascular stroke therapy, especially with the newer stent retriever devices, has been shown in numerous, recent randomized controlled trials to improve patient outcome.5-9 The technical
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2016: pp ■■–■■
1
ARTICLE IN PRESS T.V. KODANKANDATH ET AL.
2
complexity and equipment requirements of these procedures and the postoperative management of these patients necessitate their performance at comprehensive stroke centers (CSCs). In the drip-and-ship paradigm, IV-rtPA is initiated at a local community hospital or primary stroke center, and then the patient is rapidly transferred to a CSC, often while the recombinant tissue plasminogen activator is still infusing. Previous studies have explored drip-and-ship paradigm safety in smaller populations.10 The purpose of the present study is to assess factors associated with poor outcome in a larger drip-and-ship population transported by ambulance within a major metropolitan area.
the NIHSS score as documented in the vascular neurology attending notes. Poor patient outcome was defined as discharge to hospice or in-hospital death, a discharge mRS score higher than 2, and symptomatic ICH. For statistical analysis, the association between each outcome and each categorical variable was examined using the chi-square test, or the Fisher exact test, as appropriate. The association between each outcome and each continuous variable was determined using logistic regression. A P value less than .05 was considered statistically significant. The statistical analysis was performed using SAS Version 9.3 (SAS Institute Inc., Cary, NC) software.
Results Materials and Methods A retrospective observational study was performed, following institutional review board approval, on a consecutive series of AIS patients treated by the dripand-ship paradigm and transported by ambulance to a single CSC within a large stroke care network in the New York metropolitan area between July 2012 and June 2014. All patients were treated within the standard 0- to 3-hour or extended 3.0- to 4.5-hour time window with intravenous thrombolysis (IVT) using eligibility criteria based on national guidelines.11 The patients were received by the CSC from 16 referring hospitals varying in size and distance from the accepting facility. Interfacility distances ranged from 3 to 35 mi, and primary hospital sizes varied from 103 to 827 beds. All interfacility transports were conducted by the receiving health system’s emergency medical service (EMS), ensuring consistent patient transfer protocols. Data were gathered from the CSC’s “Get With the Guidelines” database. Compiled data points included patient demographics and the presence of standard vascular risk factors, initial National Institutes of Health Stroke Scale (NIHSS) at the transferring facility, NIHSS score and blood pressure (BP) upon CSC arrival, transport duration, symptomatic intracerebral hemorrhage (ICH), discharge modified Rankin Scale (mRS) score, and discharge status. The initial NIHSS score was used to determine the severity of the neurological deficit and was obtained in the documentation from the transferring facility. Patients whose initial NIHSS score was not available were excluded from the study. Patients with a systolic BP greater than 180 mmHg or a diastolic BP greater than 105 mmHg during transport or upon CSC arrival were considered to have a BP guideline violation. Transportation time between the referring and accepting facility was recorded using ambulance run sheets. The mRS score was determined using the vascular neurology attending progress notes, as well as notes from the rehabilitation team including occupational, speech, and physical therapists. Symptomatic ICH was defined as an ICH detected by CT or MRI associated with a neurological decline of 4 points or higher in
A total of 123 drip-and-ship patients were confirmed to have an ischemic stroke (7 stroke mimics were excluded from the analysis). BP at CSC arrival was available for 120 patients, defining the final cohort. The mean age of the cohort was 62.7 years (range: 24-100 years). Mean outside hospital NIHSS score was 12.5 (range: 0-32). The mean CSC admission NIHSS score was 11.0 (range: 0-28). The mean BP upon CSC arrival was 143.3/77.8 mmHg (systolic range: 90-200 mmHg/diastolic range: 44112 mmHg). The mean mRS score at discharge was 2.8. Transport times were available for 83 of 123 confirmed drip-and-ship AIS patients. The mean transport time to the CSC was 21.6 minutes (range: 4-51 minutes). There was a significant association between BP upon CSC arrival and discharge status (Fisher exact test, P < .0007). Seven out of 15 (46.7%) patients with BP guideline violation on CSC arrival expired or were discharged to hospice, compared to 9 of 105 (8.6%) patients without BP guideline violations. Symptomatic ICH frequency was not significantly different between groups, being observed in 1 of 15 (6.7%) patients with BP violations compared to 10 of 105 (9.5%) patients without BP parameter violations. Eleven of 15 (73.3%) patients with BP violations had a discharge mRS score higher than 2, compared to 54 of 103 (52.4%) patients without BP parameter violation (not significant). Transport time was also significantly associated with discharge status (P < .0351). Subjects with longer transport times were more likely to die or be discharged to hospice (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 1.01-1.15). For every 1-minute increase in transport time, the odds of dying or discharge to hospice were increased by 7%. For every 5-minute increase in transport time, the odds were increased by 42% (OR for 5 minutes: 1.42, 95% CI: 1.03-1.97). There was also a significant association between the mRS score at discharge and transport time (P < .0174). Patients with longer transport times were more likely to have mRS scores of 3-6 (OR: 1.06, 95% CI: 1.01-1.11). For every 1-minute increase in transport time, the odds of having an mRS score of 3-6 increased by 6%. For every 5-minute increase in transport time, the odds
ARTICLE IN PRESS FACTORS ASSOCIATED WITH POOR DRIP-AND-SHIP OUTCOME
increased by 33% (OR for 5 minutes: 1.33, 95% CI: 1.051.67). Neither BP guideline violation (P < .26) nor symptomatic ICH (P < .21) was associated with longer transportation time.
Discussion We found that patients with BP protocol violations upon CSC arrival had a higher rate of poor outcomes. In a study done by Qureshi et al of 40 drip-and-ship patients, nonadherance to BP guidelines in transit did not lead to an unfavorable outcome.10 Qureshi et al’s small sample might have led to a type II error. Recent studies have suggested that modest differences in mortality during the drip-and-ship transport may be due to a variety of causes such as patient selection bias and post-tissue plasminogen activator care differences.12 Higher BP levels are observed in the majority of patients during an acute stroke and may represent the hemodynamic response to ischemia to increase penumbral perfusion, or patients with larger infarcts might have higher BP as part of the natural history of their stroke. These patients might have had a worse prognosis to begin with. Unfortunately, we were not able to control for infarct volume to address this issue. Previous studies have described a U-shaped relationship between mortality and admission BP in patients with AIS. The mechanism behind this relationship is unclear. High BP is hypothesized to lead to early stroke recurrence, symptomatic hemorrhagic transformation and worsening cerebral edema. Low BP may lower cerebral perfusion pressure and may enlarge infarct volumes. To achieve optimal clinical outcomes, admission BP values should be normal to mildly elevated.13 Our study suggests that early post-thrombolysis BP control may influence stroke patient mortality and that strict BP control during the drip-and-ship transport process may be needed to prevent a poor outcome. Although this explanation is plausible, we cannot rule out reverse causality. Additionally, patients with longer transportation times had higher disability at discharge and mortality. For every 1-minute increase in transportation time, the odds of having a poor discharge mRS score and death increased by 6% and 7%, respectively. Even more alarming was that for every 5-minute delay, the odds of having a poor discharge mRS score and mortality increased by 33% and 42%, respectively. The cause of the association between poor outcome and longer transport times is not clear. We found no association between longer transportation time and BP guideline violations or the rate of symptomatic ICH. One possibility is that patients are more likely to be excluded form endovascular stroke therapy as imaging and time windows for intervention may be lost by prolonged transport times to a CSC. This association could not be further analyzed in this data set. Others have shown, however, that rapid transfer of drip-and-ship patients to a CSC is essential.14 Nonetheless, this finding must be
3
interpreted with caution because we were missing transport times in roughly one third of our patients. Ideally, patients should be transported by EMS immediately after the IV-rtPA bolus is given and while the patients are receiving the infusion. Strict adherence to guidelines, including adequate hemodynamic and neurological monitoring, and providing treatments, including intravenous antihypertensive therapy by EMS personnel when indicated, are critical for safe transfer to a CSC. Nearly half of the United States population is at least 60 minutes away from a primary stroke center,15 making rapid transport outside of a major metropolitan area challenging, both to primary stroke centers as well as to CSCs. If transport time is confirmed in other studies to be associated with poor outcome, then further data will be needed to determine ideal transport times to avoid adverse clinical outcomes. Various factors can cause delays in interfacility transport of acute stroke patients, including greater time to stabilize sicker patients, referring hospital transfer inefficiencies, and variable EMS provider skill set and protocols. From our data set, the cause of individual transport time delays cannot be identified. One important factor to consider is the amount of time the EMS spends in the referring emergency department before transport to a CSC. Transfer delay is an important reason why AIS patients are often excluded from endovascular treatment.16 Previous studies have also shown that prehospital delays, as measured by total transport time exceeding guidelines, are influenced by the season, the responsible EMS agency, patient age, and whether or not the patient is transported to a specialty center.17 In our study, one probable source of increased transport time is travel distance between the referring hospital and the CSC, with longer distances yielding longer transport times. Our stroke network utilizes a single EMS system, paramedic transport, and has implemented predefined acute stroke transfer protocols, thus minimizing the role of EMS variability as the basis for transport delays. The rate of IV-rtPA administration has increased in the United States over the years, with current estimates of 3.4%-5.2% of AIS patients receiving thrombolytic therapy.18 States with higher rates of thrombolytic utilization have higher rates of patients treated using the drip-and-ship paradigm.19 The drip-and-ship method has been proven to be as safe and effective as patients treated directly by a stroke specialist.20 The drip-and-ship approach accounts for approximately a quarter of all patients receiving IVT. Currently, clinical outcomes including in-hospital mortality, ICH, life-threatening systemic bleeding, independent ambulation at discharge, discharge destination home, and length of stay favor patients staying at a primary stroke center post IVT as opposed to being transferred as a drip and ship for a higher level of care. The absolute differences, however, are small and may be an overestimate due to poor documentation of stroke severity (initial NIHSS
ARTICLE IN PRESS T.V. KODANKANDATH ET AL.
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score) and a higher frequency of large-vessel occlusion in the drip-and-ship group.12 Therefore, promoting the drip-and-ship paradigm when indicated is critical to improving national utilization of IVT and endovascular stroke therapy for AIS patients. Standardization of stroke patient transfer protocols between facilities is a key area that needs further research for the advancement of stroke systems of care. Limitations of the present study include the retrospective design with missing data such as transportation time for a number of patients in the cohort. Our observations are based on a population of patients admitted to a single CSC and should be confirmed in other CSCs and populations. Furthermore, BP guideline violations may be underestimated because of a lack of adequate documentation. For instance, it is possible that missing information, such as serial hemodynamic assessments, was performed but not documented. As noted above, we cannot be certain that suboptimal BP control led to poor outcomes, as opposed to pre-existing high BP reflecting more severe strokes and predicting a worse prognosis. All of these limitations are inherent to a retrospective study, as we can only show the association but not prove the causation. Acknowledging these limitations, we believe that our study highlights the need for better BP guideline adherence in drip-and-ship patients. This includes further education of transferring hospitals, as well as EMS providers, and the creation of and adherence to standardized transfer protocols. While the association between longer transportation time and poor outcome is shown, the source of this association is unclear. Further studies are needed to determine the safest transport time window for ground transport of drip-and-ship patients, and the role of air transportation for patients outside of this window, to minimize the risks associated with the drip-and-ship transfer paradigm. Acknowledgments: The authors would like to thank Aaron Burshtein and Joshua Burshtein for their help with the data collection and chart review for this study.
References 1. Kochanek KD, Xu JQ, Murphy SL, et al. Deaths: final data for 2009. Natl Vital Stat Rep 2011;60:1-116. 2. Kochanek KD, Murphy SL, Xu JQ, et al. Mortality in the United States, 2013. NCHS data brief, no. 178. Hyattsville, MD: National Center for Health Statistics., 2014. 3. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581-1587.
4. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-1329. 5. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11-20. 6. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015;372:1019-1030. 7. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015;372:1009-1018. 8. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015;372:2285-2295. 9. Jovin TG, Bonafe A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015;372:2296-2306. 10. Asaithambi G, Chaudhry SA, Hassan AE, et al. Adherence to guidelines by emergency medical services during transport of stroke patients receiving intravenous thrombolytic infusion. J Stroke Cerebrovasc Dis 2003;22:e42-e45. 11. Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870-947. 12. Sheth KN, Smith EE, Grau-Sepulveda MV, et al. Drip and ship thrombolytic therapy for acute ischemic stroke: use, temporal trends, and outcomes. Stroke 2015;46:732739. 13. Vemmos KN, Tsivgoulis G, Spengos K, et al. U-shaped relationship between mortality and admission blood pressure in patients with acute stroke. J Intern Med 2004;255:257-265. 14. Saler M, Switzer JA, Hess DC. Use of telemedicine and helicopter transport to improve stroke care in remote locations. Curr Treat Options Cardiovasc Med 2011;13:215-224. 15. Albright KC, Branas CC, Meyer BC, et al. Acute cerebrovascular care in emergency stroke systems. Arch Neurol 2010;67:1210-1218. 16. Prabhakaran S, Ward E, John S, et al. Transfer delay is a major factor limiting the use of intra-arterial treatment in acute ischemic stroke. Stroke 2011;42:1626-1630. 17. Golden AP, Odoi A. Emergency medical services transport delays for suspected stroke and myocardial infarction patients. BMC Emerg Med 2015;15:34. 18. Adeoye O, Hornung R, Khatri P, et al. Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke 2011;42:1952-1955. 19. Tekle WG, Chaudhry SA, Hassan AE, et al. Drip-and-ship thrombolytic treatment paradigm among acute ischemic stroke patients in the United States. Stroke 2012;43:19711974. 20. Martin-Schild S, Morales MM, Khaja AM, et al. Is the drip-and-ship approach to delivering thrombolysis for acute ischemic stroke safe? J Emerg Med 2011;41:135-141.
Poor Hypertension Control and Longer Transport Times Are Associated with Worse Outcome in Drip-and-Ship Stroke Patients Thomas V. Kodankandath, MD, Jane Shaji, BA, Nina Kohn, MBA, MA, Rohan Arora, MBBS, Elliott Salamon, DO, Richard B. Libman, MD, and Jeffrey M. Katz, MD
Background: The “drip-and-ship” paradigm is an important treatment modality for acute ischemic stroke (AIS) patients who do not have immediate access to a comprehensive stroke center (CSC). Intravenous thrombolysis is initiated at a primary stroke center followed by expeditious transfer to a CSC. We sought to determine factors associated with poor outcomes in drip-and-ship AIS patients transferred to a CSC. Methods: This study is a retrospective analysis of 130 consecutive dripand-ship patients transferred by ambulance to a single CSC between July 2012 and June 2014. Multiple patient and transport factors were analyzed. Transport blood pressure (BP) control was considered inadequate if the systolic BP was greater than 180 mmHg and/or diastolic BP was greater than 105 mmHg upon CSC arrival. Poor patient outcome was defined as discharge to hospice or expiry, a discharge modified Rankin Scale (mRS) score higher than 2, or symptomatic intracerebral hemorrhage (ICH). Results: There was a significant association between inadequate BP control upon CSC arrival and in-hospital mortality or discharge to hospice (P < .0007). Arrival BP was not associated with the risk of post-thrombolysis symptomatic ICH. Longer transport time was significantly associated with a poorer mRS score at discharge (P < .0174) and death (P < .0351). Conclusions: Post-thrombolysis BP guideline violations and longer transport times during drip-and-ship transfers were significantly associated with poor outcome. Guidelines for strict transport BP management and alternative modes of transfer for longer-distance transports may be warranted. Key Words: Ischemic stroke—drip and ship—endovascular therapy—thrombolysis—acute therapy. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction Stroke is a major health concern in the United States, affecting more than 795,000 people each year.1 On average, From the Department of Neurology, North Shore University Hospital, Manhasset, New York. Received March 4, 2016; revision received April 6, 2016; accepted April 13, 2016. Address correspondence to Jeffrey M. Katz, MD, Department of Neurology, NSUH, 300 Community Drive, 9 Tower, Manhasset, NY, 11030. E-mail: [email protected] 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.04.013
every 4 minutes a person dies from a stroke, making it the fifth leading cause of death.2 The current mainstay treatment for acute ischemic stroke (AIS) is the administration of intravenous recombinant tissue plasminogen activator (IV-rtPA) within a 3.0- to 4.5-hour window from the last known well time. IV-rtPA was first approved by the Food and Drug Administration in 1996 for the treatment of AIS.3,4 However, IV-rtPA still has a low frequency of use due to the narrow time frame for administration and the concern for hemorrhagic complications. For patients with large-vessel occlusions, endovascular stroke therapy, especially with the newer stent retriever devices, has been shown in numerous, recent randomized controlled trials to improve patient outcome.5-9 The technical
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2016: pp ■■–■■
1
ARTICLE IN PRESS T.V. KODANKANDATH ET AL.
2
complexity and equipment requirements of these procedures and the postoperative management of these patients necessitate their performance at comprehensive stroke centers (CSCs). In the drip-and-ship paradigm, IV-rtPA is initiated at a local community hospital or primary stroke center, and then the patient is rapidly transferred to a CSC, often while the recombinant tissue plasminogen activator is still infusing. Previous studies have explored drip-and-ship paradigm safety in smaller populations.10 The purpose of the present study is to assess factors associated with poor outcome in a larger drip-and-ship population transported by ambulance within a major metropolitan area.
the NIHSS score as documented in the vascular neurology attending notes. Poor patient outcome was defined as discharge to hospice or in-hospital death, a discharge mRS score higher than 2, and symptomatic ICH. For statistical analysis, the association between each outcome and each categorical variable was examined using the chi-square test, or the Fisher exact test, as appropriate. The association between each outcome and each continuous variable was determined using logistic regression. A P value less than .05 was considered statistically significant. The statistical analysis was performed using SAS Version 9.3 (SAS Institute Inc., Cary, NC) software.
Results Materials and Methods A retrospective observational study was performed, following institutional review board approval, on a consecutive series of AIS patients treated by the dripand-ship paradigm and transported by ambulance to a single CSC within a large stroke care network in the New York metropolitan area between July 2012 and June 2014. All patients were treated within the standard 0- to 3-hour or extended 3.0- to 4.5-hour time window with intravenous thrombolysis (IVT) using eligibility criteria based on national guidelines.11 The patients were received by the CSC from 16 referring hospitals varying in size and distance from the accepting facility. Interfacility distances ranged from 3 to 35 mi, and primary hospital sizes varied from 103 to 827 beds. All interfacility transports were conducted by the receiving health system’s emergency medical service (EMS), ensuring consistent patient transfer protocols. Data were gathered from the CSC’s “Get With the Guidelines” database. Compiled data points included patient demographics and the presence of standard vascular risk factors, initial National Institutes of Health Stroke Scale (NIHSS) at the transferring facility, NIHSS score and blood pressure (BP) upon CSC arrival, transport duration, symptomatic intracerebral hemorrhage (ICH), discharge modified Rankin Scale (mRS) score, and discharge status. The initial NIHSS score was used to determine the severity of the neurological deficit and was obtained in the documentation from the transferring facility. Patients whose initial NIHSS score was not available were excluded from the study. Patients with a systolic BP greater than 180 mmHg or a diastolic BP greater than 105 mmHg during transport or upon CSC arrival were considered to have a BP guideline violation. Transportation time between the referring and accepting facility was recorded using ambulance run sheets. The mRS score was determined using the vascular neurology attending progress notes, as well as notes from the rehabilitation team including occupational, speech, and physical therapists. Symptomatic ICH was defined as an ICH detected by CT or MRI associated with a neurological decline of 4 points or higher in
A total of 123 drip-and-ship patients were confirmed to have an ischemic stroke (7 stroke mimics were excluded from the analysis). BP at CSC arrival was available for 120 patients, defining the final cohort. The mean age of the cohort was 62.7 years (range: 24-100 years). Mean outside hospital NIHSS score was 12.5 (range: 0-32). The mean CSC admission NIHSS score was 11.0 (range: 0-28). The mean BP upon CSC arrival was 143.3/77.8 mmHg (systolic range: 90-200 mmHg/diastolic range: 44112 mmHg). The mean mRS score at discharge was 2.8. Transport times were available for 83 of 123 confirmed drip-and-ship AIS patients. The mean transport time to the CSC was 21.6 minutes (range: 4-51 minutes). There was a significant association between BP upon CSC arrival and discharge status (Fisher exact test, P < .0007). Seven out of 15 (46.7%) patients with BP guideline violation on CSC arrival expired or were discharged to hospice, compared to 9 of 105 (8.6%) patients without BP guideline violations. Symptomatic ICH frequency was not significantly different between groups, being observed in 1 of 15 (6.7%) patients with BP violations compared to 10 of 105 (9.5%) patients without BP parameter violations. Eleven of 15 (73.3%) patients with BP violations had a discharge mRS score higher than 2, compared to 54 of 103 (52.4%) patients without BP parameter violation (not significant). Transport time was also significantly associated with discharge status (P < .0351). Subjects with longer transport times were more likely to die or be discharged to hospice (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 1.01-1.15). For every 1-minute increase in transport time, the odds of dying or discharge to hospice were increased by 7%. For every 5-minute increase in transport time, the odds were increased by 42% (OR for 5 minutes: 1.42, 95% CI: 1.03-1.97). There was also a significant association between the mRS score at discharge and transport time (P < .0174). Patients with longer transport times were more likely to have mRS scores of 3-6 (OR: 1.06, 95% CI: 1.01-1.11). For every 1-minute increase in transport time, the odds of having an mRS score of 3-6 increased by 6%. For every 5-minute increase in transport time, the odds
ARTICLE IN PRESS FACTORS ASSOCIATED WITH POOR DRIP-AND-SHIP OUTCOME
increased by 33% (OR for 5 minutes: 1.33, 95% CI: 1.051.67). Neither BP guideline violation (P < .26) nor symptomatic ICH (P < .21) was associated with longer transportation time.
Discussion We found that patients with BP protocol violations upon CSC arrival had a higher rate of poor outcomes. In a study done by Qureshi et al of 40 drip-and-ship patients, nonadherance to BP guidelines in transit did not lead to an unfavorable outcome.10 Qureshi et al’s small sample might have led to a type II error. Recent studies have suggested that modest differences in mortality during the drip-and-ship transport may be due to a variety of causes such as patient selection bias and post-tissue plasminogen activator care differences.12 Higher BP levels are observed in the majority of patients during an acute stroke and may represent the hemodynamic response to ischemia to increase penumbral perfusion, or patients with larger infarcts might have higher BP as part of the natural history of their stroke. These patients might have had a worse prognosis to begin with. Unfortunately, we were not able to control for infarct volume to address this issue. Previous studies have described a U-shaped relationship between mortality and admission BP in patients with AIS. The mechanism behind this relationship is unclear. High BP is hypothesized to lead to early stroke recurrence, symptomatic hemorrhagic transformation and worsening cerebral edema. Low BP may lower cerebral perfusion pressure and may enlarge infarct volumes. To achieve optimal clinical outcomes, admission BP values should be normal to mildly elevated.13 Our study suggests that early post-thrombolysis BP control may influence stroke patient mortality and that strict BP control during the drip-and-ship transport process may be needed to prevent a poor outcome. Although this explanation is plausible, we cannot rule out reverse causality. Additionally, patients with longer transportation times had higher disability at discharge and mortality. For every 1-minute increase in transportation time, the odds of having a poor discharge mRS score and death increased by 6% and 7%, respectively. Even more alarming was that for every 5-minute delay, the odds of having a poor discharge mRS score and mortality increased by 33% and 42%, respectively. The cause of the association between poor outcome and longer transport times is not clear. We found no association between longer transportation time and BP guideline violations or the rate of symptomatic ICH. One possibility is that patients are more likely to be excluded form endovascular stroke therapy as imaging and time windows for intervention may be lost by prolonged transport times to a CSC. This association could not be further analyzed in this data set. Others have shown, however, that rapid transfer of drip-and-ship patients to a CSC is essential.14 Nonetheless, this finding must be
3
interpreted with caution because we were missing transport times in roughly one third of our patients. Ideally, patients should be transported by EMS immediately after the IV-rtPA bolus is given and while the patients are receiving the infusion. Strict adherence to guidelines, including adequate hemodynamic and neurological monitoring, and providing treatments, including intravenous antihypertensive therapy by EMS personnel when indicated, are critical for safe transfer to a CSC. Nearly half of the United States population is at least 60 minutes away from a primary stroke center,15 making rapid transport outside of a major metropolitan area challenging, both to primary stroke centers as well as to CSCs. If transport time is confirmed in other studies to be associated with poor outcome, then further data will be needed to determine ideal transport times to avoid adverse clinical outcomes. Various factors can cause delays in interfacility transport of acute stroke patients, including greater time to stabilize sicker patients, referring hospital transfer inefficiencies, and variable EMS provider skill set and protocols. From our data set, the cause of individual transport time delays cannot be identified. One important factor to consider is the amount of time the EMS spends in the referring emergency department before transport to a CSC. Transfer delay is an important reason why AIS patients are often excluded from endovascular treatment.16 Previous studies have also shown that prehospital delays, as measured by total transport time exceeding guidelines, are influenced by the season, the responsible EMS agency, patient age, and whether or not the patient is transported to a specialty center.17 In our study, one probable source of increased transport time is travel distance between the referring hospital and the CSC, with longer distances yielding longer transport times. Our stroke network utilizes a single EMS system, paramedic transport, and has implemented predefined acute stroke transfer protocols, thus minimizing the role of EMS variability as the basis for transport delays. The rate of IV-rtPA administration has increased in the United States over the years, with current estimates of 3.4%-5.2% of AIS patients receiving thrombolytic therapy.18 States with higher rates of thrombolytic utilization have higher rates of patients treated using the drip-and-ship paradigm.19 The drip-and-ship method has been proven to be as safe and effective as patients treated directly by a stroke specialist.20 The drip-and-ship approach accounts for approximately a quarter of all patients receiving IVT. Currently, clinical outcomes including in-hospital mortality, ICH, life-threatening systemic bleeding, independent ambulation at discharge, discharge destination home, and length of stay favor patients staying at a primary stroke center post IVT as opposed to being transferred as a drip and ship for a higher level of care. The absolute differences, however, are small and may be an overestimate due to poor documentation of stroke severity (initial NIHSS
ARTICLE IN PRESS T.V. KODANKANDATH ET AL.
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score) and a higher frequency of large-vessel occlusion in the drip-and-ship group.12 Therefore, promoting the drip-and-ship paradigm when indicated is critical to improving national utilization of IVT and endovascular stroke therapy for AIS patients. Standardization of stroke patient transfer protocols between facilities is a key area that needs further research for the advancement of stroke systems of care. Limitations of the present study include the retrospective design with missing data such as transportation time for a number of patients in the cohort. Our observations are based on a population of patients admitted to a single CSC and should be confirmed in other CSCs and populations. Furthermore, BP guideline violations may be underestimated because of a lack of adequate documentation. For instance, it is possible that missing information, such as serial hemodynamic assessments, was performed but not documented. As noted above, we cannot be certain that suboptimal BP control led to poor outcomes, as opposed to pre-existing high BP reflecting more severe strokes and predicting a worse prognosis. All of these limitations are inherent to a retrospective study, as we can only show the association but not prove the causation. Acknowledging these limitations, we believe that our study highlights the need for better BP guideline adherence in drip-and-ship patients. This includes further education of transferring hospitals, as well as EMS providers, and the creation of and adherence to standardized transfer protocols. While the association between longer transportation time and poor outcome is shown, the source of this association is unclear. Further studies are needed to determine the safest transport time window for ground transport of drip-and-ship patients, and the role of air transportation for patients outside of this window, to minimize the risks associated with the drip-and-ship transfer paradigm. Acknowledgments: The authors would like to thank Aaron Burshtein and Joshua Burshtein for their help with the data collection and chart review for this study.
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