sábado, 6 de junho de 2015

Comportamiento fisiológico cardiorespiratorio en el adulto mayor durante el ejercicio físico

Physiological Cardiorespiratory Behavior in the Elderly During Physical Exercise

Carmen Ramos Pupo 1,  Aldo Santos Hernández 2, Miguel O. Ochoa Rodríguez 3, Noel Peña Franco 4, Raúl Ramos Ochoa 5, Raúl Ramos Pupo 6.



RESUMEN
El envejecimiento poblacional es un reto para la sociedad contemporánea. Cuba, es uno de los países latinoamericanos más envejecidos. El adulto mayor, tiene características morfofuncionales propias  que en ocasiones se confunden con enfermedades nosológicas también frecuentes en este grupo de edad. El conocimiento de la fisiología del ejercicio en el anciano constituye un tema de actualidad tanto para el profesional de la salud vinculado a la atención geriátrica como para aquellos que participan en la formación de los recursos humanos de salud. Por tal motivo, se realizó una revisión bibliográfica sobre el  comportamiento fisiológico cardiorespiratorio en el adulto mayor durante el ejercicio físico. Se abordaron los aspectos más relevantes sobre las variaciones de la frecuencia cardiaca, respiratoria, presión arterial, saturación de oxigeno arterial, carga máxima y consumo de oxígeno.
Palabras clave: adulto mayor, Fisiología, ejercicio físico

ABSTRACT
The aging is a challenge for modern society. Cuba is one of the most aged countries in Latin America. The elderly has morphofunctional characteristics which are often mistaken for nosological diseases that are frequent in these persons. The awareness of exercise physiology in old people is an important issue nowadays for both geriatric care professionals and professors involved in the training of future health staff. A bibliographical review study on physiological cardiorespiratory behavior in the elderly during physical exercises was carried out.The most outstanding features about variations in the cardiac and respiratory frequency, blood pressure, oxygen saturation, maximum load and oxygen consumption were reported.
Key words: elderly, Physiology, physical exercise.

INTRODUCCIÓN
Cada vez más personas sobrepasan las barreras cronológicas que tradicionalmente han sido situadas como etapa de vejez (1). Los expertos estiman que para 2050, por primera vez en la historia de la humanidad, la cantidad de personas con edad avanzada en el mundo superará a la de jóvenes (2). Nuestro país no escapa de esta situación ya que es uno de los países latinoamericanos más envejecidos. (1, 2,3)
A nivel internacional existen políticas de trabajo orientadas a un cambio en la concepción de la vejez, considerándola como una etapa de vida activa, en la que se puede lograr el máximo de autonomía individual. (1,2)
En nuestro país existen diversas instituciones y programas de investigación, atención, y acompañamiento del adulto mayor que persiguen su promoción integral para una longevidad satisfactoria, lo cual constituye una prioridad para nuestro Estado y Gobierno (2,4). En ese sentido, se adoptan estrategias para el perfeccionamiento de los servicios de salud a este sector poblacional (5, 6,7).
Cada grupo de edad tiene sus características fisiológicas propias y asociado al proceso de envejecimiento se producen una serie de cambios morfológicos y fisiológicos en el aparato cardiovascular que otorgan singularidad a la fisiología del ejercicio en el adulto mayor (8, 9,10).
No obstante, tanto a nivel internacional como en nuestro medio, existe escasez de estudios acerca de los parámetros fisiológicos en personas mayores de 60 años durante el ejercicio físico (11, 12,13).
Por tal motivo es preciso disponer de la documentación necesaria para la preparación de los recursos humanos encargados de la atención a este importante sector poblacional. De esta manera, nos motivamos a realizar una revisión bibliográfica con el objetivo de crear un material complementario para el estudio del comportamiento fisiológico cardiorespiratorio en el adulto mayor durante el ejercicio físico. Lo que sin dudas redundará en una mejor preparación  de los residentes de fisiología y cardiología.
DESARROLLO
Al inicio del ejercicio se transmiten señales del cerebro por las vías motoras piramidal y extrapiramidal a los músculos, para producir la contracción, las cuales dejan colaterales en el centro vasomotor (CVM). Ello genera una descarga simpática masiva, que atenúa las señales parasimpáticas al corazón. La noradrenalina liberada por las terminaciones simpáticas, aumenta la permeabilidad de las células marcapaso al Na+ y al Ca++ con lo que disminuye la electronegatividad del potencial de membrana en reposo y por ende, aumenta la excitabilidad del nodo sinusal y con ello el incremento de la frecuencia cardiaca (FC). Además, se estima que los productos finales del metabolismo muscular, provocan la transmisión de señales reflejas directas, que ascienden por la médula espinal hasta el CVM, favoreciendo la respuesta cronotrópica. (14)
Por otro lado, durante el ejercicio, el aumento de la tasa metabólica, eleva en el tejido muscular las concentraciones de sustancias vasodilatadoras como la adenosina, el Coy el ácido láctico. Lo cual, unido a la disminución de la  presión de oxígeno, provoca dilatación de los esfínteres precapilares con el consiguiente aumento del flujo sanguíneo muscular (14,15). La estimulación simpática, por su parte, produce vasoconstricción en la mayoría de los tejidos, preservando el sistema coronario, el cerebro y el tejido muscular. La redistribución del flujo sanguíneo, determina un préstamo de hasta 2 litros de sangre a los músculos en actividad. El aumento del flujo sanguíneo muscular unido a la propia actividad contráctil, facilita el retorno venoso, lo cual provoca distensión del atrio derecho y con ello, la estimulación directa del nodo sinusal, al tiempo que activa el reflejo de Bainbridge. Todo lo cual, explica el aumento lineal de la FC conforme se incrementa la carga física. (14)
A medida que avanza la edad hay una disminución significativa de la FC máxima teórica, esto se debe a varios factores, entre los que se describen los cambios en la respuesta a los quimiorreceptores y barorreceptores, el aumento del tono vagal, las alteraciones de la célula miocárdica y del sistema excito conductor, dentro de las que se destacan la apoptosis, el depósito de colágeno y grasa tisular. (16)  Esto redunda en una disminución en el número de las células marcapasos tan notoria, que algunos autores han reportado a los 75 años una pérdida  del 90% de dichas células respecto a las presentes a los 20 años de edad. (17)
Dado el menor índice de masa cardíaca con respecto al peso en las féminas y la actividad física inferior a los hombres, es fisiológica la existencia de un mayor incremento de la FCcomparada con estos a un mismo nivel de carga. (17,18)
En lo referente a la presión arterial sistólica (PAS), esta experimenta una elevación lineal conforme aumenta la carga, fenómeno ampliamente validado en la literatura consultada.(15,17,19,20) En la que se describe que la PAS, puede llegar de forma fisiológica a alcanzar un valor máximo entre 160 y 200 mm Hg, correspondiendo el límite superior de la escala, a los pacientes de más edad y con sistemas vasculares menos distensibles. (21)
La respuesta presora fisiológica, se explica por la vasoconstricción de las arteriolas y pequeñas arterias en el sistema esplácnico y la piel, lo que provoca elevación de la resistencia vascular periférica, aumento del gasto cardiaco y de la presión circulatoria media de llenado. (14, 15,20)
Así mismo, ha sido ampliamente verificado un mayor aumento de la presión arterial sistólica (PAS)  con la edad, debido a cambios entre los que se encuentran: el aumento de grosor de las paredes de las grandes arterias de distribución, así como a su dilatación y alargamiento. Tal engrosamiento ocurre a expensas de la capa íntima por la acumulación de células y depósito de matriz; también se produce fragmentación de la membrana elástica interna, aumento y cambios en el cruzamiento del colágeno dentro de la media vascular, lo que disminuye la elasticidad de esta capa. (17,22)    
Las glucoproteínas acaban por desaparecer de las fibras de elastina y esta se deshilacha. Cambios,  en parte, ocurridos durante el proceso aterosclerótico. Ello, unido al aumento de la actividad elastasa y al depósito de Ca++ y colesterol sobre la elastina, contribuye a la fragmentación de esta última o a la reducción de su contenido. Finalmente, el resultado es la rigidez de las arterias y el aumento de la onda y de la presión de  pulso. (17,22)    
Resulta tan importante esta respuesta fisiológica tensional que algunos autores, consideran anormal que la presión sistólica no supere los 120 mm Hg, que experimente un descenso mantenido superior a 10 mm Hg o que descienda durante el ejercicio por debajo de los valores medios en reposo con el paciente erecto. Todo lo cual reflejaría un aumento insuficiente del gasto cardiaco a causa de una disfunción sistólica del ventrículo izquierdo (VI) o a una reducción excesiva de la resistencia vascular periférica (RVP). (21) 
En investigaciones realizadas, en algunos adultos mayores sanos sometidos a una carga física, se observa una reacción excesiva de la PAS al comenzar el ejercicio. Ello pudiera explicarse por la fuerte activación del sistema simpático en sujetos ansiosos al inicio de la prueba, quienes además por ser personas envejecidas tienen, de por sí, una mayor respuesta simpática debido a mayores concentraciones de catecolaminas circulantes, lo cual se corrobora si se logra la estabilización de este parámetro posteriormente. (14, 17,21)  
Por su parte, la presión arterial diastólica en personas normales no suele variar de modo significativo, aunque puede elevarse ligeramente dada las resistencias vasculares periféricas (RVP) más altas en los adultos mayores. (20,21) 
La frecuencia respiratoria (FR) se incrementa de forma lineal a medida que la carga aumenta, con valores similares para ambos sexos. Fisiológicamente, durante la primera fase del ejercicio, como consecuencia de la obtención de energía por el metabolismo anaeróbico, se elevan las concentraciones del ácido láctico, y por ende, de los hidrogeniones en sangre. Esto, conjuntamente con la estimulación refleja del centro respiratorio por las colaterales motoras, provoca el consiguiente incremento de la FR y del volumen corriente, a expensas de los volúmenes inspiratorios y espiratorios de reserva. Paralelamente, ocurre una disminución del espacio muerto fisiológico, como consecuencia de una mejor distribución de la ventilación y la perfusión en el parénquima pulmonar, además de la apertura de los bronquiolos en respuesta a la adrenalina circulante. (14,15)
A partir de este reajuste, se logra pasar a la fase estable, durante la cual hay un equilibrio entre la necesidad de Oy la velocidad con la que este puede ser transportado, hasta que se alcanzan los valores pico. En la etapa de recuperación, la FR comienza a descender, aunque no de manera brusca, ya que se debe pagar la deuda de Ocontraída en la fase inicial. (23)
Otra de las variables estudiadas en sujetos sanos es la saturación arterial de oxígeno (SO2), este parámetro se mantiene prácticamente constante durante la actividad física en ambos sexos. La literatura consultada plantea como rango fisiológico disminuciones no superiores al 5% durante el ejercicio. (14)
Con los datos obtenidos de la prueba de esfuerzo se pueden calcular otras variables de interés cardiorespiratorio, una de ellas es el índice de respuesta cronotrópica (IRC).  Autores como Chaitman, consideran  patológicas las cifras por debajo de 0,80 debido a su demostrada asociación con mayor mortalidad a largo plazo. (21)
Al ser este parámetro dependiente de la FC de reserva, es lógico suponer que disminuye con la edad, así, la FC sinusal intrínseca, es decir, medida tras el bloqueo simpático y parasimpático, disminuye a pesar de que en las personas envejecidas la actividad del sistema nervioso simpático se incrementa, debido a la mayor cantidad de catecolaminas circulantes ( 16,17) .
La presencia de niveles elevados de noradrenalina en los ancianos, se debe a una menor recaptación en las terminales nerviosas, así como a la disminución de su degradación. Tal aumento, lleva a una mayor ocupación de los receptores β-adrenérgicos en la superficie de las células cardiacas y de los vasos sanguíneos, al tiempo que disminuye su expresión. Estos factores provocan un fenómeno de desensibilización y disminución de la densidad de receptores en las células blanco, denominado «regulación hacia la baja», lo cual interfiere en el acoplamiento de las señales intracelulares mediadas por los sistemas de segundos mensajeros (17,24).
También han sido descritos en sujetos ancianos, cambios a nivel molecular y bioquímico en el acople de los receptores β1 y β2 para el mecanismo post-receptor, entre los que se destaca, el relativo al receptor β-adrenérgico con las proteínas Gs y la adenilciclasa. Ello implica, una reducción de la función máxima de la adenilciclasa, con disminución en la capacidad para aumentar de forma suficiente el AMPc intracelular, imprescindible en la fosforilación de proteínas claves para el adecuado funcionamiento cardiaco. (17)
En relación con la recuperación de la frecuencia cardiaca (RFC), Chaitman sin discriminar entre los sexos, considera anormales los valores por debajo de 18 lat. /min en pacientes colocados en decúbito supino después del ejercicio, pues indican que tras la interrupción de la actividad física, la recuperación anormal de la FC por desaceleración relativamente lenta, implica una disminución del tono vagal que ha sido incluso asociada a un aumento de la mortalidad. (21)
Por su parte, las determinantes fisiológicas del consumo de oxígeno del músculo cardíaco (MVO2) son principalmente la FC, la postcarga (representada por la PAS) y el estado contráctil de las fibras miocárdicas. En la práctica clínica, el MVO2 es difícil de medir directamente, pues requiere de métodos invasivos, sin embargo, se ha precisado que el producto de la PAS máxima (PASmx) la FC máxima (FCmx) para una carga dada, valor conocido como «doble producto», es el indicador que tiene mayor correspondencia con el MVO2 (15). Cifras de esta variable, superiores a 23,000 son relacionadas con un desempeño cardiaco normal (21). Al tener a la FCmx y la PAmx como sus componentes, el doble producto resultante, es un fiel marcador de su adecuado rendimiento cardiovascular. 
Respecto a la carga máxima alcanzada (CMx) es de suponer la existencia de diferencias significativas entre las mujeres y los hombres. Según la literatura revisada, los hombres alcanzan más carga debido a la mayor masa muscular, talla y hemoglobina de estos respecto a las mujeres (19).
En relación con el consumo de oxígeno máximo (VO2mx)la literatura consultada reporta que suele ser menor en las mujeres (21,22). En estas últimas, además de las razones arriba expuestas, se aduce que su mayor masa de tejido adiposo, el cual tiene una relativa inactividad metabólica frente al muscular, es responsable de un menor VO2.  Woo y Derleth añaden a esto el menor tamaño del corazón en las féminas. (18) Allison, plantea que el VO2 en las mujeres equivale a un 80 a 90% del alcanzado por los hombres a nivel igual de carga (25). Fleg y Morrell hallaron un 17% inferior en mujeres respecto a los hombres (26).
Ha sido ampliamente comprobado que el VO2 disminuye con la edad, esto se debe a un deterioro en un 25% del gasto cardíaco máximo y al descenso de la utilización periférica del O2, dada la reducción en una cuarta parte de la diferencia arteriovenosa de O2, así como a  los valores menores de frecuencia cardiaca máxima, de volumen máximo de eyección y de los parámetros de la función pulmonar (27).
Lakatta y Chantler añaden a lo anterior, una eficiencia reducida de la respiración mitocondrial con deficiente  utilización del O2 a nivel del músculo (28). Woo y Derleth  aducen que con el envejecimiento disminuye la capilarización muscular, así como la distancia para la difusión de O2, factores estos que contribuyen a una disminución de su consumo paralelo a la edad (18)
La American Heart Association según sus recomendaciones vigentes, establece que los individuos con rangos entre 18 y 22,5 ml/kg/min tienen un riesgo cardiovascular intermedio, mientras que aquellos con valores inferiores a 18 ml/kg/min, sufren un deterioro cardiorespiratorio crítico (25).
Por su parte, el consumo de oxígeno efectivo (VOEmx), variable que hace referencia a la capacidad funcional pico, al relacionar el VO2 mx  alcanzado con el VO2 mx  teórico calculado según la edad, el sexo y la talla debe superar el 85%. Chaitman plantea que cifras inferiores al  85-90%, se corresponden con una menor capacidad de ejercicio (21). El American College of Sports Medicine y la American Heart Association recomiendan un rango de  50–85% (29) 

CONCLUSIONES

1- La frecuencia cardiaca máxima, el índice de respuesta cronotrópica, la carga máxima y el consumo de oxígeno disminuyen a medida que aumenta la edad, lo que se debe a los cambios morfofuncionales propios del envejecimiento.
2-En los adultos mayores la presión arterial sistólica durante el ejercicio puede alcanzar cifras de 160 y 200 mm Hg, correspondiendo el límite superior de la escala, a los pacientes de más edad y con sistemas vasculares menos distensibles.
3-La frecuencia respiratoria, la saturación de oxígeno y el doble producto mantienen rangos similares al de los individuos jóvenes y no experimentan variación significativa durante el ejercicio.

REFERENCIAS BIBLIOGRÁFICAS
1          Organización Mundial de la Salud.  Segunda Asamblea Mundial sobre el Envejecimiento. Envejecimiento de la población: hechos y cifras. Madrid: Organización Mundial de la Salud; 2002.
2          Alonso Galbán P; Sansó Soberats FJ; Diaz- Canel Navarro AM; Carrasco García M; Oliva Tania. Envejecimiento poblacional y fragilidad en el adulto mayor. Rev Cub Salud Pública 2007; 33(1): 24-28.
3          Zacca Peña E. Situación de salud en Cuba: Indicadores básicos 2007. La Habana: Ministerio de Salud Pública; 2008.
4          Ministerio de Salud Pública. Programa del Adulto Mayor. La Habana: MINSAP; 1997.
5          Vega García E, Menéndez Jiménez JE, Rodríguez Rivera L, Ojeda Hernández M, Leyva Salermo B, Cardoso Lunar N…et al. Atención al Adulto Mayor. En: Álvarez Sintes R. Medicina General Integral Vol.1. 2ªed. La Habana: Editorial Ciencias Médicas; 2008; p. 420-435.
6        Ramonet I. Cien horas con Fidel. La Habana: Oficina de Publicaciones del Consejo de Estado; 2006.
7             Negrín S, Sosa A, Ayala M, Fernández JR, Pujols M, González LJ, et al.  Biotecnología y adulto mayor. La Habana; Universidad para todos-Editorial Academia; 2008.
8          Lai S, Kaykha A, Yamazaki T, et al: Treadmill scores in elderly men.  J Am Coll Cardiol 2004; 43:606-607.
9             Woo JS, Derleth C, Stratton JR, Levy WC. The Influence of Age, Gender, and Training on Exercise Efficiency. J Am Coll Cardiol. 2006; 47(5): 1049-1056.
10      Fleg JL, Morrell CH, Bos AG, et al: Accelerated longitudinal decline of aerobic capacity in healthy older adults.  Circulation 2005; 112:674-675.
11      Rivero Varona MM, Ramos Emperador C, Oliva Martínez D. Prueba ergométrica en el anciano. Acta Médica 2002; 10(1-2).
12      Erikssen G, Bodegard J, Bjornholt JV, et al: Exercise testing of healthy men in a new perspective: From diagnosis to prognosis.  Eur Heart J 2004; 25:978-986.
13      Shishehbor MH, Litaker D, Pothier CE, Lauer MS: Association of socioeconomic status with functional capacity, heart rate recovery, and all-cause mortality.  JAMA 2006; 295:784-785.
14    Guyton AC: Textbook of Medical Physiology. 11th ed. Philadelphia: Saunders-Elsevier; 2006.
15    Pérez Coronel PL. Aspectos básicos sobre fisiología del ejercicio, control médico del entrenamiento. Pérez Coronel PL. Rehabilitación cardiaca integral. 1 ed. La Habana: Ciencias Médicas; 2009. p. 37-44.
16    Lakatta EG. La vejez y el sistema cardiovascular. En: Beers MH, Berkow R, Bogin RM, Fletcher AJ, Rahman MI. Manual Merck de Geriatría. 3da ed. ?Offline Explorer enterprise HTML?New Jersey: Merck & Co., Inc; 2002.
17    Alexander KP, O'Connor C M. The Elderly and Aging. Topol E J, Califf R M, Prystowsky EN, Thomas JD, Thompson PD. Textbook of Cardiovascular Medicine. 3 ed. USA: Lippincott Williams & Wilkins; 2007. p. 562-586. 
18         Woo JS, Derleth C, Stratton JR, Levy WC. The Influence of Age, Gender, and Training on Exercise Efficiency. J Am Coll Cardiol. 2006; 47(5): 1049-1056.
19    Engel G. ECG Exercise Testing. Uster V, Walsh RA, O'Rourke RA, Poole-Wilson P. Hurst's the Heart. 12 ed. USA: The McGraw-Hill Companies; 2008. p. 505-519.
20    Espinosa Caliani JS, de Teresa  E, Castellano Reyes C. Prueba de esfuerzo y test farmacológicos. Castellano Reyes C. Electrocardiografía clínica. 2 ed. España: Elsevier; 2004. p. 127-173.
21    Chaitman BR. Exercise stress testing. En: Libby P, Bonow RO, Mann DL, Zipes DP. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine Vol.1, 8th ed. Philadelphia: Saunders-Elsevier; 2008. p. 195-219.
22    Beers MH. Manual Merck de Geriatría. 2 ed. Madrid: Elsevier España 2001.                                                                              
23    Wasserman K, Principles of Exercise Testing and Interpretation, 4th ed. Philadelphia; Lippincott Williams & Wilkins; 2005.
24         Correia LC, Lakatta EG, O’Connor FC, Becker LC, Clulow J, Townsend S, et al. Attenuated Cardiovascular Reserve During Prolonged Submaximal Cycle Exercise in Healthy Older Subject. J Am Coll Cardiol. 2002; 40(7): 1290-1296. 
25    Allison TG. Cardiopulmonary exercise testing. En: Murphy JG, Lloyd MA, Barsness GW, Jahangir A, Kane GC, Olson LJ. Mayo clinic cardiology, Concise Textbook. 3th ed.Rochester: Mayo Clinic Scientific Press; 2007.  p. 231-239.
26    Fleg JL, Morrell CH, Bos AG, Brant LJ, Talbot LA, Wright JG, et al. Accelerated Longitudinal Decline of Aerobic Capacity in Healthy Older Adults. Circulation. 2005 August; 112: 674-682.
27    Erikssen G, Bodegard J, Bjornholt JV, et al: Exercise testing of healthy men in a new perspective: From diagnosis to prognosis.  Eur Heart J 2004; 25:978-986.
28    Lakatta EG, Chantler PD. Payments for Debts Associated With Exercise Can Become Higher as We Age and Limit Exercise Capacity. J Am Coll Cardiol. 2006; 47(5): 1058-1059.
29     Nelson ME, Rejeski WJ, Blair SN, Duncan PW, Judge JO, King AC, et al. Physical Activity and Public Health in Older Adults: Recommendation from the American College of Spo. Circulation. 2007; 116(1): 1094-1105.

Risk of Stroke After Chiropractic Spinal Manipulation in Medicare B Beneficiaries Aged 66 to 99 Years With Neck Pain

,
 Yunjie Song, PhD
, ,
 Reed B. Phillips, DC, PhD
, ,
 Jon D. Lurie, MD, MS


Risk of Stroke After Spinal Manipulation

Manipulation of the cervical spine is a treatment for neck pain often performed by chiropractic physicians, but the safety of cervical spine manipulation has been questioned because observational studies have linked cervical spine manipulation to vertebral artery dissection and subsequent vertebrobasilar stroke (VBS).1, 2, 3 A considerable amount of controversy persists regarding the safety of cervical spine manipulation.4
Vertebrobasilar stroke is an uncommon type of stroke, with a reported population incidence of 0.97 cases per 100 000.5The likelihood of VBS after spinal manipulation has been examined in 3 studies using case-control designs, an approach well suited to the evaluation of rare conditions such as VBS. Smith et al3 compared patients with ischemic stroke or transient ischemic attack, with and without vertebral artery dissection, and concluded that spinal manipulation is an independent risk factor for vertebral artery dissection. Rothwell et al2 studied 582 cases of VBS and found that patients with stroke younger than 45 years were 5 times more likely than controls to have visited a chiropractor within 1 week of the stroke. Cassidy et al1 also found an increased association between chiropractic visits and vertebrobasilar artery stroke in patients younger than 45 years, but the association was no greater than that associated with visits to primary care physicians. Taken together, the results of these case-control studies constitute the strongest evidence regarding the association between spinal manipulation and VBS.
More subject to bias in favor of a stronger association with spinal manipulation was an observational study of 1897 subjects conducted by Engelter et al,6 who used a questionnaire to assess for “prior cervical trauma.” Spinal manipulation was found to be a determinant of cervical (vertebral or carotid) artery dissection but not an independent risk factor. Also with greater potential for bias—in either direction—was the use of an ecological study design by Boyle et al,7 who found that marked increases in the rates of VBS in 2 Canadian provinces in 2000 were unassociated with increased utilization of chiropractic services.
Several recent systematic reviews on the safety of chiropractic care and spinal manipulation have been largely inconclusive with regard to risk of adverse events in general and stroke in particular. In 2005, Rubinstein et al8 evaluated risk factors for cervical artery dissection. They found strong associations for “trivial trauma” (including spinal manipulation) but conducted no meta-analysis. They urged caution with regard to attributing cervical artery dissection to spinal manipulation, pending further research.8 In 2007, in a systematic review on the adverse effects of spinal manipulation, Ernst9 concluded that spinal manipulation can cause vertebral artery dissection, but in 2012, a replication of that review found numerous errors and omissions that threatened its validity.10 A review of the safety of chiropractic interventions published in 2009 found no robust data on the incidence of adverse reactions after chiropractic care. Estimates of the risk of serious adverse events such as stroke ranged from 0.05 to 1.46 per 10 000 000 manipulations.11 A systematic review published in 2010 was also unable to draw any conclusions regarding the risk of adverse events associated with manipulation of the cervical spine for care of neck pain in adults.12 Similarly, a review published in 2012 found the evidence inadequate to either confirm or refute a significant association between manipulation of the cervical spine and stroke.13

Age as a Risk Factor for VBS After Spinal Manipulation

Efforts to identify either risk factors or populations at risk for VBS have been largely unsuccessful.14, 15 The risk of stroke in general increases with age,16 but it is not known how age might affect the risk of stroke after spinal manipulation.17 Current best knowledge of the risk of stroke temporally associated with spinal manipulation in older patients is based upon the work of Rothwell et al2 and Cassidy et al,18 who collectively found only 53 patients older than 45 years with stroke after spinal manipulation, of a total of 1400 cases of VBS. Rothwell et al analyzed 582 cases of VBS and found no significant association between VBS and chiropractic care for those 45 years and older. Cassidy et al analyzed 818 cases of VBS, stratified by age, and also found no association between VBS and chiropractic care for those 45 years and older.1Subsequently, Choi et al17 examined patient demographic data in 3 case series and 3 surveys on characteristics of patients with stroke after spinal manipulation. Where reported, mean patient age in these studies ranged from 34.0 years (n = 10) 19 to 44 years (n = 74).20 However, Choi et al17 found a population at risk that was significantly older than that previously reported: in a population-based case series of 93 patients with VBS who had visited a chiropractor in the previous year, mean patient age was 57.6 years.

Risk of Stroke After Chiropractic Spinal Manipulation in Elderly US Adults

No population-based studies of risk of stroke after spinal manipulation have been conducted in the United States or focused upon older adults. In this study, we sought to answer the research question: “In Medicare beneficiaries aged 66-99 with neck pain, what is the probability of stroke following chiropractic spinal manipulation, as compared to a control group of subjects evaluated for neck pain by a primary care physician?” Among Medicare beneficiaries aged 66 to 99 years, we hypothesized no difference in risk of stroke between those exposed to chiropractic spinal manipulation for neck pain and those exposed to evaluation by a primary care physician for neck pain. Because chiropractors frequently treat neck pain with spinal manipulation and the temporal association between provider office visits and stroke has been observed to be stronger in patients with neck pain,18 we limited our sample to beneficiaries with neck pain. (Choi et al17found that among 93 patients with VBS and a chiropractic visit within the previous year, the most common comorbidities [reported by 67%] were neck pain and headache.) An understanding of the relationship between spinal manipulation and stroke among US Medicare beneficiaries should help facilitate the safe and appropriate utilization of chiropractic care for neck pain in older adults. Thus, the purpose of this study was to quantify risk of stroke after chiropractic spinal manipulation, as compared to evaluation by a primary care physician, for Medicare beneficiaries aged 66 to 99 years with neck pain.

Methods

The Dartmouth College Committee for Protection of Human Subjects reviewed and approved the research plan. This study was supported by the National Institutes of Health under Award Number K01AT005092.

Data Sources and Sampling

We conducted a retrospective cohort study using Medicare administrative data. Our data sources were 100% ofDenominator files (for beneficiary demographics), Carrier files (for outpatient claims), and MEDPAR files (for inpatient claims) for the years 2006 to 2008. The data files were merged on unique beneficiary identifiers to generate the analytic files.

Cohort Definition

Each included beneficiary was assigned to 1 of 2 cohorts, in which beneficiaries with neck pain used either chiropractic care or primary care exclusively:
  • Chiropractic cohort: Beneficiaries with at least 1 allowed Medicare B claim in 2007 for chiropractic office visit with spinal manipulation, identified as claim with provider specialty code number 35, with current procedural terminology code for spinal manipulation (98940, 98941, or 98942), but without a primary care office visit for neck pain in 2007.
  • Primary care cohort: Beneficiaries with at least 1 allowed Medicare B claim in 2007 for primary care office visit for evaluation and management, but without a chiropractic office visit for neck pain in 2007. (Primary care visits were identified as claims associated with the provider specialty code for family medicine [08], internal medicine [11], or general practice [01].) Evaluation and management services were identified by BETOS Code “M”.

Exposures

We included all beneficiaries covered under the Medicare B fee for service plan, aged 66 to 99 years, and living as of January 1 of each year, with at least 1 allowed Medicare B claim in 2007 for an office visit associated with a diagnosis of neck pain to either a chiropractor or primary care physician. Neck pain was identified by any of the following International Classification of DiseasesNinth Revision (ICD-9), codes: 721.0, 721.1, 722.0, 722.4, 722.71, 722.81, 722.91, 723.0, 723.1, 723.2, 723.3, 723.5, 723.7, 723.8, 723.9, 739.1, 756.16, 756.2, 839.00, 839.01, 839.02, 839.03, 839.04, 839.05, 839.06, 839.07, 839.08, 847.0, 953.0, or 953.4. We excluded duplicate claims for the same patient, provider, procedure, and date of service. We also excluded beneficiaries with a previous history of cerebrovascular disease (in Part A or Part B data) at any time during the 1-year period before the date of first exposure and accrual to cohort. Prior cerebrovascular disease was identified by any of the following codes for stroke (ICD-9 430, 431, 432-432.9, 433-433.9, 434-434.9, 436, 437.1, 443.21, 443.24, or 900-900.9), transient cerebral ischemia (ICD-9 435-435.9), or late effects of cerebrovascular diseases (ICD-9 438-438.9). A 1-year look back window from first exposure to office visit for neck pain and accrual to cohort served to exclude beneficiaries with a recent history of cerebrovascular disease and to calculate Charlson comorbidity scores for risk adjustment (Fig 1). The Charlson comorbidity index is a validated prognostic tool based upon the risk of mortality associated with a range of comorbid chronic diseases. For each patient, individual conditions are assigned scores, which are summed to provide a total score.
Medicare allows coverage for chiropractic spinal manipulation of up to 5 spinal regions (cervical, thoracic, lumbar, sacral, and pelvic). It is not possible to specifically identify manipulation of the cervical spine through analysis of Medicare data because the procedure codes for chiropractic spinal manipulation identify the number of spinal regions manipulated but not the specific spinal regions at which the manipulations were performed. However, Medicare does require that the level at which the manipulation is performed must be tied to the patient's complaint.21 Therefore, assuming compliance with Medicare clinical practice guidelines, a patient complaint of neck pain should be associated with the delivery of cervical spine manipulation.

Outcomes Measurement

The hazard (observation) period for identifying outcomes was a 30-day window after each exposure to an office visit for neck pain. We set the hazard period at 30 days to allow for comparison of our results with the findings of previous reports.1The primary outcome measure was VBS within 30 days of office visit for neck pain. However, because of the potential for bias resulting from the imprecise use of diagnosis codes in claims data, we also analyzed for any type of stroke. We identified stroke by ICD-9 codes 430, 431, 432–432.9, 433-433.9, 434-434.9, 436, 437.1, 443.21, 443.24, or 900-900.9, recorded in hospital emergency department or inpatient claims. We categorized strokes as VBS and non-VBS—identifying VBS by diagnosis code 433.00, 433.01, 433.20, or 433.21—all other stroke codes were categorized as non-VBS. As a secondary outcome measure, among those diagnosed with stroke, we also evaluated for death within 30 days of office visit. For each successive office visit, we evaluated for days to diagnosis of stroke and censored the previous visit. Subjects were removed from follow-up upon occurrence of their first stroke. Evaluation of risk by office visit allowed comparison of risk between cohorts while allowing for the high degree of variability in number, frequency, and timing of office visits. For analysis of hazard of stroke within 30 days, we excluded subjects who were hospitalized for stroke on the same day as the office visit because these patients likely presented with signs or symptoms of stroke (Fig 2). The data used in this study were analyzed in accordance with a data user agreement with The Centers for Medicare and Medicaid Services. Rules for the conduct of Medicare-approved research projects stipulate that specific quantities may not be disclosed if the unit of observation contains less than 11 subjects.
Thumbnail image of Fig 2. Opens large image

Fig 2

Exclusions and censoring.

Analysis

We initially measured incidence of first stroke after exposure to office visit and analyzed for 30-day mortality after stroke. We compared the hazard of stroke within 30 days between patients visiting chiropractors and those visiting primary care physicians, using a Cox proportional hazards model. The model was adjusted for subject age, sex, race and Charlson comorbidity index. We used the same approach to estimate the hazard ratio of stroke within the first 7 days (by right censoring all subjects at 7 days). To estimate the cumulative probability of stroke up to 30 days for the chiropractic and primary care physician groups while adjusting for the covariates stated above, we used direct adjusted survival curves, as described by Zhang et al.22, 23 We performed data analyses in SAS (SAS Institute, Inc, Cary, NC).

Results

We found 1 157 475 Medicare beneficiaries with an office visit to either a chiropractic or primary care physician for neck pain (Fig 2). Of these, 38 138 (3%) had seen both types of providers: we excluded these subjects from the study population, thus creating 2 mutually exclusive cohorts of chiropractic and primary care patients. We excluded 55 patients (7.5 per 100 000) from the chiropractic cohort and 278 patients (72 per 100 000) from the primary care cohort who were diagnosed with stroke on the same day as an office visit for neck pain. The chiropractic cohort (n = 733 321) was nearly twice as large as the primary care cohort (n = 385 683), and the number of chiropractic office visits (7 041 912) was more than 11 times greater than the number of primary care office visits (608 374).
The 2 cohorts also differed with regard to age, sex, race, and comorbidity score (Table 1). The chiropractic cohort was younger, with a significantly greater proportion of subjects younger than 75 years and a lesser proportion older than 80 years. The chiropractic cohort also was composed of a higher proportion of males and significantly lower proportions of blacks and other minorities. The chiropractic cohort appeared to be healthier than the primary care cohort, as indicated by a significant difference in Charlson comorbidity scores (0.92 vs 1.29; difference, −0.37; 95% confidence interval [CI] −0.38 to −0.36).
Table 1Subject Characteristics
CohortChiropracticPrimary CareDifference (A-B)95% CI
Subjects733 321385 683347 638
Office visits for neck pain7 041 912608 3746 433 538
Subjects with stroke377310692704
Age in years
 % 66-6929.2724.255.02a4.84-5.19
 % 70-7429.1625.453.71a3.54-3.88
 % 75-7921.4621.990.53a0.69 to −0.37
 % 80-8412.8316.223.39a3.52 to −3.25
 % 85-997.2712.084.80a4.92 to −4.39
 % Male38.7733.575.20a5.02-5.39
Race
 % White96.6286.989.63a9.54-9.74
 % Black1.416.985.56a5.64 to −5.47
 % Other1.966.044.08a4.15 to −4.01
Mean Charlson comorbidity score0.921.290.37a0.38 to −0.36
CI, confidence interval.
aP < .05.
The specific incidence of VBS was too small to report and thus precluded further analysis. The proportion of subjects with stroke of any type in the chiropractic cohort was 1.2 per 1000 at 7 days after office visit for neck pain and 5.1 per 1000 at 30 days. In the primary care cohort, the proportion of subjects with stroke of any type was 1.4 per 1000 at 7 days after office visit for neck pain and 2.8 per 1000 at 30 days (Fig 2). Among subjects who sustained any type of stroke, there was no significant difference in 30-day mortality between cohorts (chiropractic cohort, 9.65%; primary care cohort, 9.1%; difference, 0.52%; 95% CI, −1.88 to 2.93).
From the day after office visit (day 1) to day 24, the probability of stroke was lower in the chiropractic cohort as compared to the primary care cohort (2 vs 7 strokes per 100 000 subjects, respectively, at day 1; 110 vs 111 strokes per 100 000 subjects, respectively, at day 24). However, on days 25 to 30, the probability of stroke for the chiropractic cohort exceeded that for the primary care cohort (116 vs 115 strokes per 100 000 subjects, respectively, at day 25; 162 vs 134 strokes per 100 000 subjects, respectively, at day 30). Figure 3 illustrates the adjusted probability of stroke for the 2 cohorts over the 30-day hazard period. The unadjusted hazard ratio for the chiropractic cohort vs the primary care cohort was 0.33 (95% CI, 0.28-0.37) at 7 days and 0.91 (95% CI, 0.85-0.99) at 30 days. With adjustment for differences in patient characteristics, however, hazard ratios at days 7 and 30 (Table 2) reflected the crossover effect illustrated in Figure 3. In the chiropractic cohort, risk of stroke was significantly lower at 7 days as compared to the primary care cohort (hazard ratio, 0.39; 95% CI, 0.33-0.45), but at 30 days, a slight but statistically significant elevation in risk was observed for the chiropractic cohort (hazard ratio, 1.10; 95% CI, 1.01-1.19). Male sex, increasing age category, and increased Charlson comorbidity score were all associated with increased risk of stroke in the study population.
Thumbnail image of Fig 3. Opens large image

Fig 3

Adjusted probability of stroke over the first 30 days after office visit for neck pain.
Day 1 = Day after the day of office visit.
Table 2Risk of Stroke After Office Visit for Neck Pain
7 d30 d
Hazard Ratio95% CIHazard Ratio95% CI
Chiropractic (vs primary care)0.39a0.330.451.10a1.01-1.19
Male sex (vs female)1.44a1.271.621.37a1.29-1.45
Age category (vs 66-69)
 70-741.29a1.041.601.16a1.04-1.29
 75-791.90a1.542.341.93a1.74-2.14
 80-843.03a2.463.7422.50a2.25-2.78
 85+3.70a2.964.633.59a3.21-4.00
Race (vs white)
 African American1.210.851.711.20.99-1.46
 Other1.110.791.571.030.85-1.25
Charlson comorbidity score1.08a1.051.121.13a1.11-1.15
CI, confidence interval.
aP < .05.

Discussion

Because risk of stroke in general increases with age, understanding the relationship between cervical spine manipulation and stroke and in older adults will help assure the safe utilization of chiropractic care in this vulnerable population. This is the first study to focus upon the risk of stroke after spinal manipulation in older adults, so the results are not directly comparable to previous studies, but our results are consistent with reports by Rothwell et al2 and Cassidy et al,24 which suggest that VBS is uncommon in older adults. Aging may be protective against VBS stroke, as compared to other types of stroke. With regard to risk of any type of stroke, we found that increasing age category was associated with increased risk of any type of stroke, consistent with morbidity data published by The National Institutes of Health.25
The specific incidence of VBS was too low to report, but the incidence was less than 9.8 per million Medicare part B beneficiaries aged 66 to 99 years with office visit for neck pain. This result is remarkably consistent with the incidence rate of 9.7 cases of VBS per 1 000 000 population reported by Lee et al.5 Because vertebral artery dissection and associated thromboembolism are the most plausible mechanism by which spinal manipulation could cause stroke, our findings support current best evidence suggesting that manipulation of the cervical spine is unlikely to be a significant cause of stroke in older adults.1, 26, 27
Blacks, Hispanics, and Native Americans are known to be at higher risk for stroke than Asians and non-Hispanic whites,28and the lack of effect of race in this study is most likely due to the fact that minorities were underrepresented in the study population because minorities comprise only 3% to 4% of chiropractic users under Medicare.29 The increased risk associated with increased Charlson comorbidity score is likely due to the well-established increased risk of stroke associated with cardiovascular disease, diabetes, and previous history of cerebrovascular disease.28
We found that the probability of any type of stroke on the day of office visit (day 0) was much lower in the chiropractic cohort as compared to the primary care cohort. With exclusion of strokes that occurred on the same day of office visit, the adjusted probability of stroke remained lower in the chiropractic cohort until day 25, when relative risk was reversed and remained higher in the chiropractic cohort for the remainder of the hazard period. At day 0, the higher probability of stroke in the primary care cohort may have been due to a propensity to seek medical rather than chiropractic care among patients with neck pain who also had other symptoms potentially related to stroke. The differences between cohorts in the timing of the diagnosis of stroke may also be related to differences in diagnostic practices between chiropractic and primary care physicians. Song et al30 reported that significant differences in physician's diagnostic practices may be unrelated to patient characteristics. The observed between-cohort differences in probability of stroke may be due to earlier and more aggressive diagnostic testing practices among primary care physicians as compared to chiropractic physicians. It is possible that the short-term increase in hazard of stroke in the primary care cohort was associated with increased treatment of neck pain with nonsteroidal anti-inflammatory drugs, which have been linked to increased risk of ischemic stroke.31 Although a purely speculative observation, investigation of this potential association may be indicated.
Regardless of the reason for the observed differences, with the exclusion of same-day strokes, the maximum observed effect size (observed at day 15) was an additional risk of 3 strokes per 10 000 office visits for the primary care cohort. Although statistically significant, this difference as well as the crossover effect seen in Figure 3 may not be clinically significant. The lack of a mechanism by which an office visit might cause a non-VBS stroke and the decreasing likelihood of a causal relationship over 30 days also cast doubt upon the clinical significance of these between-cohort differences in results.
The true probability of stroke is probably unaffected by an office visit to either type of provider and likely resides between the 2 trend lines seen in Figure 3. Chiropractic physicians must be able to recognize symptoms of stroke to provide early detection and when necessary refer patients for appropriate treatment.24 In a retrospective case series, 6 of approximately 500 active chiropractic patients presented with symptoms and signs of stroke.32 Among respondents to a survey of 2000 randomly selected US chiropractors, first recognition of undiagnosed life-threatening conditions, including stroke, reportedly occurred in the normal course of practice at a rate of 1 case every 2.5 years.33

Limitations

In designing this study, we strove to reduce bias due to inaccurate diagnostic coding by including any type of stroke as an outcome of interest (despite the lack of evidence for a relationship between spinal manipulation and stroke other than VBS), but it is possible that our analysis may have been biased by an underrepresentation in claims data of the true incidence of VBS. However, patients presenting to a hospital with symptoms of stroke and a recent history of visiting a chiropractor may be subjected to a more aggressive workup for VBS, and consequent bias toward increased diagnosis of VBS.7 Therefore, because diagnostic misclassification in the chiropractic cohort is more likely to result in more claims for VBS rather than fewer, we are confident that our results do not significantly underestimate the risk of VBS stroke in this study population. The results for the chiropractic cohort reflect the risk of stroke after chiropractic spinal manipulation, not that after all clinical encounters with chiropractors, who routinely screen patients for contraindications to spinal manipulation and withhold manipulation from those perceived as being at risk.21 Finally, because not all Medicare beneficiaries are enrolled in Medicare Part B, the subjects did not represent a random sample of older US adults. However, the study population does represent the population of older US adults who are eligible to receive chiropractic services under Medicare Part B, and the very large sample size of more than 1 million subjects provided the analysis with high statistical power.

Conclusions

This is the first population-based study in the United States on risk of stroke after spinal manipulation and the first such study to focus on older adults. Among Medicare B beneficiaries aged 66 to 99 years with neck pain, the incidence of vertebrobasilar stroke was too low to allow further analysis. Chiropractic cervical spine manipulation is unlikely to cause stroke in patients aged 66 to 99 years with neck pain. For patients who saw a chiropractic physician, the adjusted probability of any type of stroke was lower than those who saw a primary care physician at days 1 through 24 after office visit, but higher at days 25 to 30, but these temporal associations are of doubtful clinical significance.

Funding Sources and Potential Conflicts of Interest

This study was supported by the National Institutes of Health under award number K01AT005092 . No conflicts of interest were reported for this study.

Contributorship Information

  • Concept development (provided idea for the research); J.W.
  • Design (planned the methods to generate the results); J.W., T.L.
  • Supervision (provided oversight, responsible for organization and implementation, writing of the manuscript); J.W., J.L., R.P., T.L.
  • Data collection/processing (responsible for experiments, patient management, organization, or reporting data); J.W., Y.S.
  • Analysis/interpretation (responsible for statistical analysis, evaluation, and presentation of the results); J.W., Y.S., T.M., R.P.
  • Literature search (performed the literature search); J.W.
  • Writing (responsible for writing a substantive part of the manuscript); J.W., T.M.
  • Critical review (revised manuscript for intellectual content, this does not relate to spelling and grammar checking); J.W., J.L., Y.S., T.M., T.L., R.P.
+

References

  1. Cassidy, JD, Boyle, E, Cote, P et al. Risk of vertebrobasilar stroke and chiropractic care: results of a population-based case-control and case-crossover study. Spine (Phila Pa 1976)200833S176–S183
  2. Rothwell, DM, Bondy, SJ, and Williams, JI. Chiropractic manipulation and stroke: a population-based case-control study. Stroke2001321054–1060
  3. Smith, WS, Johnston, SC, Skalabrin, EJ et al. Spinal manipulative therapy is an independent risk factor for vertebral artery dissection. Neurology2003601424–1428
  4. Chestnut, JL. The stroke issue: paucity of valid data, plethora of unsubstantiated conjecture. J Manipulative Physiol Ther200427368–372
  5. Lee, VH, Brown, RD Jr., Mandrekar, JN, and Mokri, B. Incidence and outcome of cervical artery dissection: a population-based study. Neurology2006671809–1812
  6. Engelter, ST, Grond-Ginsbach, C, Metso, TM et al. Cervical artery dissection: trauma and other potential mechanical trigger events. Neurology2013801950–1957
  7. Boyle, E, Cote, P, Grier, AR, and Cassidy, JD. Examining vertebrobasilar artery stroke in two Canadian provinces. Spine (Phila Pa 1976)200833S170–S175
  8. Rubinstein, SM, Peerdeman, SM, van Tulder, MW, Riphagen, I, and Haldeman, S. A systematic review of the risk factors for cervical artery dissection. Stroke2005361575–1580
  9. Ernst, E. Adverse effects of spinal manipulation: a systematic review. J R Soc Med2007100330–338
  10. Tuchin, P. A replication of the study “Adverse effects of spinal manipulation: a systematic review”. Chiropr Man Ther20122030
  11. Gouveia, LO, Castanho, P, and Ferreira, JJ. Safety of chiropractic interventions: a systematic review. Spine (Phila Pa 1976)200934E405–E413
  12. Carlesso, LC, Gross, AR, Santaguida, PL, Burnie, S, Voth, S, and Sadi, J. Adverse events associated with the use of cervical manipulation and mobilization for the treatment of neck pain in adults: a systematic review. Man Ther201015434–444
  13. Haynes, MJ, Vincent, K, Fischhoff, C, Bremner, AP, Lanlo, O, and Hankey, GJ. Assessing the risk of stroke from neck manipulation: a systematic review. Int J Clin Pract201266940–947
  14. Haneline, MT and Rosner, AL. The etiology of cervical artery dissection. J Chiropr Med20076110–120
  15. Paciaroni, M and Bogousslavsky, J. Cerebrovascular complications of neck manipulation. Eur Neurol2009;61112–118
  16. Hollander, M, Koudstaal, PJ, Bots, ML, Grobbee, DE, Hofman, A, and Breteler, MM. Incidence, risk, and case fatality of first ever stroke in the elderly population. The Rotterdam Study. J Neurol Neurosurg Psychiatry2003;74317–321
  17. Choi, S, Boyle, E, Cote, P, and Cassidy, JD. A population-based case-series of Ontario patients who develop a vertebrobasilar artery stroke after seeing a chiropractor. J Manipulative Physiol Ther20113415–22
  18. Cassidy, JD, Boyle, E, Cote, P et al. Risk of vertebrobasilar stroke and chiropractic care: results of a population-based case-control and case-crossover study. Spine200833S176–S183
  19. Hufnagel, A, Hammers, A, Schonle, PW, Bohm, KD, and Leonhardt, G. Stroke following chiropractic manipulation of the cervical spine. J Neurol1999246683–688
  20. Norris, JW, Beletsky, V, and Nadareishvili, ZG. Sudden neck movement and cervical artery dissection. The Canadian Stroke Consortium. CMAJ200016338–40
  21. Centers for Medicare and Medicaid Services. Chiropractic Billing Guide April 2013. NHIC Corp.Hingham, MA;2012
  22. MacKenzie, TA, Brown, JR, Likosky, DS, Wu, Y, and Grunkemeier, GL. Review of case-mix corrected survival curves. Ann Thorac Surg2012931416–1425
  23. Zhang, X, Loberiza, FR, Klein, JP, and Zhang, MJ. A SAS macro for estimation of direct adjusted survival curves based on a stratified Cox regression model. Comput Methods Programs Biomed20078895–101
  24. Cassidy, JD, Boyle, E, Cote, P et al. Risk of vertebrobasilar stroke and chiropractic care: results of a population-based case-control and case-crossover study. J Manipulative Physiol Ther200932S201–S208
  25. National Institutes of Health. Morbidity and Mortality: 2009 Chartbook on Cardiovascular, Lung, and Blood Diseases. in: National Heart L, and Blood Institute (Ed.) US Department of Health and Human ServicesBethesda, MD2009
  26. Murphy, DR. Current understanding of the relationship between cervical manipulation and stroke: what does it mean for the chiropractic profession?. Chiropr Osteopat20101822
  27. Tuchin, P. Chiropractic and stroke: association or causation?. Int J Clin Pract201367825–833
  28. Centers for Disease Control and Prevention. Stroke. http://www.cdc.gov/stroke/index.htm. ([Accessed Nov 22, 2013])
  29. Whedon, JM and Song, Y. Racial disparities in the use of chiropractic care under Medicare. Altern Ther Health Med20121820–26
  30. Song, Y, Skinner, J, Bynum, J, Sutherland, J, Wennberg, JE, and Fisher, ES. Regional variations in diagnostic practices. N Engl J Med201036345–53
  31. Varas-Lorenzo, C, Riera-Guardia, N, Calingaert, B et al. Stroke risk and NSAIDs: a systematic review of observational studies. Pharmacoepidemiol Drug Saf2011201225–1236
  32. Leach, RA. Patients with symptoms and signs of stroke presenting to a rural chiropractic practice. J Manipulative Physiol Ther20103362–69
  33. Daniel, DM, Ndetan, H, Rupert, RL, and Martinez, D. Self-reported recognition of undiagnosed life threatening conditions in chiropractic practice: a random survey. Chiropr Man Ther20122021