Mini Review

published: 20 November 2017

doi: 10.3389/fneur.2017.00617

Jeremy N. Pulvers and John D. G. Watson*

Sydney Adventist Hospital Clinical School, Sydney Medical School, The University of Sydney, Wahroonga, NSW, Australia

Despite the availability of thrombolytic and endovascular therapy for acute ischemic
stroke, many patients are ineligible due to delayed hospital arrival. The identification of
factors related to either early or delayed hospital arrival may reveal potential targets of
intervention to reduce prehospital delay and improve access to time-critical thrombolysis
and clot retrieval therapy. Here, we have reviewed studies reporting on factors associated
with either early or delayed hospital arrival after stroke, together with an analysis of stroke
onset to hospital arrival times. Much effort in the stroke treatment community has been
devoted to reducing door-to-needle times with encouraging improvements. However,
this review has revealed that the median onset-to-door times and the percentage of
stroke patients arriving before the logistically critical 3 h have shown little improvement
in the past two decades. Major factors affecting prehospital time were related to emer-
Edited by:
Tracey Weiland,
gency medical pathways, stroke symptomatology, patient and bystander behavior,
University of Melbourne, Australia patient health characteristics, and stroke treatment awareness. Interventions addressing
Reviewed by: these factors may prove effective in reducing prehospital delay, allowing prompt diag-
Sandra Leanne Neate, nosis, which in turn may increase the rates and/or efficacy of acute treatments such as
University of Melbourne, Australia
Daniel Fatovich, thrombolysis and clot retrieval therapy and thereby improve stroke outcomes.
University of Western Australia,
Keywords: stroke, prehospital delay, thrombolysis, tissue plasminogen activator, emergency medical services
Australia
Mark William Parsons,
University of Newcastle, Australia INTRODUCTION
*Correspondence:
John D. G. Watson The “time is brain” concept introduced more than two decades ago (1) encapsulates the crucial
john.watson@sydney.edu.au importance of time in treating acute stroke. This has become more pertinent since the advent of
thrombolysis treatment using tissue plasminogen activator (2, 3) and endovascular therapy (4).
Specialty section: Regarding thrombolysis, benefit has been shown for initiating treatment up to 4.5  h after acute
This article was submitted stroke onset (5, 6). A major obstacle to their use however is a long onset-to-door time (from stroke
to Neuroepidemiology, symptom onset or time last known well to hospital arrival), which in general is the largest component
a section of the journal of total onset-to-needle time (from stroke onset to thrombolysis) (7, 8).
Frontiers in Neurology
Previous reviews of prehospital delay have shown little improvement in onset-to-door times over
Received: 30 July 2017 the years (7, 8). Much effort to reduce door-to-needle times have led to remarkable improvements (9);
Accepted: 06 November 2017
however, these efforts on reducing in-hospital delay are diminished by the minimal improvements
Published: 20 November 2017
in prehospital delay. The battle to increase thrombolysis rates will remain futile unless significant
Citation: improvements are seen in reducing onset-to-door times after acute stroke (8, 10).
Pulvers JN and Watson JDG (2017)
Reducing the time to hospital arrival is crucial for prompt diagnosis and timely delivery of
If Time Is Brain Where
Is the Improvement in
therapies such as thrombolysis and clot retrieval. However, analysis of trial data has not consistently
Prehospital Time after Stroke? shown a relationship between time to treatment and better outcomes (11–13). Nevertheless, early
Front. Neurol. 8:617. arrival will naturally lead to a higher proportion of acute strokes arriving within the therapeutic time
doi: 10.3389/fneur.2017.00617 windows, conferring improved outcomes on a higher proportion of patients, regardless of whether

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Pulvers and Watson Review of Hospital Arrival Time after Stroke

there is increased benefit earlier in the 4.5-h thrombolysis time Table 1 | Factors associated with early and delayed hospital arrival after stroke.
window. A study analyzing the baseline penumbra volume, Factors associated with early presentation
baseline ischemic core volume, and the penumbra salvaged from
infarction after thrombolysis, showed that greater penumbral Emergency Medical Services admission (40) (30–69)
Severe stroke (NIHSS and equivalent) (26) (38, 43, 45, 46, 50, 54, 56, 58,
salvage had the greatest effect on disability-free life, rather than 63–65, 69–83)
onset to treatment time (14). However, this does not negate the Hemorrhagic stroke (10) (57, 59, 61, 66, 84–89)
importance of early presentation in this context, as it allows more Consciousness: lowered, disturbed, lost (9) (41, 49, 61, 81, 85, 90–93)
time for prompt clinical and imaging assessment. Moreover, History of stroke or TIA (7) (41, 62, 73, 81, 94–96)
earlier presentation should allow for a more extensive evaluation History of atrial fibrillation, cardiac arrhythmia (7) (43, 56, 61, 62, 67, 97, 98)
Attributing symptoms to stroke (7) (53, 55, 69, 92, 98–100)
of stroke mimics and potential misdiagnoses (15–17), within the CAD, IHD, prior myocardial infarction (6) (56, 59, 61, 62, 96, 101)
time window of eligibility for acute stroke therapies. Perception of severity, urgency (6) (32, 43, 47, 52, 53, 100)
The identification of factors associated with early or delayed Speech disturbance, aphasia (6) (41, 44, 52, 57, 102, 103)
hospital arrival after stroke is of crucial importance in improving 911 (or equivalent) called first or early (6) (32, 99, 104–107)
Bystander response (5) (32, 47, 49, 58, 99)
thrombolysis rates (10, 18) and by extrapolation the rates of other
Not living alone (4) (33, 39, 60, 82)
acute interventions. We therefore conducted a review of studies Higher education level (4) (43, 60, 77, 101)
that analyzed factors associated with either early or delayed hos- TIA (4) (43, 57, 89, 100)
pital arrival after stroke, with the aim of identifying modifiable tar- Increasing disability (4) (71, 78, 86, 88)
gets of interventions in reducing prehospital delay. Knowledge of Daytime onset (4) (70, 79, 86, 108)
Sudden onset of symptoms (3) (39, 71, 99)
these factors may be helpful in reducing onset-to-door times, and
Reduced GCS (3) (45, 78, 95)
thus increase the implementation rates of acute stroke therapies. Knowledge of thrombolysis (3) (53, 58, 68)
Cardioembolic stroke (3) (89, 109, 110)
Motor impairment (3) (41, 71, 111)
REVIEW METHODS White race/ethnicity (USA) (3) (33, 48, 62)
Directly reaching hospital (3) (89, 101, 102)
A search of MEDLINE was performed via Ovid (http://ovidsp. Factors associated with delayed presentation
ovid.com) using a previously published search strategy (7, 8) Primary care facility (GP) visited first (14) (34, 59, 61, 68, 85, 90, 112–119)
Referral from other hospital (10) (49, 58, 66, 74, 92, 97, 115, 117, 120, 121)
between 2008 to the access date of November 1st 2016. For the
Living alone (9) (43, 59, 60, 66, 68, 71, 94, 95, 122)
years prior to 2008, references of previous reviews were exam- Stroke in the evening or night (8) (40, 59, 66, 82, 85, 92, 104, 122)
ined (7, 8, 10, 18, 19). The same search strategy was also used Diabetes mellitus (7) (52, 55, 56, 61, 62, 67, 92)
in Embase via Ovid excluding MEDLINE journals but with no Private transport to hospital (6) (60, 63, 97, 113, 119, 121)
limit on publication year. Studies not published in English, review Black race/ethnicity (USA, UK) (5) (54, 56, 82, 123, 124)
Lacunar stroke, small vessel stroke (5) (46, 90, 95, 96, 109)
articles, and Letters to the Editor were excluded. The following
Mild neurological symptoms (5) (34, 59, 63, 94, 113)
were also excluded: studies focusing solely on transient ischemic Symptoms not taken seriously, low threat perception (4) (43, 59, 114, 117)
attacks (TIA); studies that reported on hospital arrival times but Awakening with symptoms (3) (35, 125, 126)
did not analyze factors associated with early or delayed arrival; Symptom onset at home (3) (61, 97, 104)
studies on decision delay after stroke; studies on delay to alerting Regular drinker, history of alcohol abuse (3) (61, 79, 96)
Worsening symptoms compared to onset (3) (49, 97, 121)
medical services or delay to first medical contact, and delay to
admission to stroke unit; and studies on factors associated with Factors significantly associated (P < 0.05) with early hospital arrival after stroke are
shown. Factors were included in this table if they were reported as significant in
Emergency Medical Services (EMS) use.
three or more studies. Factors independently associated with early or delayed arrival
115 studies, published between 1990 (20) and 2016 (21) (multivariate analysis) were included in the list; however, for studies that performed
reporting on data acquired between 1985 (20) and 2013 (22), univariate analyses only, these factors are also listed.
were identified that focused primarily on analyzing factors asso- The first number in parentheses indicates the number of studies canvassing each
factor, followed by the references.
ciated with early or delayed hospital arrival after stroke. From NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack; CAD,
these studies, factors significantly associated with early or delayed coronary artery disease; IHD, ischemic heart disease; GCS, Glasgow Coma Scale;
hospital arrival were extracted and are listed in Table 1. Factors GP, general practitioner.
from studies that did not describe any statistical analyses were
excluded (22–29). Factor data were excluded from one study obtained over a range of years, the mean of the years was used
which defined early arrival as before 24 h (20). (8). Time data were excluded from one study that only included
Median onset-to-door times, and the cumulative percentage patients that received thrombolysis (80). Inclusion criteria based
of patients arriving at hospital within: 1, 2, 3, 6, and/or 24  h on stroke subtype varied widely (7, 8, 18), for example: stroke
(majority of studies described data for these time intervals), and stroke-like symptoms (32), ischemic only (58), ischemic and
were collected when available. When median times were lacking hemorrhagic (127), stroke excluding subarachnoid hemorrhage
in a study, but a percent arriving before a given hour was 50% (50), intracerebral hemorrhage only (78), and some included
(±1%), this time was used as the median arrival time. Similarly, TIA (43). Other notable methodological variations were (i) time
when median times fell exactly on the time intervals above, then interval defining early versus delayed arrival; (ii) whether a cutoff
50% was added to the data as the cumulative percentage arriving was used to exclude prehospital time data from cases of prolonged
before that time. When time data were subdivided into certain (e.g., >24 h) delay; and (iii) how prehospital time was defined in
population subgroups, these were excluded. When time data were cases of patients awakening with stroke (7, 8, 18).

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Pulvers and Watson Review of Hospital Arrival Time after Stroke

TIME FROM SYMPTOM ONSET TO remained unchanged, as previously reported for data up to
HOSPITAL ARRIVAL: TRENDS OVER 2006 (7, 8). The majority of studies reported a median onset-
TWO DECADES to-door time well beyond 3  h, which when taking door-to-
needle time in consideration, prohibits the effective and timely
Within the 115 studies reviewed here, 58 studies from 26 coun- commencement of thrombolytic therapy. Only two studies
tries contained median onset-to-door times and the year/s of (54, 59) showed median onset-to-door times from different
data acquisition (Figure 1A). The key and perhaps unexpected years, which exhibited only modest improvements (Figure 1B).
result is that onset-to-door time over the years has essentially Eleven studies originating from the United States, the country

Figure 1 | Median onset-to-door times after stroke and percentages of patients arriving to hospital after stroke at 1, 2, 3, 6, and 24 h. (A) Data points represent
median onset-to-door times (hours) of stroke patients plotted against the year/s of data acquisition, in studies of factors associated with hospital arrival times after
stroke, from 58 studies. For studies conducted over multiple years, the mean of the years was taken (8). Black line shows the local polynomial regression (LOESS),
and the horizontal gray line indicates 3 h. (B) Median onset-to-door times (hours) from two studies that reported data for multiple years, from the United States
(USA) (54) and Greece (59). Black lines connect data from the same study. (C) Subset of median onset-to-door time data in panel (A) showing studies from the
United States (31–33, 35, 36, 44, 48, 53, 54, 73), excluding one outlier of median 16 h in 2000–2001 (128). (D) The cumulative percentages of patients arriving to
hospital after stroke, at 1, 2, 3, 6, and 24 h after onset. Data points represent percentages from individual studies plotted against year/s of data acquisition. Black
line shows the local polynomial regression (LOESS). An improvement in prehospital delay over the years would manifest as an upwards curve within each box, which
is not seen. (E) Subset of the cumulative percentage of patients arriving before 2 h from studies that reported on data for multiple years from Italy [1986–1990 to
1991–1995 (71); 2004–2012 (83)] and the United States [2001–2004 (54), 2003–2009 (62)].

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Pulvers and Watson Review of Hospital Arrival Time after Stroke

with the most studies available for secular trend comparison, use, appearing high in the list of factors associated with delay.
showed no meaningful improvement overall (Figure  1C). An A review of surveys on the knowledge of what action to take
analysis of onset-to-door time data from the Get With The upon stroke symptom onset has shown that, although the
Guidelines program between 2003 and 2009 (62) showed essen- majority stated calling EMS, a sizable proportion responded
tially no improvement (Figure 1E). contacting their GP (129). It is essential that educational pro-
Within the 115 studies reviewed here, 100 studies contained grams further emphasize contacting EMS immediately upon
data on the cumulative percentage of stroke patients arriving at stroke onset (10, 18).
hospital before at least one of the following time intervals: 1, 2, 3, Three factors frequently associated with delayed arrival
6, and/or 24 h, and also the year/s of data acquisition (Figure 1D). were closely related: primary care facility visited first, referral
The majority of patients failed to arrive before 3 h, and the local from another hospital, and private transport to hospital. These
regression shows no improvement over the two decades. Four reveal the importance of patient and/or bystander factors, such
studies (54, 62, 71, 83) showed percentages of patients arriving as misjudgment at symptom onset or poor awareness of stroke
before 2 h from different years, and these essentially showed no symptoms and emergency pathways, and further stress the nece­
improvement overall (Figure 1E). ssity of raising the awareness of the variability of stroke symptoms
Despite the advent of thrombolytic therapy for acute ischemic (18). This is exemplified by the fact that mild neurological symp-
stroke in the late 1990s (2, 3), the majority of patients in the toms, which may be misinterpreted as general malaise and thus
majority of locations around the world failed to arrive at hos- minimized in seriousness by patients and bystanders (34), were
pital before 3  h (7, 8). When taking door-to-needle time into significantly associated with delayed arrival.
consideration, which although improving (9) is commonly in One study that analyzed factors associated with EMS-use after
excess of 1  h (7, 8), a 3-h onset-to-door time would generally stroke found that of the cases where EMS was activated, only
be the maximum delay possible to meet a 4.5-h onset-to-needle 4.3% of calls were made by the patient compared to 60.1% by
time target for thrombolysis (5, 6). Improvements in prehospital family members, stressing the importance of targeting potential
time have been stagnant, and it remains the largest component latent bystanders (family, caregivers, and coworkers) in educa-
of total onset-to-needle time (7, 8). A dramatic example of this tional programs (130). A study of a community and professional
is a study from Greece analyzing 16 years of onset-to-emergency behavioral intervention program on stroke identification and
room presentation (prehospital time) and emergency room to management showed an increase in thrombolysis rates between
completion of CT times (a component of in-hospital time), which the intervention and comparison group, however not in delay
showed a more than 10 h decrease in in-hospital time (median of time (131). EMS use is known to have additional benefits beyond
12.34 to 1.05 h), whereas prehospital time was reduced only by shortening of prehospital time. Studies have shown that, due
about 1 h (median of 3.15 to 2.0 h) (59). to hospital pre-notification (132), EMS use is associated with
prompter evaluation by imaging, shorter door-to-needle times,
and increased thrombolysis rates (133). Therefore, the nature
FACTORS ASSOCIATED WITH EARLY AND
of transport to hospital (EMS versus private transport) has
DELAYED HOSPITAL ARRIVAL AFTER an added benefit to in-hospital stroke care beyond the simple
STROKE shortening of prehospital time.
From the studies reviewed here, factors associated with either
early or delayed arrival after stroke were extracted (Table  1).
STROKE SUBTYPE, SYMPTOMATOLOGY,
Patient age and sex were associated in different studies with both
early and delayed arrival and are discussed separately. AND COMORBIDITIES
Hospital arrival by EMS was the factor most frequently Severe stroke was a major factor associated with early arrival,
associated with early hospital arrival after stroke, with 40 report- which is to be expected by its debilitating symptomatology,
ing studies. Severe stroke was the second most frequent factor, naturally raising a sense of urgency in the patient or bystander.
as measured by the National Institutes of Health Stroke Scale Interestingly, a history of cardiac arrhythmia or atrial fibrilla-
(NIHSS) or other scales. Other factors associated with early tion (AF) was associated with early arrival. Patients with AF are
arrival were related to stroke symptomatology, stroke subtype, known generally to present with more severe strokes (134) which
comorbidities, patient and/or bystander behavior or perception may be a contributing factor to early presentation. Patients may
at stroke onset, and timing of stroke onset. also have a latent sense of urgency to present to hospital with
The top three factors associated with delayed arrival were if a new symptoms, because of their known cardiac condition (43),
general practitioner (GP) or primary care facility was visited first, or have a raised awareness of stroke symptoms, with AF being a
referral from another hospital, and living alone. major stroke risk factor (135).
Diabetes mellitus was associated with delayed arrival after
THE KEY TO EARLY HOSPITAL stroke in multiple studies. This may be due to patients or
ARRIVAL: EMS bystanders misinterpreting symptoms as hypoglycemia (92).
Moreover, diabetics versus non-diabetics were shown to more
Hospital admission via EMS was by far the most frequently likely present with lacunar and ischemic strokes with a lower
associated factor with early arrival, with the converse non-EMS rate of hemorrhagic strokes (136, 137). Patients with lacunar

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Pulvers and Watson Review of Hospital Arrival Time after Stroke

strokes show delayed presentation and hemorrhagic strokes INTERACTION BETWEEN ONSET-TO-
present earlier (Table 1), and thus the delay in stroke patients DOOR AND DOOR-TO NEEDLE TIME:
with diabetes may be due to differences in stroke subtype or
symptomatology rather than diabetes per se. More investigation
A VIRTUOUS CYCLE
is required as this may be a promising target for intervention. Numerous studies have reported on the phenomenon of an inverse
A number of other vascular risk factors were also associated correlation between onset-to-door time and door-to-needle time
with delayed arrival (52) such as smoking and hypertension (153–156). This is thought to be due to physicians treating more
(56, 62). urgently those patients who are approaching the end of the throm-
bolysis time window than patients with earlier presentations
PERCEPTUAL AND BEHAVIORAL (156). Door-to-needle time may be taken as a surrogate global
measure of health service-controlled stroke care quality, and
FACTORS
given that a personal or family history of cerebrovascular disease
Perceptual and behavioral factors (99) such as symptoms not and knowledge of thrombolysis are factors associated with early
taken seriously and low threat perception were also associ- presentation, a scenario can be imagined where improvements
ated with delayed arrival. Past research on stroke knowledge in door-to-needle times may, in turn, lead to an improvement in
has shown that having stroke risk factors in general does not onset-to-door times, supported by the fact that family and friends
contribute to an increase in stroke knowledge (129, 138), are a source of stroke knowledge and awareness (129, 138).
which further stresses the importance of improving knowledge As patients further recognize the benefits of available acute
through public awareness campaigns (18, 139, 140). Such cam- therapy for stroke, and if in-hospital pathways can be improved
paigns must target those with stroke risk factors (141), and also so that early presentations are not negated by delayed treatment,
be tailored to target minority populations (142). However, the a virtuous cycle can be established, in which better onset-to-door
fact that a personal history of stroke or TIA was significantly and door-to-needle times may further improve each other, lead-
associated with early arrival points to the effectiveness of the ing to a higher proportion of stroke patients arriving within the
sense of urgency or awareness that comes about by a first-hand therapeutic time window for acute stroke therapies.
experience of cerebrovascular disease in reducing onset-to-door
time (71, 94). Family history of stroke was also associated with TOWARD AN IMPROVEMENT
early arrival (71, 114), and this has also been shown to be an
IN ONSET-TO-DOOR TIMES
independent predictor of knowing at least one stroke risk factor
(143). Promisingly, the knowledge of thrombolysis treatment Delayed hospital arrival after acute ischemic stroke is a major
by patients was associated with early arrival (Table 1). factor contributing to low thrombolysis rates. We have reviewed
many modifiable factors associated with hospital arrival times,
TIME TO HOSPITAL ARRIVAL: MALE with patient awareness of emergency pathways and the improve-
ment of emergency medical systems being the strongest targets
VERSUS FEMALE AND PATIENT AGE for intervention. Raising the awareness of the varied symptoma-
Depending on the study, female compared with male patients tology of stroke may also be effective.
were associated with both early (39, 54) and delayed arrival Studies on factors associated with prehospital delay after stroke
(47, 56, 62, 99, 144, 145). Many factors may contribute to vary widely in their methodology and a more unified approach
this difference, including comorbidities, prestroke disability to this problem and appropriate data collection is warranted.
(145, 146) and whether they live alone (147, 148). Differences in Awareness of stroke represents a key factor, and public education
stroke subtype and symptomatology between men and women campaigns must be improved and expanded with the view to
may underlie differences in arrival time (148–150), and moreo- improve stroke outcomes.
ver it is important to consider disparities in stroke outcomes not
just arrival times (151). AUTHOR CONTRIBUTIONS
There is no conclusive relationship between patient age
and prehospital time. Studies utilized various methods for Both authors have read and approved the submitted manuscript,
analyzing the effect of age. In short, being younger was asso- and the manuscript has not been published elsewhere in whole or
ciated both with early (63, 83, 96) and delayed (57, 91, 126) in part. Both authors listed have contributed significantly to the
presentation, and similarly older patients were associated project. Contributions specifically were JW to the conception of
with both early (37, 43, 59, 77, 114) and delayed (56, 57, 62, the project, interpretation of the data, and critical revision of the
74, 83, 121) presentation. There may be a lack of urgency in manuscript; JP to the acquisition, analysis, and interpretation of
younger patients with stroke (152), and symptoms exhibited the data and drafting of the manuscript.
by older patients may be more readily interpreted as stroke
and perceived as an emergency (43). Interestingly, a review on ACKNOWLEDGMENTS
studies of stroke knowledge reported that stroke knowledge
is generally lowest in the young (18–25 years) and the elderly We thank Dr. Bronwyn Gaut for her critical reading of the
(≥80 years) (18). manuscript.

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Pulvers and Watson Review of Hospital Arrival Time after Stroke

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144. Cheung RT. Hong Kong patients’ knowledge of stroke does not influence author(s) or licensor are credited and that the original publication in this journal
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Frontiers in Neurology  |  www.frontiersin.org 9 November 2017 | Volume 8 | Article 617