Frequency, Predictors, and Outcomes of Prehospital and Early Postarrival Neurological Deterioration in Acute Stroke: Exploratory Analysis of the FAST-MAG Randomized Clinical Trial

Kristina Shkirkova; Jeffrey L Saver; Sidney Starkman; Gregory Wong; Julius Weng; Scott Hamilton; David S Liebeskind; Marc Eckstein; Samuel Stratton; Frank Pratt; Robin Conwit; Nerses Sanossian

doi:10.1001/jamaneurol.2018.1893

. 2018 Jul 23;75(11):1364–1374. doi: 10.1001/jamaneurol.2018.1893

Frequency, Predictors, and Outcomes of Prehospital and Early Postarrival Neurological Deterioration in Acute Stroke

Exploratory Analysis of the FAST-MAG Randomized Clinical Trial

Kristina Shkirkova ^1,^✉, Jeffrey L Saver ¹, Sidney Starkman ², Gregory Wong ², Julius Weng ², Scott Hamilton ³, David S Liebeskind ¹, Marc Eckstein ^4,⁵, Samuel Stratton ^6,^7,⁸, Frank Pratt ⁹, Robin Conwit ¹⁰, Nerses Sanossian ¹¹, for the FAST-MAG Trial Coordinators and Investigators

¹Stroke Center, Department of Neurology, University of California, Los Angeles

²Department of Emergency Medicine, University of California, Los Angeles

³Department of Neurology, Stanford University, Stanford, California

⁴Department of Emergency Medicine, University of Southern California, Los Angeles

⁵Los Angeles Fire Department, Los Angeles, California

⁶Department of Emergency Medicine, Harbor-University of California, Los Angeles Medical Center, Los Angeles

⁷Los Angeles EMS Agency, Los Angeles, California

⁸Orange County EMS Agency, Orange County, California

⁹Los Angeles County Department of Public Health, Los Angeles, California

¹⁰National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

¹¹Department of Neurology, University of Southern California, Los Angeles

Group Information: The FAST-MAG Trial coordinators and investigators are listed at the end of this article.

Accepted for Publication: May 17, 2018.

^✉

Corresponding Author: Kristina Shkirkova, BS, Stroke Center, Department of Neurology, UCLA, 710 Westwood Plaza, Ste 4-126, Los Angeles, CA, 90095 (kshkirkova@gmail.com).

Published Online: July 23, 2018. doi:10.1001/jamaneurol.2018.1893

Author Contributions: Miss Shkirkova and Dr Saver had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Saver, Starkman, Hamilton, Eckstein, Pratt, Conwit, Sanossian.

Acquisition, analysis, or interpretation of data: Shkirkova, Saver, Starkman, Wong, Weng, Hamilton, Liebeskind, Eckstein, Stratton, Sanossian.

Drafting of the manuscript: Shkirkova, Sanossian.

Critical revision of the manuscript for important intellectual content: Saver, Starkman, Wong, Weng, Hamilton, Liebeskind, Eckstein, Stratton, Pratt, Conwit, Sanossian.

Statistical analysis: Shkirkova, Saver, Hamilton, Stratton, Sanossian.

Obtained funding: Saver, Starkman, Conwit.

Administrative, technical, or material support: Saver, Starkman, Wong, Liebeskind, Eckstein, Stratton, Pratt.

Supervision: Saver, Liebeskind, Eckstein.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by a Research Project Cooperative Agreement award (U01 NS44364) from the National Institute of Neurological Disorders and Stroke.

Role of the Funder/Sponsor: The National Institute of Neurological Disorders and Stroke had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The Field Administration of Stroke Therapy-Magnesium (FAST-MAG) Trial Coordinators and Investigators are as follows: Presbyterian Intercommunity Hospital, Whittier, California: Ian Kramer, MD; Atif Ali, MD; Kevin Andruss, MD; Brian Beck, MD; Steven Chin, MD; Dennis Conneen, MD; Dane Copeland, MD; Adrian Crisan, MD; Leonard Gale, MD; Gautam Ganguly, MD; Jamie E. Gonzalez, MD; Paul Helfgott, MD; Hoori Hovanessian, MD; Edward Jarema, MD; Michael Liu, MD; Michael L Martin, MD; Gregory Meyer, MD; Haig Minassian, MD; Tuan Nguyen, MD; Richard Rison, MD; Megan Salinas, MD; Aliso Sato, MD; Robert Shapiro, MD; Glen Donald Shook, MD; Mustafa Suleiman, MD; Michael Thomas, MD; Richard Zoraster, MD; Anna Aguayo, RN; Kristina Balauag, RN; Nalani Coleman, RN; Star Feudi, RN; Suzanne Hentho, RN; Long Beach Memorial, Long Beach, California: Gary Moreau, MD; Christine Anderegg, MD; Celina Barba, MD; Billy Burden, MD; Gregory Bush, MD; Ignacio Carrillo-Nunez, MD; Gail Carruthers, MD; Kenneth Chuang, MD; James Collier, MD; Brenda Crawford, MD; Joanne Crowley, MD; GianCarlo DiMassa, MD; Jason Fisher, MD; Ron Forgey, MD; Atul Gupta, MD; Gary Hofmann, MD; Enoch Huang, MD; Amy Kaji, MD; Duk Kim, MD; William Koenig, MD; Amy Koplovsky, MD; Christopher Joseph Lampe, MD; Timothy Lee, MD; Bobby Massoudian, MD; Tuan Nguyen, MD; Omid Omidvar, MD; Nirav Patel, MD; Shahrzad Raifiee, MD; Nima Ramezan-Arab, MD; Anne Rutkowski, MD; Raynard Sebastian, MD; Randolph Shey, MD; Amy Stone, MD; Rich Taraska, MD; Andrew Wittenberg, MD; Scott Youngquist, MD; Christel Zeumer, MD; Nalani Coleman, RN; Maria Fitzgerald, RN; Kanika McCall, RN; Beverly Nighswonger, RN; Pamela Nye, RN; Courtney Real, RN; Randy Sanoff, RN; Huntington Memorial Hospital, Pasadena, California: Robert Goldweber, MD; Jonathan Crabb, MD; Igor Fineman, MD; William Gregory, MD; Stanley Kalter, MD; Taline Kilaghbian, MD; John Leung, MD; Henry Levenson, MD; Brandon Lew, MD; James Luna, MD; Asbasia Aboelkhair Mikhail, MD; Yafa Minazad, MD; Ridgely Muller, MD; Mihoko Nelsen, MD; Arbi Ohanian, MD; Mark A Papish, MD; Paul Rhee, MD; Jai Hyon Rho, MD; Megan Salinas, MD; Georgia Sotiropoulos, MD; David Ulick, MD; Ximena Vargas, MD; Douglas Willard, MD; Jeremy Williams, MD; Roger Yang, MD; Steve Zielinski, MD; Miranda Gordon, RN; Star Feudi, RN; Ann Lahn, RN; Keta Hodgson, RN; Molly Hoffman, RN; Ronald Reagan UCLA (University of California, Los Angeles) Medical Center, Los Angeles: Sidney Starkman, MD; Latisha Ali, MD; Kim Doojin, MD; May Kim-Tenser, MD; David S. Liebeskind, MD; Bruce Izeokhai Ovbiagele, MD; Lucas Restrepo-Jimenez, MD; Nerses Sanossian, MD; Jeffrey L. Saver, MD; Scott Selco, MD; Miguel Valdes-Sueiras, MD; Gillian Devereux, RN; Samantha Theaker, RN; Theresa Haley, RN; Providence Little Company of Mary, Torrance, California: Kent Shoji, MD; David Amin, MD; Bradford Baldridge, MD; Frederick Jay Carr, MD; Michelle Charfen, MD; Robert Chavez, MD; Schenley Co, MD; Marc Richard Cohen, MD; William Conrad, MD; Bao Duong, MD; Michelle Finkel, MD; Marianne Gausche-Hill, MD; Andrew Louie, MD; Joseph Mueller, MD; George Rederich, MD; Bernard Ullman, MD; Jorge Vournas, MD; Joesph Zibulewsky, MD; Gillian Devereux, RN; Theresa Haley, RN; Keta Hodgson, RN; Memorial Medical Center, Torrance, California: Mike Tarnay, MD; Elisa Anhalt, MD; Schenley Co, MD; Carlos Medina, MD; Brian Miura, MD; Eric Nakkim, MD; Frank Pratt, MD; David Presser, MD; George Rederich, MD; John Schugt, MD; Andrew Hansen Shen, MD; Gina Sulmeyer, MD; Peter Tseng, MD; Bernard Ullman, MD; Curtice Wong, MD; Gillian Devereux, RN; Kanika McCall, RN; Theresa Haley, RN; Cedars-Sinai Medical Center, Los Angeles, California: Joel Geiderman, MD; Sam Torbati, MD; Karen Altman, MD; Ron Andiman, MD; John Bibb, MD; William Chow, MD; Stanley Cohen, MD; Ken Corre, MD; Asha Das, MD; Dawn Eliashiv, MD; Clarke Espy, MD; James Fishkin, MD; David Frankle, MD; Laurence Friedman, MD; Susan Gardner, MD; Israel Gorinshtein, MD; Tiffany Hackett, MD; Gregory Hallert, MD; David Hardy, MD; Brian Jeffords, MD; Dan Katz, MD; Rick Kulkarni, MD; Wendy Lin, MD; James Loftus, MD; Patrick Lyden, MD; Diku Mandavia, MD; Sujal Mandavia, MD; Ed Massey, MD; Jan Merman, MD; Chad Miller, MD; Asma Moheet, MD; David Palestrant, MD; Stefan Pulst, MD; Daniel Rovner, MD; Steven Rudd, MD; Natan Shaolian, MD; Paul Silka, MD; Ravinder Singh, MD; Shlee Song, MD; Colin Stokol, MD; Benjamin Sun, MD; Guven Uzun, MD; Michael Waters, MD; Paula Whiteman, MD; Randy Sanoff, RN; Providence Saint Joseph Medical Center, Burbank, California: Philip Schwarzman, MD; Serge Akopov, MD; Melvin Belafsky, MD; Pamela Biren, MD; Angelique Campen, MD; Emilio Cruz, MD; Fawaz Faisal, MD; Richard Goldberg, MD; Ahed Hanna, MD; Christian Herrera, MD; Ravin Jain, MD; Ronnie Karayan, MD; Christopher Keane, MD; Stephen Edward Kishineff, MD; Roger Lai, MD; Stan Lee, MD; Lin LeMay, MD; Franklin Lum, MD; Francois Martin, MD; Michael Marvi, MD; Pete Obligato, MD; Margarita Oveian, MD; Lorraine Purino, MD; Michael Sarti, MD; P. John Simic, MD; Jason Toth, MD; Tina Wang, MD; Lawrence Edward Wells, MD; Randy Sanoff, RN; Methodist Hospital of Southern California, Arcadia: Michael Agron, MD; Rami Apelian, MD; Charmaine Bobo, MD; James Burke, MD; Phillip Cabasso, MD; Jacob Fakoory, MD; Thomas J Fauble, MD; James David Grant, MD; John Leung, MD; John Levin, MD; Jerome Lisk, MD; June-Chin Liu, MD; Robert Joseph Lynch, MD; Russell E. Maatz, MD; John Mucia, MD; Phong Xuan Ngo, MD; Howard Romero, MD; Brigeli P Westerband, MD; Kenneth Wogensen, MD; Sharon Craig, RN; Miranda Gordon, RN; Pamela Nye, RN; Lea Ross, RN; RN; Randy Sanoff, RN; Henry Mayo Newhall, Valencia, California: Heather Flaherty, MD; John Anis, MD; Clay Cormier, MD; Travis Deuson, MD; Surisham Dhillon, MD; David Henry, MD; Rob Hook, MD; Deborah Hyde, MD; Tracy (Bud) Lawrence, MD; Mark Liker, MD; Fredrick M. Abrahamian, DO; M. Mehdi Meratee, MD; Hites Patel, MD; Darrin Privett, MD; Oliver Sahagun, MD; David Schmidt, MD; Charles Malcolm Schultz, MD; Mark Schultz, MD; Garrett Sutter, MD; Roger Wallace, MD; Rob Zappacosta, MD; Jason Ziemba, MD; Gillian Devereux, RN; Barbara Tone, RN; Antelope Valley Hospital, Lancaster, California: John Lynn, MD; Richard Allison, MD; Frederick Auerbach, MD; Rocky Benoit, MD; Patricia Boyatt, MD; Mark Brown, MD; Frank DeTrana, MD; Travis Deuson, MD; Michael Gertz, MD; William Gregory, MD; Malkeet Gupta, MD; Thomas Jared Hemingway, MD; Lingaiah Janumpally, MD; Thomas Lee, MD; Michael Leidner, MD; Michael Menchine, MD; Joe Nakagawa, MD; Vijay Shanmugam, MD; Eric Snyder, MD; Christopher Spencer, MD; Lawrence Stock, MD; Jonathan Watson, MD; Adrienne Binning, RN; Miranda Gordon, RN; Star Feudi, RN; Suzanne HenthoRN; RN; Amy Ingram, RN; Barbara Tone, RN; White Memorial Medical Center, Los Angeles, California: Brian Johnston, MD; Manuel Bautista, MD; Brant Blair, MD; Giancarlo Dimassa, MD; Anthony Hernandez, MD; Helen H. Ho, MD; Raafat Iskander, MD; Scott Jacobs, MD; Robin Kaminsky, MD; Antonio Liu, MD; John Murray, MD; Michael Pham, MD; Michael Phillips, MD; John Plosay, MD; Julian Stanley, MD; Paul Swanson, MD; Scott Takano, MD; Elga Tinger, MD; Melvin Webb, MD; Molly Hoffman, RN; Samantha Theaker, RN; Barbara Tone, RN; Northridge Hospital Medical Center, Northridge, California: Stephen Jones, MD; Jeffrey Abrahams, MD; David Brandes, MD; Robert Cohenour, MD; Steven Cole, MD; Brian Gantwerker, MD; Deborah Hyde, MD; Edward Jeon, MD; Daniel Kijner, MD; John McConnellogue, MD; Ann McKittrick, MD; Judi Meindlholman, MD; Wei Mi, MD; Ivan Rokos, MD; Joseph Sachs, MD; Vivek Savur, MD; Lawrence Weinberg, MD; Ronald Ziman, MD; Star Feudi, RN; Vicky Padilla, RN; Brenda Pierce, RN; Pomona Valley Hospital, Pomona, California: Ken Moore, MD; Mark Boettger, MD; Gregory Burke, MD; Bhupatrai H. Desai, MD; Richard Dorosh, MD; Thomas Edholm, MD; Howard Friedman, MD; Ali Jamehdor, MD; Matthew Janssen, MD; James S. Kim, MD; John Lee, MD; Lee Maas, MD; Gregory Murphy, MD; Kenneth Nakamoto, MD; Geoffrey Pableo, MD; Phillip Piccinini, MD; Brian Rhee, MD; Jeffrey Ries, MD; Susan Marie Salazar, MD; Ivan Schatz, MD; Matthew Schultz, MD; Victoria Shook, MD; Benjamin Squire, MD; Pierre Ujkic, MD; Anna Aguayo, RN; Gillian Devereux, RN; Miranda Gordon, RN; Anna Grace, RN; Providence Holy Cross Medical Center, Mission Hills, California: Jason Fisher, MD; Michael Blum, MD; Jay Brown, MD; Bruce Cummings, MD; Charles Deng, MD; Jamie Diaz, MD; Eric El-Tobgy, MD; Victor Hogen, MD; George Inglizian, MD; George Kijner, MD; John Lalli, MD; Mark Liker, MD; Marc Mendes, MD; Kanwal Nayyar, MD; Gregory Pousson, MD; Michael Sarti, MD; Jeff Sung, MD; Scott Wang, MD; Thomas Waskiewicz, MD; Alexander Zlidenny, MD; Randy Sanoff, RN; Barbara Tone, RN; Lakewood Regional Medical Center, Lakewood, California: Jeremy Kroes, MD; Bruce Jetton, MD; Andrew Steven Kassinove, MD; Monica Serna, MD; Constantine Svimonoff, MD; Peyam Vafadari, MD; Sharon Craig, RN; Maria Fitzgerald, RN; Keta Hodgson, RN; Chisom Onwunyi, RN; Courtney Real, RN; Barbara Tone, RN; St Francis Medical Center, Lynwood, California: Maria Davis, MD; Jose Luis Cervantes, MD; Dane Copeland, MD; Monica Derbigny, MD; Robert Flashman, MD; Ryun Harper, MD; Stephen Daniel Higgins, MD; Alexander Kaplan, MD; Amy Koplovsky, MD; Mark Louden, MD; Khalifa Mansour, MD; Van Hubert Miller, MD; Arturo Pelayo, MD; Michael Stephen, MD; Patricia Wong, MD; Kanika McCall, RN; Courtney Real, RN; Dolores Tatgenhorst, RN; Glendale Adventist Medical Center, Glendale, California: Cheryl Lee, MD; Noujan Adl-Tabatabai, MD; Sergey Ayvazyan, MD; James Burke, MD; Anthony Michael Cardillo, MD; Pao Yen Chiu, MD; Igor Fineman, MD; Bruce Finestead, MD; David Friend, MD; Harlan Gibbs, MD; Sylvia Kotikian, MD; Lance Lee, MD; Ronald Lieberman, MD; Edmond Noll, MD; Peter Shin, MD; Brian Stanford, MD; David Thompson, MD; Peter Utas, MD; Serineh Voskanian, MD; Andy Wong, MD; Evelyn Wong, MD; Garnik Yegyan, MD; Ann Lahn, RN; Kanika McCall, RN; Randy Sanoff, RN; Barbara Tone, RN; West Hills Hospital and Medical Center, West Hills, California: Lee Weiss, MD; James Allen, MD; Eileen Bastian, MD; Loren Caira, MD; James De La Torre, MD; Eric El-Tobgy, MD; Teri Engelberg, MD; Bradley Gerberich, MD; Hossein Gharakhani, MD; Edward Jeon, MD; Michael Jones, MD; Michael Kirk, MD; Alan Kuban, MD; Marc Martinez, MD; Meril Platzer, MD; Vivek Savur, MD; Veena Sengupta, MD; Gary Sindell, MD; Jennifer Butel, RN; Amy Ingram, RN; Vicky Padilla, RN; Randy Sanoff, RN; Santa Monica-UCLA Medical Center, Santa Monica: Wally Ghurabi, MD; Robert Bei, MD; Michelle Charfen, MD; Martin Chenevert, MD; Harriet Cokely, MD; Mark Futernick, MD; Larry Halem, MD; Doojin Kim, MD; Zachary Lutsky, MD; Skeet McCain, MD; John Plosay, MD; Mark Pulera, MD; Sidney Starkman, MD; Theresa Haley, RN; Samantha Theaker, RN; California Hospital Medical Center, Los Angeles: Marc Futernick, MD; Betty Sunmee Ahn, MD; Gregory Alfred, MD; Sanjay Banerji, MD; Troy Cashatt, MD; Bao Duong, MD; Richard Graham, MD; Scott Gwaltney, MD; Gordon R. Haas, MD; Vineeta Keswani, MD; Timothy Stephen Lee, MD; Sara Levy, MD; Antonio Liu, MD; Stephen Liu, MD; Peter Lorber, MD; Christine McDavit, MD; Kristen Mewaldt, MD; Elizabeth Mitchell, MD; Derrick Myers, MD; Candice Myher, MD; Martin Ogle, MD; Joshua Partnow, MD; Joshua Raetnow, MD; Emily Rose, MD; Jessica Sims, MD; Robert Splawn, MD; Tran Huy Thai, MD; Barbara Victor, MD; David Wagner, MD; Kathleen Waltz, MD; Chris Warner, MD; Giorgio Zadini, MD; Elizabeth Zide, MD; Jennifer Butel, RN; Molly Hoffman, RN; Vicky Padilla, RN; Randy Sanoff, RN; Sherman Oaks Hospital, Sherman Oaks, California: Dallas Smith, MD; Danny Chang, MD; Jason Greenspan, MD; Lilly Marshall, MD; Steven Novom, MD; Jenny Cavanaugh, RN; Randy Sanoff, RN; St John’s Hospital and Health Center, Santa Monica, California: Russ Kino, MD; Edwin Amos, MD; Isaac Bash, MD; Victor Candioty, MD; Anthony Cardillo, MD; Grace Chen, MD; Harriet Cokely, MD; Edward Cotner, MD; Sabrina Diaz, MD; Heather Enomoto, MD; Michael T. Froehler, MD; Michael Gertz, MD; Robert Giombetti, MD; Michael Gold, MD; Hyman Gross, MD; Daniel Grossman, MD; Sheldon Jordan, MD; Robin Kaminsky, MD; Christopher Keane, MD; David Kudrow, MD; Cori Anne McClure-Poffenberger, MD; Fardad Mobin, MD; Edward O’Connor, MD; Ryan O’Connor, MD; Carl Orfuss, MD; Joshua Partnow, MD; Jolie Pfahler, MD; Mark Pulera, MD; Sanjeev Seth, MD; Russ Shimizu, MD; Natalie Shum, MD; Sidney Starkman, MD; Simone Tizes-Gold, MD; Leo Treciokas, MD; Susan Urstein, MD; Guven Uzun, MD; Ali Varzgah, MD; Michael Weitz, MD; Andrew Woo, MD; Valeri Yarema, MD; Joseph Zibulewsky, MD; Miranda Gordon, RN; Anna Grace, RN; Keta Hodgson, RN; Providence Little Company of Mary, San Pedro, California: Stephen R. Shea, MD; William Brown, MD; Patrick D. Cichon, MD; Matthew B. Deutsch, MD; Marco A. Diaz, MD; Brian Fong, MD; Valerie Grant, MD; Shaghayegh (Sherry) Haghighat, MD; Barry Heller, MD; Mark Joyner, MD; Knef V. Lizaso, MD; John S. McCall, MD; Douglas W. McFarland, MD; Parag Mehta, MD; Ron Melendez, MD; Sameer Mistry, MD; Majid Molaie, MD; David Munoz, MD; Usha Rani K. Reddy, MD; Miles Shaw, MD; Keith D. Stamler, MD; Arlene Vernon, MD; Maria Fitzgerald, RN; Keta Hodgson, RN; Kanika McCall, RN; Samantha Theaker, RN; Citrus Valley Med Center–Queen of the Valley Campus, West Covina, California: James Paul Holland, MD; John Anthony Hatherley, MD; James Linder Jones, MD; James Kojian, MD; Norman Owashi, MD; Kenneth Min Chai Pak, MD; Anna Aguayo, RN; Kristina Balauag, RN; Nalani Coleman, RN; Star Feudi, RN; Molly Hoffman, RN; Marina Del Rey Hospital, Marina Del Rey, California: Robert Slay, MD; Luke Conovaloff, MD; Robert Giombetti, MD; Paula Gonella, MD; Rosanne Kay, MD; David Kheradyar, MD; Mickey Kolodny, MD; William Sheer, MD; Kent Shoji, MD; Theresa Haley, RN; Keta Hodgson, RN; Randy Sanoff, RN; Dolores Tatgenhorst, RN; Barbara Tone, RN; LAC-USC Medical Center, Los Angeles, California: Marc Eckstein, MD; Kirsten Calder, MD; Steven Giannotta, MD; Mel Herbert, MD; Cherlin Johnson, MD; Diku Mandavia, MD; Nerses Sanossian, MD; Gene Sung, MD; Keta Hodgson, RN; Brenda Pierce, RN; Palmdale Regional Medical Center, Palmdale, California: Vincent Bennett, MD; Lingauah Janumpally, MD; Vijay Shanmugam, MD; Gillian Devereux, RN; Miranda Gordon, RN; Adrienne Binning, RN; Amy Ingram, RN; Barbara Tone, RN; Verdugo Hills Hospital, Glendale, California: David Tashman, MD; Leonard Berkenbile, MD; Jennifer Chen, MD; Jonathan Crabb, MD; Armand Dorian, MD; Bruce Finstead, MD; Theodore Hackett, MD; Lance Lee, MD; Maria Montoya, MD; Farsheed Nikbakht, MD; David Thompson, MD; Erika Wilson, MD; Miranda Gordon, RN; Suzanne Henthorn; RN; Ann Lahn, RN; Brenda Pierce, RN; Samantha Theaker, RN; Barbara Tone, RN; Providence Tarzana Medical Center, Tarzana, California: Gregory Scott Brewster, MD; Peter-Brian Andersson, MD; Ralph Baca, MD; Mark Bell, MD; Neil Canby, MD; Eric Carlisle, MD; Robert Cohenour, MD; Fred Dennis, MD; Jose Diaz, MD; Irv Edwards, MD; Stuart Goldfarb, MD; Vincent Green, MD; Jason Greenspan, MD; Oren Hirsch, MD; Edward Jeon, MD; Tracy Lawrence, MD; Victor Manuel Lopez-Cuenca, MD; Wei Mi, MD; Kenneth Moy, MD; Meril Platzer, MD; Carlo Reyes, MD; Houtan Sabahi, MD; Tamar Sauer, MD; Jeff Sung, MD; Garrett Sutter, MD; Lawrence Weinberg, MD; Ronald Ziman, MD; Jennifer Butel, RN; Gillian Devereux, RN; Suzanne Henthorn; RN; Amy Ingram, RN; Robert Phoenix, RN; Randy Sanoff, RN; Heavenly Swendson, BA; Glendale Memorial Hospital and Health Center, Glendale, California: Michael Agron, MD; Jodi Aragona, MD; Bernard Dannenberg, MD; Josiah Friedlander, MD; Faraaz Khan, MD; Lance Lee, MD; Samar Sami Masri-Phillips, MD; Phong Ngo, MD; Edmond Noll, MD; Edward Rapetti, MD; Brigili Westerband, MD; Jennifer Butel, RN; Star Feudi, RN; Ann Lahn, RN; Randy Sanoff, RN; Barbara Tone, RN; Olive View UCLA Medical Center, Sylmar: Venela B. Ricketts, MD; Janet Au, MD; Pamela Dyne, MD; Thomas Jared Hemingway, MD; Timothy Jang, MD; Nader Kamangar, MD; Raghavendra Kulkarni, MD; Scott Lundberg, MD; Fredrick M. Abrahamian, DO, Gregory Moran, MD; Sam Ong, MD; Bruce Ovbiagele, MD; John Pi, MD; Mark Richman, MD; Ivan Rokos, MD; Robert Rosenbloom, MD; Gil Shlamovitz, MD; David Andrew Talan, MD; Miguel Valdes-Sueiras, MD; Michael Weitz, MD; Dennis Yick, MD; Keta Hodgson, RN; Brenda Pierce, RN; Kaiser Permanente, Woodland Hills, California: Garo Balkian, MD; Mona Balogh, MD; Hugh Chen, MD; Mitchell Danesh, MD; Fausto Farfan, MD; Ara Gabrielian, MD; Donald Jong, MD; Michael LaFemenia, MD; Stanley Yu, MD; Jenny Cavanaugh, RN; Star Feudi, RN; Pam Nye, RN; Vicky Padilla, RN; Heavenly Swendson, BA; San Dimas Community Hospital, San Dimas, California: James Pagano, MD; Donaciano Teodoro Astidillo, MD; Andrea E. Carrillo, MD; John Chon, MD; Paul Giem, MD; James Johnson Jr, MD; Jeff Judson, MD; Nadine Konia, MD; Ali Ibrahim Mohsen, MD; Corbett Grant Peek, MD; David Tsai, MD; Star Feudi, RN; Kathy Valenti, RN; Kaiser Permanente, Los Angeles, California: Nagi Sous, MD; Zahra Ajani, MD; Michael Lucas Domiano, MD; Bruce Edward Enos, MD; Rani Nirmala Gowrinathan, MD; Michael Charles Hopkins, MD; Janes Y. Hwang, MD; Reza N. Jadvar, MD; Joseph Gordon Krainin, MD; Kevin Lin, MD; Brendan Robert Mull, MD; Sonja Potrebic, MD; Leon Salem, MD; Lisa Martine Sanders, MD; Charles Fidel Schmitz, MD; Gary David Schoeman, MD; Matthew Pierce Smith, MD; Satish Ramamoorthy Subramanian, MD; Brian E. Thompson, MD; Ira Howard Tilles, MD; Robert Allan Ungar, MD; Peter H. Yoo, MD; Jenny Cavanaugh, RN; Gillian Devereux, RN; Amy Ingram, RN; Kanika McCall, RN; St Mary Medical Center, Long Beach, California: Stephen R. Shea, MD; Ralph William Brown, MD; Ignacio Carrillo-Nunez, MD; Patrick D. Cichon, MD; Matthew B. Deutsch, MD; Marco Diaz, MD; Brian Fong, MD; Valerie Grant, MD; Shaghayegh (Sherry) Haghighat, MD; Barry Heller, MD; Mark Joyner, MD; Jon Lawrence, MD; Timothy Lee, MD; Knef Lizaso, MD; John McCall, MD; Douglas W. McFarland, MD; Sameer Mistry, MD; David Munoz, MD; Usha Rani K. Reddy, MD; Miles Shaw, MD; Keith D. Stamler, MD; Arlene Vernon, MD; Jeremy Williams, MD; Maria Fitzgerald, RN; Kanika McCall, RN; Beverly Nighswonger, RN; Courtney Real, RN; Barbara Tone, RN; Brotman Medical Center, Culver City, California: Stephen Carney, MD; Ziba Chavoshi, MD; Frederick Dennis, MD; David Eisner, MD; Hyman Gross, MD; Karen Sue Johnson, MD; John Lalli, MD; Scott Lopata, MD; Gregory Ouligian, MD; Robert Rosenbloom, MD; Ravinder Singh, MD; Sara Stagg, MD; Andrew Tomasi, MD; Michele Vargas, MD; Star Feudi, RN; Molly Hoffman, RN; Amy Ingram, RN; Dolores Tatgenhorst, RN; Samantha Theaker, RN; Citrus Valley Med Center–Intercommunity Campus, Covina, California: Dan Kiss, MD; Bruce Alan Bullias, MD; John Chon, MD; James Kojian, MD; Kenneth Pak, MD; Rio Sutikno-Ong, MD; Kristina Balauag, RN; Nalani Coleman, RN; Star Feudi, RN; Harbor UCLA Hospital, Torrance: Marianne Gausche-Hill, MD; Thomas Leif Anderson, MD; David Burbulys, MD; Michelle Charfen, MD; Wendy C. Coates, MD; Terri Edwards-Lee, MD; M. Fernandez-Frackelton, MD; Mark Goldberg, MD; Robert Hockberger, MD; Amy Kaji, MD; Roger Jay Lewis, MD; Ari Lipsky, MD; Hugh McIntyre, MD; James Niemann, MD; Mike Peterson, MD; Deepti Pisupati, MD; Charles Fidel Schmitz, MD; Carl Stevens, MD; Kristina Balauag, RN; Anna Grace, RN; Keta Hodgson, RN; Chisom Onwunyi, RN; Ana Cecilia Venturo, RN; Olympia Medical Center, Los Angeles, California: Jeffrey Tsai, MD; Gregory Alfred, MD; John Anis, MD; Walter Bush, MD; Stephen Carney, MD; Ziba Chavoshi, MD; Anthony Hernandez, MD; Marco Felix Hernandez, MD; Diku Mandavia, MD; Sujal Mandavia, MD; Ravinder Singh, MD; Garret Sutter, MD; Michele Teresa Vargas, MD; Star Feudi, RN; Molly Hoffman, RN; Amy Ingram, RN; Kanika McCall, RN; Vicky Padilla, RN; Dolores Tatgenhorst, RN; Samantha Theaker, RN; Whittier Hospital Medical Center-AHMC, Whitter, California: Randall Johnson, MD; Sandra Donnelly, MD; Amitabh Prakash, MD; P. Douglas Slabaugh, MD; Adrienne Binning, RN; Gillian Devereux, RN; Chisom Onwunyi, RN; Barbara Tone, RN; Ana Cecilia Venturo, RN; Valley Presbyterian Hospital, Van Nuys, California: Ricky Bush, MD; Stanley Azen, MD; Paul Batmanis, MD; Hrak Derderian, MD; Philip Fagan, MD; Marco Felix Hernandez, MD; Julie Ann Jacob, MD; David Kwon, MD; Laura Leistiko, MD; Steven Novom, MD; Okemefuna Okpara, MD; Michael Pham, MD; Jonathan Prince, MD; Loretta Samaniego, MD; David Zohrabian, MD; Jenny Cavanaugh, RN; Star Feudi, RN; Amy Ingram, RN; Brenda Pierce, RN; Robert Phoenix, RN; Heavenly Swendson, BA, Samantha Theaker, RN; Garfield Medical Center, Monterey Park, California: Mai Lai, MD; Dolores De Cruz, MD; Steven Mark Goldberg, MD; Andy C. Hsu, MD; John Leung, MD; James T. Lin, MD; Winston Camacho Sanagustin, MD; Jeffrey Farrell Wade, MD; Julia Wang, MD; Jeremy Demetri Williams, MD; Sean X. Xie, MD; Sharon Craig, RN; Gillian Devereux, RN; Amy Ingram, RN; Lea Ross, RN; Hollywood Presbyterian, Los Angeles, California: Lee Weiss, MD; Vincent Bennett, MD; Pamela Biren, MD; Troy Cashatt, MD; Marco Hernandez, MD; David Milstein, MD; Siobhan Newman, MD; Christopher Ng, MD; Loretta Samaniego, MD; Shahram Tabib, MD; Nicholas Testa, MD; Brian Webb, MD; Carin Van Zyl, MD; Amy Ingram, RN; Suzanne Henthorn; RN; Molly Hoffman, RN; Keta Hudgson, RN; Vicky Padilla, RN; Kathy Valenti, RN; Mission Community Hospital, Panorama City, California: Jason Greenspan, MD; Peter-Brian Anderson, MD; Stan Azen, MD; Eric Carlisle, MD; Martin Carrillo, MD; Douglas Cochrane, MD; Robert Cohenour, MD; Frederick Dennis, MD; Irv Edwards, MD; Stuart Goldfarb, MD; Edward Jeon, MD; Victor Manuel Lopez-Cuenca, MD; Wei Mi, MD; Raymundo de Guzman Paras, MD; Michael Pham, MD; Meril Platzer, MD; Houtan Sabahi, MD; Tamar Sauer, MD; Jennifer Siegel, MD; Lawrence Weinberg, MD; Ronald Ziman, MD; Keta Hodgson, RN; Pamela Nye, RN; Vicky Padilla, RN; Barbara Tone, RN; Good Samaritan, Los Angeles, California: Philip Fagan, MD; Sanjay Banerji, MD; Brian Harris, MD; John A. Hatherley, MD; Diane Johnson, MD; Robert Kerns, MD; Nancy Kuhn, MD; Peter Lorber, MD; Daniel Oblitas, MD; Loretta Samaniego, MD; Deborah Volk, MD; Sean Xie, MD; Adrienne Binning, RN; Suzanne Henthorn; RN; Pamela Nye, RN; Vicky Padilla, RN; Samantha Theaker, RN; Kathy Valenti, RN; Kaiser West Los Angeles, Los Angeles, California: Matthew Berry, MD; Adrienne Binning, RN; Star Feudi, RN; Kanika McCall, RN; Vicky Padilla, RN; Kathy Valenti, RN; Centinela Freeman Regional Medical Center Memorial Campus, Inglewood, California: Robert Slay, MD; Luke Conovaloff, MD; Paula Gonella, MD; Rosanne Kay, MD; David Kheradyar, MD; Mickey Kolodny, MD; William Sheer, MD; Kent Shoji, MD; Bailes Yarnell, MD; Dolores Tatgenhorst, RN; Encino Medical Center, Encino, California: Jason Greenspan, MD; Peter-Brian Andersson, MD; Ralph Baca, MD; Mark Bell, MD; Gregory Scott Brewster, MD; Neil Canby, MD; Eric Carlisle, MD; Robert Cohenour, MD; James De La Torre, MD; Fred Dennis, MD; Jose Diaz, MD; Irv Edwards, MD; Stuart Goldfarb, MD; Vincent Green, MD; Oren Hirsch, MD; Edward Jeon, MD; David Kwon, MD; Tracy Lawrence, MD; Victor Manuel Lopez-Cuenca, MD; Wei Mi, MD; Kenneth Moy, MD; Meril Platzer, MD; Jonathan A. Prince, MD; Carlo Reyes, MD; Houtan Sabahi, MD; Tamar Sauer, MD; Jeff Sung, MD; Garrett Sutter, MD; Lawrence Weinberg, MD; Tina Wu, MD; Ronald Ziman, MD; Jennifer Butel, RN; Amy Ingram, RN; Keta Hodgson, RN; Robert Phoenix, RN; Heavenly Swendson, BA, Barbara Tone, RN; Los Angeles County Emergency Medical Services Agency, Santa Ana, California: Sam Stratton, MD; Mark Eckstein, MD; Frank Pratt, MD; Latisha Ali, MD; Chelsea Kidwell, MD; Doojin Kim, MD; David S. Liebeskind, MD; Bruce Ovbiagale, MD; Lucas Restrepo, MD; Nerses Sanossian, MD; Jeffrey L. Saver, MD; Sidney Starkman, MD; Beverly Nighswonger, RN; Randy Sanoff, RN; Regulatory oversight–William Koenig, MD. St Jude Medical Center, Fullerton, California: Timothy Greco, MD; Kiran Bath, MD; Anthony Ciabarra, MD; Anson Lam, MD; Cheryl Larsen, MD; Johnson Moon, MD; Erwin Song, MD; Stephen Waldman, MD; Laura Cross, RN; Gillian Devereux, RN; Nicole Nasseri, RN; Hoag Memorial Hospital, Newport Beach, California: William Cloud, MD; David Brown, MD; Matthew Hunt, MD; Andrew Ly, MD; Jason Muir, MD; Howard Nakashioya, MD; Jose Puangco, MD; Laura Cross, RN; Amy Perez, RN; Los Alamitos Medical Center, Los Alamitos, California: Bruce Jetton, MD; Jeremy Kroes, MD; Nirav Patel, MD; Nima Ramezan- Arab, MD; Laura Cross, RN; Star Feudi, RN; Nicole Nasseri, RN; Fountain Valley Regional Hospital, Fountain Valley, California: Peter G. Anderson, MD; Ignacio Carrillo-Nunez, MD; Paul Maistros, MD; Chad Miller, MD; Adrian Miranda, MD; Paul Vespa, MD; Laura Cross, RN; Amy Perez, RN; Mission Hospital, Mission Viejo, California: Richard Kozak, MD; Lance Allgower, MD; Michael Cummings, MD; Daniel Firestone, MD; Joey Gee, MD; Matthew Kaplan, MD; Kenneth Kwon, MD; Andrew Lawson, MD; Raj Patel, MD; Laura Cross, RN; St Joseph Hospital, Orange, California: James Pierog, MD; Anwar Abdelhadi, MD; Roger Chang, MD; Amir Ghiassi, MD; Shahid Hayat, MD; Kang Hsu, MD; Reza Mina-Araghi, MD; Joseph Preston, MD; James Roum, MD; Desmond Sjauwfoekloy, MD; Peter Smethurst, MD; Keta Hodgson, RN; Nicole Nasseri, RN; Amy Perez, RN; Western Medical Center, Santa Ana, California: Stewart Brash, MD; Joseph Kim, MD; John Chen, MD; Wilfred T. Escober, MD; Gagendeep Grewal, MD; David Holstein, MD; Vu Huynh, MD; Imran Imam, MD; Nguyen Khuu, MD; Clark Lew, MD; David Lombardi, MD; Larisa Zeltser, MD; Laura Cross, RN; Saddleback Memorial Regional Medical Center, Laguna Hills, California: Mark Taub, MD; Larry Burbridge, MD; David Chen, MD; R. Gordon Haas, MD; Robert Kingston, MD; Dean Le, MD; Carlos Medina, MD; Jennifer Newton, MD; Matthew Schultz, MD; Michael Shen, MD; Eric Siedenburg, MD; Elizabeth Traynor, MD; Laura Cross, RN; University of California Irvine Medical Center, Orange: Mark Langdorf, MD; Michael Burns, MD; Bharath Chakravarthy, MD; Steve Cramer, MD; Johnathan C. Fox, MD; Mauricio Gomez, MD; Vivac Jain, MD; Shahram Lotfipour, MD; Jennifer Oman, MD; Scott Rudkin, MD; Andrew C. Wong, MD; Laura Cross, RN; Amy Perez, RN; Orange County Emergency Medical Services Agency, Santa Ana, California: Sam Stratton, MD; Latisha Ali, MD; Chelsea Kidwell, MD; Doojin Kim, MD; David S. Liebeskind, MD; Bruce Ovbiagale, MD; Lucas Restrepo, MD; Nerses Sanossian, MD; Jeffrey L. Saver, Sidney Starkman, MD; Laura Cross, RN; Kanika McCall, RN; Amy Perez, RN. Clinical Coordinating Center: Pharmacovigilance Officers: Arezou Sadighi, MD; Bogdan Filip, MD; Deborah Dorsey, RN; Sharon Craig, RN; Melissa Paras, MSN; Cardiology Adverse Event Adjudicator: Noel Boyle, MD. Study Monitors: Sharon Craig, RN; Anne Lahn, RN. Data Coordinators: Ricki Klutch, RN; Joan Krause, RN; Sandy Cerda. Community Education Liaison: Denise Leeper. Chief Nurse Coordinators: Fiona Chatfield, RN; Anna Grace, RN; Gigi Gaughran, RN. Statistical Management Center: Scott Hamilton, PhD, Stanford; Data Management Center: InClin: Anita Das, PhD; Pacific Data Designs: Kelli Greene, PhD; Data and Safety Monitoring Board: E. Clarke Haley Jr, MD; David Sherman, MD; Oscar Benavente, MD; Jeffrey Dawson, ScD, Edward Jauch, MD; Rafael Llinas, MD; Medical Monitor: Steven R. Levine, MD; Neuroimaging Core Laboratory: Pablo Villablanca, MD; David S. Liebeskind, MD; National Institutes of Health/National Institute of Neurological Disorders and Stroke Administration: Scott Janis, PhD; Claudia Moy, PhD; External Advisory Committee: Greg Albers, MD; Brian Alldredge, PhD; William Barsan, MD; William Clarke, PhD; James Grotta, MD; Ken Lees, MD; William Longstreth, MD; Keith Muir, MD; Ralph Sacco, MD; Executive Committee: Robin Conwit, MD; Marc Eckstein, MD; Scott Hamilton, PhD; David S. Liebeskind, MD; Frank Pratt, MD; MPHTM, Nerses Sanossian, MD; Jeffrey L. Saver, MD; Sidney Starkman, MD; Samuel J. Stratton, MD; Gene Sung, MD.

^✉

Corresponding author.

PMCID: PMC6248118 PMID: 30039165

This exploratory analysis of 1690 patients enrolled in the Field Administration of Stroke Therapy-Magnesium Trial assesses the frequency, predictors, and outcomes of the neurological deterioration that occurs among patients during the ultra-early period after ischemic stroke or intracranial hemorrhage.

Key Points

Question

What are the frequency, predictors, and outcomes of neurological deterioration in the ultra-early period after ischemic stroke and intracranial hemorrhage?

Findings

In this exploratory analysis of 1690 patients enrolled in the double-blind, placebo-controlled, randomized Field Administration of Stroke Therapy-Magnesium Trial, ultra-early neurological deterioration occurred in 1 in 3 patients with intracranial hemorrhage and in 1 in 16 patients with acute cerebral ischemia. Ultra-early neurological deterioration was associated with markedly reduced functional independence and increased mortality.

Meaning

Reducing ultra-early neurological deterioration during prehospital and early postarrival is an important target to improve outcomes among patients with acute stroke.

Abstract

Importance

Studies of neurological deterioration in stroke have focused on the subacute period, but stroke treatment is increasingly migrating to the prehospital setting, where the neurological course has not been well delineated.

Objective

To describe the frequency, predictors, and outcomes of neurological deterioration among patients in the ultra-early period following ischemic stroke or intracranial hemorrhage.

Design, Settings, and Participants

Exploratory analysis of the prehospital, randomized Field Administration of Stroke Therapy-Magnesium (FAST-MAG) Trial conducted from 2005 to 2013 within 315 ambulances and 60 stroke patient receiving hospitals in Southern California. Participants were consecutively enrolled patients with suspected acute stroke who were transported by ambulance within 2 hours of stroke onset.

Main Outcomes and Measures

The main outcome was neurological deterioration, defined as a worsening of 2 or more points on the Glasgow Coma Scale (GCS), a level of consciousness scale ranging from 3 to 15, with higher scores indicating more alertness. Imaging outcomes were ischemic or hemorrhagic injury extent identified during the first brain imaging scan. Outcomes at 3 months included global disability level (assessed using the modified Rankin Scale [mRS]; range, 0-6, with higher numbers indicating greater disability) and mortality.

Results

Among the 1690 patients (99.4%), the mean (SD) age was 69.4 (13.5) years, and 43% were female. Final diagnoses were acute cerebral ischemia in 1237 patients (73.2%), intracranial hemorrhage in 386 patients (22.8%), and neurovascular mimic in 67 patients (4.0%). The median (interquartile range [IQR]) minutes between the last well-known time and GCS assessments were 23 (14-42) minutes for prehospital, 58 (46-79) minutes for ED arrival, and 149 (120-180) minutes for early ED course assessments. From prehospital to early postarrival, ultra-early neurological deterioration (U-END) occurred in 200 of 1690 patients (11.8%), more often among patients with intracranial hemorrhage than among those with acute cerebral ischemia (119 of 386 [30.8%] vs 75 of 1237 [6.1%], P < .001). Patterns of U-END were prehospital U-END without early recovery in 30 of 965 patients (3.1%), stable prehospital course but early ED deterioration in 49 of 965 patients (5.1%), and continuous deterioration in both prehospital and early ED phases in 27 of 965 patients (2.8%). Ultra-early neurological deterioration was associated with worse 3-month outcomes, including increased global disability (mRS score, 4.6 vs 2.4; P < .001), reduced functional independence (mRS score 0-2, 32 of 200 [16.0%] vs 844 of 1490 [56.6%]; P < .001), and increased mortality (87 of 200 [43.5%] vs 176 of 1490 [11.8%]; P < .001).

Conclusions and Relevance

Ultra-early neurological deterioration occurs in 1 in 8 ambulance-transported patients with acute cerebrovascular disease, including 1 in 3 patients with intracranial hemorrhage and 1 in 16 patients with acute cerebral ischemia, and is associated with markedly reduced functional independence and increased mortality. Averting U-END may be a target for future prehospital therapeutics.

Trial Registration

ClinicalTrials.gov Identifier: NCT00059332

Introduction

For both acute cerebral ischemia (ACI) and acute intracranial hemorrhage (ICH), neurological progression following first symptom onset is a common and feared complication. However, the frequency, predictors, and outcomes of neurological deterioration in the ultra-early time window (3-4 hours), including the prehospital period, have not been well characterized. Instead, studies have generally examined neurological deterioration across extended time windows after hospital arrival, including at any time during the initial hospitalization,^1,2 or have examined early neurological deterioration (END), defined as within 48 hours of admission.^3,4 Although 1 study investigated prehospital deterioration among patients with intracerebral hemorrhage,⁵ we know of no systematic studies of ultra-early neurological deterioration (U-END) in both the prehospital and initial emergency department (ED) phase encompassing both patients with ACI and those with acute ICH.

Many interventions for treatment of acute stroke are most effective when initiated as soon as possible after stroke onset.^{6,7,8,9,10,11} As a result, both delivery of standard treatments and research studies of experimental treatments are increasingly migrating to the early postarrival ED time period or directly to the prehospital phase of care.^{12,13,14,15,16} The earliest point from which neurological deterioration can be systematically studied is the initial assessment by emergency medical services personnel prior to transport. The prehospital phase of stroke typically lasts 25 to 40 minutes from emergency medical services arrival on the scene to completion of transport to the ED. While in the ED, another 30 to 60 minutes are spent in triage, initial stabilization, transport to neuroimaging, and imaging interpretation prior to starting stroke subtype–specific therapy.¹⁷ There is an urgent need to characterize the frequency, predictors, and outcomes of neurological deterioration among patients in these earliest time windows for use as a baseline against which faster delivery methods and novel treatments can be assessed, to identify patients at greatest risk of U-END so that they can receive the fastest standard treatment, and to enrich enrollment in clinical trials of progression-averting research interventions.

Methods

This was an exploratory analysis of patients enrolled in the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) Trial, a phase 3, National Institute of Neurological Disorders and Stroke–sponsored, placebo-controlled randomized clinical trial of field-initiated magnesium sulfate in patients with hyperacute stroke within 2 hours after the last known well time (LKWT) conducted from 2005 to 2013.^16,18,19 Participating sites included 40 emergency medical system agencies, 315 ambulances, and 60 acute care receiving hospitals in Los Angeles and Orange counties in California. The study protocol was approved by the institutional review board at each prehospital and hospital study site. Enrollment occurred using explicit informed consent obtained via cellphone conversation between patients on the scene or their legally authorized representatives and enrolling physician-investigators off the scene or under exception from informed consent regulations.^20,21

Neurological deterioration was defined as worsening by 2 or more points on the Glasgow Coma Scale (GCS; range, 3-15, with higher numbers indicating alertness).⁵ The FAST-MAG Trial patients had up to 3 serial GCS evaluations in the ultra-early time period: the first during the initial prehospital assessment (performed by paramedics), the second at the initial ED arrival (performed by ED bedside nurses), and the third early in the ED course (performed by FAST-MAG research nurses). The prehospital and early ED course GCS evaluations were mandated by the study protocol and performed in nearly all patients. The ED arrival GCS evaluation was not required by the study protocol but was commonly performed as part of routine clinical practice at participating hospitals. Accordingly, the occurrence of U-END was assessed for all patients between the prehospital and shortly postarrival GCS evaluations. For patients with a clinically documented ED arrival GCS assessment, additional analyses were performed assessing U-END occurrence in the prehospital phase (between the prehospital and ED arrival assessments) and U-END occurrence in the early postarrival phase (between the ED arrival and ED course assessments) (eFigure in the Supplement). Specific patterns of deficit progression were identified as follows: prehospital sustained indicated prehospital deterioration and then a stable early ED phase; dipper indicated prehospital deterioration and then early ED improvement; delayed indicated stable prehospital and then ED deterioration; peaker indicated prehospital improvement and then early ED deterioration; continuous major indicated prehospital deterioration and early ED deterioration; and continuous minor indicated mild (1 point) GCS score worsening in both prehospital and early ED phases, cumulatively reaching the threshold for deterioration.

Prehospital ambulance services and hospital receiving sites were directed to provide supportive treatment and blood pressure control as well as thrombolytic, endovascular, and surgical care according to the national American Heart Association/American Stroke Association guidelines for care of patients with acute ischemic stroke or intracerebral hemorrhage in addition to the study treatment of an infusion of magnesium sulfate or placebo. Throughout the study region in accordance with the predominant US emergency medical services practice, administration of antihypertensive therapies was not initiated in the field but deferred to ED arrival if needed.

All modified Rankin Scale assessments (scores range from 0 to 6, with higher numbers indicating greater disability) were performed by physician and nurse raters certified in the validated Rankin Focused Assessment method for assigning modified Rankin Scale scores. Additional study-specific training on the use of the GCS was not performed because GCS scoring is a core competency of paramedics, neurologists, and emergency department physicians and nurses.

Statistical analysis of associations used χ² tests for binary variables and t tests for linear variables. Two-sided P ≤ .05 values were considered statistically significant. Because all analyses were considered exploratory, no adjustment for multiplicity was made. A multivariate prediction model for occurrence of neurological deterioration was derived by stepwise logistic regression using variables with univariate P ≤ .05 values as candidates. Data analyses were performed using SPSS, version 20 (SPSS Inc).

Results

Among the 1700 patients enrolled in the FAST-MAG Trial, 1690 patients (99.4%) had serial GCS assessments performed at the 2 protocol-mandated times of prehospital and early ED course (10 patients were excluded for 1 or more missing GCS scores). This population constituted the primary analytic population for the present study. Among these 1690 patients, the mean (SD) age was 69.4 (13.5) years, 725 patients (43%) were female, and the final diagnosis was ACI in 1237 patients (73.2%), acute ICH in 386 patients (22.8%), and cerebrovascular mimic in 67 patients (4.0%). The median time from LKWT to the initial paramedic GCS assessment was 23 minutes (interquartile range [IQR], 14-42 minutes), the median LKWT to ED arrival was 58 minutes (IQR, 46-79 minutes), the median LKWT to early ED course GCS assessment was 149 minutes (IQR, 120-180 minutes), and the median time from prehospital GCS assessment to early ED course GCS assessment was 117 minutes (IQR, 95-143 minutes) (Table 1).

Table 1. Time Intervals in Study Populations.

Interval	Median (IQR) Time, min
Interval	Patients With Prehospital and Early ED Course GCS Assessment (n = 1690)	Subset of Patients With Prehospital, ED Arrival, and Early ED Course GCS Assessment (n = 965)
LKWT to prehospital GCS	23 (14-42)	24 (15-45)
LKWT to ED arrival	58 (46-79)	60 (47-81)
Prehospital GCS to ED arrival	32 (27-39)	33 (28-39)
ED arrival to ED arrival GCS	ND	10 (5-22)
LKWT to ED arrival GCS	ND	76 (60-100)
Prehospital GCS to ED arrival GCS	ND	46 (37-59)
LKWT to early ED course GCS	149 (120-180)	150 (123-180)
ED arrival to early ED course GCS	82 (62-107)	83 (61-108)
ED arrival GCS to early ED course GCS	ND	70 (45-95)
Prehospital GCS to early ED course GCS	117 (95-143)	118 (97-144)

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Abbreviations: ED, emergency department; GCS, Glasgow Coma Scale; IQR, interquartile range; LKWT, last known well time; ND, not determined.

Ultra-early neurological deterioration between prehospital paramedic evaluation and the early ED course evaluation occurred in 200 of 1690 patients (11.8%). Univariate predictors of U-END among all enrolled patients were Asian race, Hispanic ethnicity, history of hypertension, absence of history of atrial fibrillation or valvular heart disease, higher prehospital systolic and diastolic blood pressure, more severe prehospital focal motor deficits on the Los Angeles Motor Scale (LAMS), and a final diagnosis of acute ICH rather than ACI (Table 2 and eTable 4 in the Supplement). In multivariate analyses, independent predictors of U-END were prehospital GCS assessment (odds ratio [OR], 0.7 per point increase; 95% CI, 0.7-0.8) and final diagnosis of acute ICH (OR, 3.9; 95% CI, 1.6-9.5).

Table 2. Demographic and Clinical Features Associated With Deterioration Among All Patients and Among Those With Cerebral Ischemia or ICH^a.

Feature	All Patients (n = 1690)			Patients With Cerebral Ischemia (n = 1237)			Patients With ICH (n = 386)
Feature	U-END (n = 200)	No U-END (n = 1490)	P Value	U-END (n = 75)	No U-END (n = 1162)	P Value	U-END (n = 119)	No U-END (n = 267)	P Value
Age, mean (SD), y	68.3 (13.6)	69.5 (13.5)	.22	65.7 (13.2)	64.9 (13.9)	.59	65.7 (13.2)	64.9 (13.9)	.59
Female, No. (%)	83 (41.1)	642 (42.9)	.63	45 (60.0)	515 (44.3)	.01	36 (30.3)	92 (34.5)	.42
Race, No. (%)
White	147 (72.8)	1178 (78.5)		54 (72.0)	907 (78.1)		90 (75.6)	215 (80.5)
Black/African American	24 (11.9)	195 (13.0)		10 (13.9)	161 (13.9)		11 (9.2)	26 (9.7)
Asian	28 (13.9)	111 (7.4)		10 (13.3)	85 (7.3)		16 (13.4)	22 (8.2)
Other	3 (1.5)	14 (0.9)		1 (1.3)	9 (0.8)		2 (1.7)	4 (1.5)
Hispanic ethnicity, No. (%)	60 (29.7)	342 (22.8)	.03	18 (24.0)	231 (19.9)	.39	40 (33.6)	88 (33.0)	.90
Medical history, No. (%)
Hypertension	168 (83.2)	1151 (76.8)	.04	59 (78.7)	901 (77.5)	.82	104 (87.4)	200 (74.9)	.01
Diabetes	54 (26.7)	323 (21.6)	.97	28 (37.3)	253 (21.8)	<.001	24 (20.2)	47 (17.6)	.55
Hyperlipidemia	92 (45.5)	713 (47.6)	.58	41 (54.7)	585 (50.3)	.47	48 (40.3)	93 (34.8)	.30
Atrial fibrillation	31 (15.3)	338 (22.6)	.02	23 (30.7)	311 (26.8)	.46	8 (6.7)	22 (8.2)	.61
Heart disease	82 (40.7)	625 (41.7)	.08	43 (57.4)	561 (48.3)	.12	36 (30.2)	47 (17.6)	.01
Prior stroke/TIA	42 (20.8)	392 (25.5)	.15	22 (29.3)	314 (31.0)	.76	19 (16.0)	48 (18.0)	.63
Tobacco use	28 (13.9)	269 (18.0)	.15	7 (9.3)	209 (18.0)	.06	20 (16.8)	46 (17.2)	.92
Any alcohol use	73 (63.1)	581 (38.8)	.47	4 (5.3)	108 (9.3)	.01	53 (44.5)	120 (44.9)	.94
Antithrombotic prior to stroke, No. (%)	None	None	None	None	None	None	43 (35.8)	78 (29.2)	.20
Time interval, median (IQR), min
Onset to paramedic evaluation	22.5 (15.0-36.8)	25.0 (15.0-46.0)	.24	23.0 (15.0-35.0)	25.0 (15.0-47.0)	.87	21.5 (14.0-34.3)	25.0 (17.0-41.0)	.18
Onset to ED arrival	57.0 (45.8-72.0)	60.0 (47.0-82.0)	.51	60.0 (49.0-76.0)	60.0 (48.0-83.0)	.71	55.0 (45.0-65.5)	59.0 (46.5-79.5)	.45
ED arrival to early ED course GCS	91.0 (66.0-110.0)	83.0 (61.0-108.0)	.05	85.0 (65.5-111.5)	82.0 (60-106)	.39	95.0 (68.0-110.5)	89.0 (65.5-111.5)	.18
SBP, mean (SD), mm Hg
Prehospital	178.5 (24.4)	173.5 (26.0)	.07	155.6 (23.2)	155.8 (27.4)	.95	178.0 (24.4)	173.5 (25.7)	.74
ED arrival	186.4 (32.1)	174.1 (30.8)	<.001	149.4 (24.2)	149.3 (24.7)	.95	186.4 (32.1)	174.1 (30.8)	<.001
Early ED course	146.2 (27.1)	147.9 (23.4)	.55	140.1 (25.2)	145.4 (23.4)	.06	146.2 (27.1)	147.9 (23.4)	.55
DBP, mean (SD), mm Hg
Prehospital	100.0 (17.5)	99.6 (19.3)	.84	85.5 (17.6)	87.3 (17.6)	.59	100.0 (17.5)	99.6 (19.3)	.85
ED arrival	100.3 (22.1)	95.3 (20.9)	.03	77.1 (17.3)	78.1 (16.0)	.61	100.3 (22.1)	95.3 (20.9)	.34
Early ED course	77.5 (19.1)	78.8 (16.2)	.39	75.1 (18.6)	76.4 (15.5)	.52	77.2 (19.1)	78.8 (16.2)	.39
Severity scores
Prehospital GCS
Median (IQR)	14.0 (12.0-15.0)	15.0 (15.0-15.0)	<.001	5.0 (3.5-5.0)	4.0 (3.0-5.0)	<.001	15.0 (12.0-15.0)	15.0 (15.0-15.0)	<.001
Mean (SD)	13.6 (1.9)	14.3 (1.6)	<.001	13.2 (2.1)	14.2 (1.8)	<.001	13.8 (1.8)	14.6 (1.2)	<.001
Prehospital LAMS
Median (IQR)	5.0 (4.0-5.0)	4.0 (3.0-5.0)	<.001	14.0 (11.0-15.0)	15.0 (14.0-15.0)	<.001	5.0 (4.0-5.0)	4.0 (3.0-5.0)	<.001
Mean (SD)	4.3 (1.0)	3.7 (1.3)	<.001	4.2 (1.2)	3.6 (1.3)	<.001	4.4 (0.9)	3.9 (1.1)	<.001

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Abbreviations: DBP, diastolic blood pressure; ED, emergency department; ICH, intracranial hemorrhage; GCS, Glasgow Coma Scale; IQR, interquartile range; LAMS, Los Angeles Motor Scale; SBP, systolic blood pressure; TIA, transient ischemic attack; U-END, ultra-early neurological deterioration.

^{^a}

See eTable 4 in the Supplement for additional baseline variables not associated with U-END and for ED arrival GCS assessment.

Among patients who received a final diagnosis of ACI, U-END occurred in 75 of 1237 patients (6.1%). Univariate predictors of U-END among patients with ACI were female sex, history of diabetes, alcohol abstinence, and more severe stroke deficits as assessed by both the GCS and the LAMS (Table 2). In addition, systolic blood pressure was nominally lower among patients with ACI and deterioration (153.6 vs 155.8, P = .06). Among patients who received a final diagnosis of ICH, U-END occurred in 119 of 386 patients (30.8%). Univariate predictors of U-END among patients with ICH were history of hypertension, coronary artery disease, myocardial infarction, and more severe stroke deficits as assessed by both the GCS and the LAMS (Table 2). In addition, systolic blood pressure at ED arrival, although not prehospital, was higher among patients with U-END.

More detailed analysis of the timing of deficit evolution was performed in the 965 patients (56.8%) who had an ED arrival GCS score documented as part of their routine care. Patients with or without a clinically performed ED arrival GCS assessment were similar in baseline characteristics and outcomes (eTable 1 in the Supplement). Among these patients, the median time from prehospital GCS assessment to ED arrival GCS assessment was 46 minutes (IQR, 37-59 minutes) and from ED arrival GCS assessment to early ED course GCS assessment was 70 minutes (IQR, 45-95 minutes) (Table 1).

Among all patients with an ED arrival GCS assessment, 93 of 965 patients (9.6%) experienced U-END only en route to the hospital, 83 of 965 patients (8.6%) experienced U-END only between the ED arrival and early ED course GCS assessments, and 23 of 965 patients (2.4%) experienced U-END in both phases. The results of a multivariate analysis indicated that the only independent predictor of prehospital U-END was receiving a final diagnosis of ICH (OR, 3.5; 95% CI, 2.3-5.3). For postarrival U-END, receiving a final diagnosis of ICH independently increased the likelihood (OR, 6.1; 95% CI, 3.8-9.8), whereas the occurrence of prehospital U-END independently decreased the likelihood (OR, 0.64; 95% CI, 0.7-0.8). Among 713 patients with cerebral ischemia, 128 patients (18.0%) had U-END, including 64 patients (8.9%) in the prehospital phase only, 52 patients (7.3%) in the early ED phase only, and 1 (0.2%) in both phases. Among 210 patients with ICH, 82 patients (39.0%) had U-END, including 27 patients (12.9%) in the prehospital phase only, 30 patients (14.3%) in the early ED phase only, and 22 patients (10.5%) in both phases. More detailed patterns of deficit progression are shown in eTables 2 and 3 in the Supplement and in Figure 1 and Figure 2.

Figure 1. — A, Acute cerebral ischemia (n = 713). B, Intracranial hemorrhage (n = 210). Colors categorize GCS scores as indicated. Inner ring indicates proportion of patients in various GCS categories at time of paramedic prehospital examination; middle ring indicates evolution of GCS scores in these patients at time of ED arrival; and outer ring indicates further GCS score evolution at time of early postarrival ED assessment.

Figure 2. — U-END indicates ultra-early neurological deterioration.

The occurrence of U-END was associated with worse early stroke outcomes (Table 3). Early intubation (intubation by the time of the early postarrival ED assessment) and in-hospital mortality were more frequent among patients with U-END than among those without U-END. Among patients with ACI, the extent of the acute ischemic change on first imaging, assessed using the Alberta Stroke Program Early Computed Tomographic Score, was higher among patients with U-END than among patients without U-END. Among patients with intraparenchymal hemorrhages, hematoma volume on first imaging was higher among patients with U-END than among patients without U-END.

Table 3. Outcomes Associated With or Without U-END Among All Patients and Among Those With Cerebral Ischemia or Intracranial Hemorrhage.

Outcome	All Patients (n = 1690)			Patients With Cerebral Ischemia (n = 1237)			Patients With Intracranial Hemorrhage (n = 386)
Outcome	U-END (n = 200)	No U-END (n = 1490)	P Value	U-END (n = 75)	No U-END (n = 1162)	P Value	U-END (n = 119)	No U-END (n = 267)	P Value
Early outcome
Early ED course GCS score, median (IQR)	8 (8-11)	15 (15-15)	<.001	9 (6-11)	15 (15-15)	<.001	12 (9-15)	15 (14-15)	<.001
Early ED course LAMS score, median (IQR)	5 (5-5)	3 (1-5)	<.001	5 (5-5)	3 (1-5)	<.001	5 (5-5)	5 (3-5)	<.001
Early ED course NIHSS score, mean (SD)	28.3 (9.2)	9.1 (7.4)	<.001	24.1 (9.3)	8.4 (9.3)	<.001	31.4 (7.8)	12.8 (7.0)	.01
Early intubation, No. (%)	82 (40.8)	6 (0.4)	<.001	14 (18.4)	1 (0.1)	<.001	66 (55.5)	5 (1.9)	<.001
Mortality during initial hospitalization, No. (%)	57 (28.2)	66 (4.4)	<.001	17 (22.4)	39 (3.4)	<.001	39 (32.8)	26 (9.7)	<.001
ASPECTS on first imaging, mean (SD)	ND	ND	ND	7.6 (2.7)	8.6 (2.4)	.01	ND	ND	ND
Intracerebral hematoma volume on first imaging, mean (SD), cm^3,^a	ND	ND	ND	ND	ND	ND	46.5 (48.5)	22.0 (30.6)	<.001
90-d Outcome
mRS score 0-1, No. (%)	16 (8.0)	591 (40.0)	<.001	14 (18.7)	523 (45.0)	<.001	0 (0)	34 (12.7)	<.001
mRS score 0-2, No. (%)	32 (16.0)	844 (56.6)	<.001	18 (24.0)	695 (60.0)	<.001	10 (8.4)	106 (39.7)	<.001
mRS score, mean (SD)	4.6 (1.8)	2.4 (2.1)	<.001	4.1 (2.1)	2.2 (2.0)	.48	5.0 (1.2)	3.4 (1.7)	<.001
Mortality, No. (%)	87 (43.5)	176 (11.8)	<.001	29 (38.7)	124 (10.7)	<.001	58 (48.7)	45 (16.9)	<.001

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Abbreviations: ASPECTS, Alberta Stroke Program Early Computed Tomographic Score; ED, emergency department; GCS, Glasgow Coma Scale; IQR, interquartile range; LAMS, Los Angeles Motor Scale; mRS, modified Rankin Scale; ND, not determined; NIHSS, National Institutes of Health Stroke Scale; U-END, ultra-early neurological deterioration.

^{^a}

Row values are for the 381 patients with intracerebral hemorrhage from among the 386 patients with intracranial hemorrhage of any kind.

The occurrence of U-END was also strongly associated with worse final clinical outcome (Table 3). For example, among all 1690 patients, rates of good functional outcome (modified Rankin Scale score of 0-2) at 3 months after stroke were 16.0% (32 of 200) among individuals with U-END and 56.6% (844 of 1490) among individuals without U-END (P < .001). Rates of good functional outcome among patients with cerebral ischemia were 24.0% (18 of 75) among those with U-END vs 59.8% (695 of 1162) among those without U-END (P < .001), and among patients with ICH, the rates were 8.4% (10 of 119) among those with U-END vs 39.7% (106 of 267) among those without U-END (P < .001). Three-month mortality rates among patients with U-END were 87 of 200 (43.5%) vs 176 of 1490 (11.8%) among those without U-END (P < .001), including 29 of 75 patients (38.7%) with cerebral ischemia and with U-END vs 124 of 1162 patients (10.7%) without U-END (P < .001) and 58 of 119 patients (48.7%) with ICH and with U-END vs 45 of 267 patients (16.9%) without U-END (P < .001). The distribution of 3-month disability outcomes among patients by detailed U-END pattern categories is shown in Figure 2.

Discussion

This study found that neurological deterioration as assessed with the GCS in the ultra-early period was frequent among ambulance-transported patients with acute cerebrovascular disease, occurring in 12% of patients. Ultra-early neurological deterioration was substantially more common among patients with ICH, occurring in nearly 1 in 3 of such patients, and less common but still notable among patients with ACI, occurring in about 1 in 16 of these patients. Among all patients with acute cerebrovascular disease, independent predictors of U-END were ICH stroke subtype and lower initial prehospital GCS score.

To our knowledge, this study is the first prospective, multicenter investigation of clinical deterioration in the prehospital and early ED course during the first minutes and hours after symptom onset in a broad cerebrovascular disease cohort. For ACI, prior studies of neurological deterioration have focused solely on later in-hospital time windows. For example, in a systematic meta-analysis and later large case-series studies, the 8 studies reporting on the frequency of neurological deterioration due to stroke progression had observation periods that were not always well demarcated but that appeared to begin 3 to 72 hours after stroke onset and end 24 to 168 hours after stroke onset.^{22,23,24,25,26,27,28,29} In these case series, neurological worsening occurred in a median of 9.6% (IQR, 5.1%-18.1%) of patients. In the present study in a much earlier and more compressed window of median observation times between 0.4 and 2.5 hours after onset, U-END occurred in 6.1% of patients with ischemic stroke.

For acute ICH, most prior studies have also focused on neurological deterioration occurring within 24 hours of ED arrival.^30,31,32 Current large studies analyzing deterioration among patients with ICH after hospital arrival have considered periods from 5 to 28 hours after the LKWT,³¹ from 1.5 to 25.5 hours,³² from up to 6 hours to 72 hours,³⁰ and from a median of 7.3 hours to 9 to 13 hours after the LKWT.^33,34 One prior single-center study did investigate the prehospital period in 98 patients with intracerebral hemorrhage and reported neurological deterioration in 22% of these patients.⁵ Our study confirms and extends this finding in a larger multicenter cohort, documenting deterioration in 23% of patients with ICH in the prehospital setting as well as finding that deterioration additionally occurs in 24% of patients in the first minutes to hours after ED arrival.

Among all patients with acute cerebrovascular disease transported by paramedics, there were only 2 independent predictors of neurological deterioration: more severe initial level of consciousness impairment as assessed by the GCS and a final stroke subtype diagnosis of ICH rather than ACI. Predictors of early neurological deterioration were largely different among patients with ACI and with ICH, although more severe initial deficits at the time of initial paramedic encounters were associated with deterioration in both stroke subtypes. Female sex and alcohol abstinence were associated with neurological deterioration in ACI, whereas history of hypertension and myocardial disease were associated with neurological deterioration in ICH. There was a suggestion of a differential association of blood pressure with progression among patients with ACI compared with those with ICH. Among patients with ACI, END tended to be associated with lower systolic blood pressure at the time of the first paramedic evaluation, whereas among patients with ICH, END tended to be associated with higher systolic blood pressure at ED arrival.

Our findings on the association of prehospital and ED arrival blood pressure with END among patients with ICH are of interest given the nascent conduct of randomized trials of blood pressure lowering in the field.^35,36,37 Two prior observational studies have investigated aspects of this association. In a single-center study of 98 ICH cases, neurological deterioration in the field was associated with higher prehospital diastolic blood pressure but not with higher prehospital systolic blood pressure.⁵ In another single-center study of 536 patients with ICH, neurological deterioration in the prehospital period was not examined, but neurological deterioration after hospital arrival was associated with higher prehospital diastolic and systolic blood pressures.³³ In the present study, END was associated with higher systolic blood pressure on ED arrival but not with higher prehospital blood pressures. The nonuniform but suggestive findings from these 3 observational studies support further formal trials of the therapeutic strategy of prehospital blood pressure moderation in patients likely to have ICH.

For prehospital system planning, the present study provides unique insight into the frequency of deterioration occurring between paramedic evaluation in the field and ED arrival. Our study findings indicated that emergency medical services system planners may anticipate that approximately 1 in 10 patients with stroke (including about 1 in 4 patients with acute ICH) will deteriorate between the scene and ED arrival. This frequency of prehospital deterioration reflects transport in a largely urban or suburban setting with relatively short transport times. In rural settings with longer transport times, the frequency of deterioration will be higher, as suggested by the 1 in 8 rate of deterioration in the present study between the scene and the later ED course evaluation.

The potential pathophysiologic mechanisms of U-END are varied. In ACI, causes of U-END may include reduction in collateral circulation, clot propagation, recurrent embolus, and hemorrhagic transformation of infarct. In acute intracerebral hemorrhage, causes of U-END may include hematoma expansion and obstructive hydrocephalus. The much larger hematoma volume observed on arrival imaging among patients with intraparenchymal hemorrhage and U-END, approximately twice the size of that among patients without U-END, suggests that hemorrhage expansion in the field and during the early ED course, prior to the collection of the first images, was likely an important contributor. In both ischemic and hemorrhagic stroke, U-END may also be caused by noncerebrovascular events, such as seizure, respiratory compromise, and myocardial infarction. These noncerebrovascular events were rare in the prehospital period,¹⁶ but intubation for respiratory compromise or concern did occur early in the ED course in about 6 in 10 of the patients with ICH and U-END. The high frequency of U-END emphasizes the importance of migrating clinical trials for acute stroke into the prehospital setting so that treatments can be initiated at the earliest moment of medical contact in advance of U-END.^{15,16,36,37,38,39,40}

Limitations

Our analysis included only those patients who were enrolled in a clinical trial. Although the FAST-MAG Trial entry criteria were broad in age, stroke severity, and comorbidities,⁴¹ the study did exclude patients with prestroke disability, systolic blood pressure higher than 220, and other uncommon features. Such patients may have different frequencies of U-END. For example, patients with ICH and systolic blood pressure greater than 220 mm Hg may have higher rates of U-END. The present study, similar to prior prehospital investigations,^5,33 used a change in GCS scores to identify neurological deterioration and improvement. Because the GCS is a measure of the level of consciousness rather than the degree of focal deficit, it may not capture all clinically relevant deficit changes in patients. Studies of in-hospital neurological deterioration among patients with ACI have most often focused on a prespecified increase in the National Institutes of Health Stroke Scale score,¹ but assessments using this scale are too time-consuming for routine use in the field by paramedics. The GCS has good interrater reliability and is universally used by prehospital personnel, making study findings of wide applicability. As in prior studies, the present investigation excluded patients who were already comatose at the time of first paramedic evaluation, as further worsening in these patients would have been difficult to detect. Comatose patients with ICH at the time of emergency medical services arrival are uncommon, but when such patients are included, rates of deterioration in the prehospital setting will be slightly lower than the current study estimates. Although initial brain imaging was obtained in all study patients, follow-up serial imaging was not mandated; thus, the present study cannot address the frequency of postarrival infarct growth or hemorrhage expansion. The timing of the early ED course GCS assessment was nonuniform; the median time was approximately 82 minutes, but the IQR was from about 61 to 108 minutes after ED arrival, which was caused by the variability in arrival time of the responding regional study nurse. The FAST-MAG Trial collected information on the timing of the start of antihypertensive medication administration, if any, after arrival. Some data on blood pressure medication use among patients with ICH were collected in a nonmonitored manner and will be analyzed in a future exploratory analysis.

Conclusions

Approximately 1 in 8 patients with suspected acute cerebrovascular disease experienced U-END as assessed with the GCS during paramedic transport and initial ED evaluation. Ultra-early neurological deterioration was more common among patients with ICH, occurring in nearly 1 in 3 of these patients, and less common but still frequent among patients with ACI, occurring in 1 in 16 of these patients. Patients with more severe initial deficits in the field had higher rates of U-END, and patients with U-END had substantially worse final functional outcomes and increased mortality. These findings suggest the desirability of initiating stroke therapies as soon as possible after stroke onset, including in the prehospital setting, to avert the occurrence of U-END.

Supplement.

eTable 1. Demographic and Clinical Characteristics of the Patients in the Secondary Analysis With Or Without GCS Available at Hospital Arrival

eTable 2. Patterns of Ultra-Early Neurological deterioration Among Patients With GCS Assessments Prehospital, on ED Arrival, and in the Early ED Course; Grouped by Ultra-Early Time Segment in Which U-END Occurred

eTable 3. Patterns of Ultra-Early Neurological deterioration Among Patients With GCS Assessments Prehospital, on ED Arrival, and in the Early ED Course; Grouped by Occurrence or Non-Occurrence of Net Deterioration

eTable 4. ED Arrival GCS and Additional Baseline Variables Not Associated With U-END in All, Cerebral Ischemia, and Intracranial Hemorrhage Patients

eFigure. Timeline Delineating Typical FAST-MAG Patient Enrollment and Assessment Activities During the First 2 Hours After Symptom Onset

Click here for additional data file.^{(158KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eTable 1. Demographic and Clinical Characteristics of the Patients in the Secondary Analysis With Or Without GCS Available at Hospital Arrival

eTable 4. ED Arrival GCS and Additional Baseline Variables Not Associated With U-END in All, Cerebral Ischemia, and Intracranial Hemorrhage Patients

eFigure. Timeline Delineating Typical FAST-MAG Patient Enrollment and Assessment Activities During the First 2 Hours After Symptom Onset

Click here for additional data file.^{(158KB, pdf)}

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PERMALINK

Frequency, Predictors, and Outcomes of Prehospital and Early Postarrival Neurological Deterioration in Acute Stroke

Kristina Shkirkova, BS

Jeffrey L Saver, MD

Sidney Starkman, MD

Gregory Wong, BS

Julius Weng, BS

Scott Hamilton, PhD

David S Liebeskind, MD

Marc Eckstein, MD

Samuel Stratton, MD

Frank Pratt, MD

Robin Conwit, MD

Nerses Sanossian, MD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Settings, and Participants

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Results

Table 1. Time Intervals in Study Populations.

Table 2. Demographic and Clinical Features Associated With Deterioration Among All Patients and Among Those With Cerebral Ischemia or ICHa.

Figure 1. Patterns of Glasgow Coma Scale (GCS) Score Evolution Among Patients With Acute Cerebral Ischemia or Intracranial Hemorrhage.

Figure 2. Three-Month Disability Outcomes (Modified Rankin Scale) Among 965 Patients With Suspected Acute Stroke Showing 6 Glasgow Coma Scale (GCS) Patterns of Evolution in the Ultra-Early Period.

Table 3. Outcomes Associated With or Without U-END Among All Patients and Among Those With Cerebral Ischemia or Intracranial Hemorrhage.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

Links to NCBI Databases

Table 2. Demographic and Clinical Features Associated With Deterioration Among All Patients and Among Those With Cerebral Ischemia or ICH^a.