Article, Neurology

Increased mortality of patients with aneurysmatic subarachnoid hemorrhage caused by prolonged transport time to a high-volume neurosurgical unit

a b s t r a c t

Background: Time has shown to be a relevant factor in the prognosis for a multitude of clinical conditions. The current analysis aimed to establish whether delayed admission to specialized care is a risk factor for increased mortality in case of high-grade Aneurysmal subarachnoid hemorrhage.

Material and methods: Consecutive patients with aneurysmal subarachnoid hemorrhage were enrolled retrospectively if they had a World Federation of Neurological Surgeons Grading System grade of 5. Predictor variables for in-hospital mortality reflecting demographic, spatial, temporal treatment, and neurological factors were recorded from hospital medical records and emergency physicians’ reports. We performed statistical analysis on the influence between the predictor variables and in-hospital mortality.

Results: The study included 61 patients with an average age of 58 years. The overall in-hospital mortality rate was 28% (17/61 patients). A delayed transport to specialized neurosurgical care was associated with increased in-hospital mortality. transportation time was mainly prolonged in cases where an alternative diagnosis was made by the emergency physician. Mortality was highest in patients with cardiovascular complications of subarachnoid hemorrhage.

Conclusion: Delayed admission to specialized care is associated with a higher mortality rate in patients with high- grade aneurysmal subarachnoid hemorrhage. Accompanying non-neurosurgical, mainly cardiac complications might be a significant factor leading to delayed admission. The emergency physician should be aware that cardioVascular abnormalities are a relevant complication and sometimes the first identified clinical feature of high-grade subarachnoid hemorrhage.

(C) 2016

Introduction

There have been several studies that aimed to identify risk factors to reduce mortality in patients with intracranial pathology [1-4]. Most of these prognostic factors for outcome are present at ictus and cannot be in- fluenced by medical management. However, for some conditions such as ischemic stroke and myocardial infarction, a substantial contribution to outcome can be made by reducing time until admission [1]. For traumatic acute subdural hematoma too, it has been shown that if all patients were taken directly to hospitals equipped to diagnose and treat the hematoma within mere hours after injury, mortality rates could be reduced [1].

In most cases of traumatic brain injury, the possibility of intracranial pathology cannot be overseen, and transport of a patient to a nontrauma

? Funding: No funding was received for this research.

* Corresponding author at: Department of neurosurgery, Heinrich-Heine-University, Dusseldorf, Moorenstrasse 5, 40225 Dusseldorf, Germany. Tel.: +49 211 81 07439.

E-mail address: [email protected] (A.K. Petridis).

1 Authors contributed equally.

center is seldom [1]. One of the problems the emergency physician faces in case of a nontraumatic loss of consciousness is to exclude intracranial pathology. If the patient arrives in a hospital without a neurosurgery department, cerebral computed tomography (CCT) has to be performed alongside other Diagnostic procedures, and in case of aSAH, the patient has to be referred to a neurosurgical department. Delay of transport to a neurosurgical hospital is therefore expected to be more likely. By studying the time from emergency call of an unconscious patient with a subarachnoid hemorrhage until arrival in our neurosurgical depart- ment, we seek to identify whether the delay from ictus to neurosurgical admission is a risk factor for increased mortality in aSAH.

Methods

Study population

We conducted a retrospective study of patients with aSAH admitted to our neurosurgical department between January 1, 2012, and

http://dx.doi.org/10.1016/j.ajem.2016.09.067

0735-6757/(C) 2016

December 31, 2014. The inclusion criteria for this study were as follows: subarachnoid hemorrhage demonstrated by computer tomography (CT) and the presence of an aneurysm confirmed by cerebral Digital subtraction angiography or CT angiography. Only patients with a World Federation of Neurological Surgeons Grading System (WFNS) grade of 5 upon arrival of the emergency response team were included. The primary outcome of the study was in-hospital mortality. The study was approved by the Heinrich Heine University Institutional Ethics Committee, study number 5277.

Treatment protocol

Patients were admitted to a specialized intensive care unit (ICU) and given treatment according to standardized management guidelines [2,3]. Patients are monitored on our ICU under a minimal touch policy until aneurysm closure. Aneurysm closure is performed within 24 hours. antifibrinolytic agents are only applied when definite aneurysm closure cannot be achieved within 36 hours [2]. Emergency surgery was performed if Hematoma evacuation or decompressive hemicraniectomy was indicated. In all patients with a WFNS grade 4 or 5, invasive neuromonitoring with an intraventricular catheter is initiated. The systol- ic blood pressure is lowered to less than 140 mm Hg. Prophylactic treat- ment with dihydopyridine L-type calcium channel antagonists is started, and all patients undergo serial perfusion CT during their stay on the ICU.

Clinical and radiological data collection

For all included patients, demographic data, suspected Initial diagnosis, and clinical features at onset were obtained from emergency response team protocols. neurological status was assessed with the WFNS grade and Glasgow Coma Scale. Significant clinical interval changes and interventions during hospitalization were retrieved from patient medical records and documentation from the primary hospitals and our patient records. Admission CT scans from the referring hospital and our own clinic were also assessed.

Definition of outcome parameters

In-hospital mortality or neurological devastation leading to withdrawal of care was identified after analyzing all available clinical and radiological data. In-hospital mortality was defined as death within 30 days after admission. The distance from the initial location of onset to our neurosurgical department was determined as the shortest distance in kilometers. Distance was measured using a desktop Web mapping service: http://maps.google.de. Transportation time was determined by retrieving the emergency units response time and emergency department admission time from the Treatment protocols. Rush hour was defined as 6:00 to 9:00 AM and 4:00 to 7:00 PM.

Statistical analysis

Categorical data are presented as counts and percentages and continuous variables as mean with standard deviation or median with interquartile range depending on the normality of data. The statistical analysis was performed with t test and ?2 test. Statistical significance was set at P b .05. All statistical analyses were performed using the R statistical computing package, R version 3.2.2 as released on August 14, 2015 (https://r-project.org/).

Results

Overall mortality

In total, 356 patients had been admitted with a subarachnoid hemorrhage during the study period. Sixty-one patients (17%) fulfilled the inclusion criteria. Excluding these patients from the analysis did

not alter the results. The mean age was 58.1 years (22-84 years). Twenty patients were male and 41 were female (1:2). The overall in hospital mortality rate was 28% (17/61 patients). Forty patients displayed an aneurysm located on the anterior circulation of the circle of Willis, and mortality was 35% (14/40). The remaining 21 patients with an aneurysm on the posterior circle had a mortality of 14% (3/21, not significant). Fig. 1 shows the distribution of aneurysms in the brain as well as the mortality rate for each location.

Transport time and mortality

The time required from arrival of the first medical response team until admission to our neurosurgical department is depicted in Fig. 2A. Thirty-five patients (57%) were admitted to another hospital for further diagnostics and transported to our hospital after CCT showed SAH, whereas 26 patients were admitted to our hospital directly (mean transportation time, 262 vs 71 minutes; P b .001). There was a signifi- cantly higher transport time in the mortality group compared with the survival group (Fig. 2B; mean transport time, 230 vs 115 minutes; P b .05). Longer hospital stay in the primary hospital was also associated with increased mortality (mean, 300 vs 150 minutes; P b .05; Fig. 2C). However, there was no significant difference in transport time between the death and survival group when patients were transported directly to our neurosurgical department (Fig. 2D, 60 vs 79 minutes).

In 9 patients, the exact time of aneurysm rupture could not be evaluated because these patients were found home in the morning. Of the 52 patients which become unconscious in front of witnesses, 19 patients had the incident at work, in the sports club, or in public, and 33 were at home.

Of the 9 patients in whom the rupture time cannot be specified, 6 were admitted immediately to neurosurgery and 3 were admitted primarily to another hospital. We did not exclude these patients from analysis. However, exclusion of these patients from the study did not change the data significantly.

The time for the ambulance to arrive after the emergency call is maximum 15-20 minutes.

Initiation of neurosurgical treatment and mortality

Shorter transportation time did not result in faster initiation of neu- rosurgical treatment for aneurysm closure. Emergency surgery did not influence the outcome in any direction. Six patients received immediate treatment by arrival at the hospital. The immediate treatment was initi- ated when an intracerebral bleeding was space occupying and needed decompression. With Surgical decompression and hematoma evacua- tion, the aneurysm was surgically clipped in all 6 patients. However,

Fig. 1. Distribution of aneurysm location in the study population. Most aneurysms were located in the anterior communicans artery. Aneurysms located in the anterior circulation were twice as common as aneurysms in the posterior circulation. The blue columns represent the absolute numbers, whereas the red columns represent fatalities. The mortality difference between anterior and posterior circulation aneurysms failed to show statistical significance.

Fig. 2. Association between mortality and onset-to-neurosurgical-center time. A, Onset-to-neurosurgical-admission time was significantly longer when the transport was indirect, that is, when a local hospital without a neurosurgical department was targeted first (P b .001). B, In fatal cases, the mean transport time to the neurosurgical center was significantly longer compared with patients who survived (230 vs 115 minutes, P b .05). C, When a non-neurosurgical center was targeted first and cranial imaging was delayed, mortality increased. The transportation time was significantly higher in the mortality group than in the survival group (300 vs 150 minutes, P b .05). D, When patients were directly transferred to our clinic, there was no difference in transport time between the 2 groups.

the patients had an unfavorable prognosis even before surgery, and this is the reason why a statistical analysis shows no benefit of immediate surgery. None of these patients were coiled. Surgical clipping or coiling was always performed in the first 24 hours and after stabilization of patients’ vitals. All aneurysms of the medial cerebral artery were surgically clipped, and 50% of arteria communicans anterior aneurysms were clipped.

Aneurysms of the Basilar artery were always coiled. Patients without External ventricular drain showed a higher mortality. However, only few patients (n = 5) had no ventricular drainage because the therapy had to be discontinued. Four of these patients came from other hospitals, and one was admitted directly to neurosurgery. However, this 1 patient was found home in the morning, and the time of aneurysm rupture cannot be evaluated.

Alternative diagnosis and mortality

When aSAH was suspected, mean transport time until admission at the neurosurgical department was 79 minutes compared with 220 minutes when alternative pathology was suspected (Fig. 3A, P b .05). Suspicion of an alternative diagnosis was associated with increased mortality (Fig. 3B). In cases where cardiac pathology was suspected (n = 8), mortality reached 75% (Fig. 3B). Four patients re- ceived a diagnostic coronary angiography, and none of them survived.

Distance to neurosurgical department

Patient mortality was not correlated with the distance from the inci- dent to the neurosurgical department. The mean distance in patients

Fig. 3. Ambulance team diagnosis and transport time. A, When aSAH was suspected, the onset-to-neurosurgical-admission time was significantly lower compared with cases where an alternative diagnosis was made. These patients had a greater chance of first admission to a non-neurosurgical hospital (P b .05). B, The suspicion of an aSAH by the emergency response team was associated with a significantly lower mortality rate compared with patients who received an alternative diagnosis (20% vs 45%). The highest mortality was seen in patients diagnosed with a myocardial infarction (75%). The patients who received a cardiac angiography had a mortality of 100% (4/4) (P b .05).

who died was 18 km against 25 km in those who survived (not signifi- cant, Fig. 4A). Fig. 5 provides an overview of the area from which pa- tients were admitted to our department, as well as the distance and transport times between the 4 university hospitals and 3 additional level I trauma centers in the area. Transport during rush hour did not affect patient survival (Fig. 4B).

Discussion

The present study demonstrates that delay of specialized care for high-grade aSAH is correlated with increased mortality. Prolonged transport is associated with suspicion of an alternative diagnosis by the emergency physician, and the highest mortality rates are reached in cases where primary cardiac pathology was suspected. Decreased mortality in patients with short or direct transportation was not due to a different neurosurgical intervention strategy in our series.

However, Medical complications are another main cause of death after SAH. A reported 15%-23% of in-hospital deaths have been attribut- ed to medical complications [6]. Early brain injury (EBI) is one of the key aspects in the pathophysiology of SAH [7-12], as the extravasation of blood in the subarachnoid space initiates several pathophysiological responses that are expected to influence patient outcome. The concom- itant increase in intracranial pressure is accompanied by a severe im- pairment of cerebral perfusion [13-23]. This reduction of cerebral perfusion as measured by the mean transit time is correlated with both the occurrence of delayed cerebral ischemia (DCI) and clinical out- come [24-31]. The impairment of cerebral blood flow can lead to either transient global or focal ischemia, which initiates a cascade of further pathophysiological changes. early initiation of neuroprotection directed at minimizing EBI-related pathophysiological changes might reduce the risk of DCI and subsequently improve patient outcome [6,32]. This could explain the better outcome of patients with a reduced transportation time.

SAH has a complex pathophysiology, and besides significant neuro- logical damage, it can also involve systemic organ injury. The high rate of alternative diagnosis in patients with prolonged transportation times or indirect admission may reflect additional non-neurosurgical challenges that often accompany the aSAH and delay transport. In our cohort, we find the highest mortality rate in patients with suspected cardiovascular complications. Subarachnoid hemorrhage frequently results in Myocardial necrosis with release of cardiac enzymes which can lead to a coronary angiography before a CCT scan has been performed [33,34,36]. High-grade subarachnoid hemorrhage is a strong independent predictor of myocardial necrosis after SAH [36]. This finding supports the hypothesis that cardiac injury after SAH is mainly a neural-mediated process with a disturbance of brain-heart connection [36]. The association of Troponin elevation with stunning of the myocardium, hypotension, and poor outcome after SAH has been well

documented and supports multimodality monitoring data which have identified hypoxia and hypotension as important factors for secondary brain injury [6,35]. Treatment aimed at minimizing myocardial toxicity to reduce adverse cardiovascular events and the risk of DCI and improve outcome therefore deserves further study.

The present study has several limitations that need to be addressed. Because of the retrospective design, we could not demonstrate causality between delayed transport and mortality. However, the association we found between delayed admission to specialized care and increased mortality is in concordance with a previous study which has shown that case volume is related to patient outcome [37]. Patients with a diag- nosis of SAH on their discharge record who initially presented through the emergency department of a hospital with a high volume of SAH cases had significantly lower mortality rates [37]. For patients with acute intracerebral hemorrhage, admission to a specialized neurosurgi- cal ICU has also been associated with reduced mortality [38]. Further- more, we could not demonstrate a positive effect of emergency surgery on patient outcome. Multiple studies have shown that ultra- early aneurysm closure (b24 hours) or even emergency application of surgical clip placement or endovascular coiling results in a reduced incidence of recurrent bleeding and improves clinical outcomes [4,5]. Within our ultra-early treatment protocol, patients qualified for emergency surgery when hematoma evacuation or decompressive hemicraniectomy was indicated. This lack of a uniform treatment protocol for aneurysm closure on an emergency basis is likely the cause why we did not observe reduced mortality after emergency surgery.

In addition, it has to be recognized that our cohort comes from a densely populated area with an abundance of medical resources, and it is questionable whether our results can be transferred to less populated areas.

In conclusion, the present study demonstrates that delay in specialized care is associated with increased mortality in high-grade SAH. Strategies directed toward minimizing EBI with prevention and treatment of cardiovascular complications hold promise for further reducing mortality after SAH. The emergency physician should be aware that cardiovascular abnormalities are a relevant complication and sometimes the first identified clinical feature of high-grade SAH. Because of the correlation with malignant SAH, high level of clinical suspicion, and prompt recognition and treatment of its complications are necessary.

Conclusion

The importance of a time-efficient and adequate transport of patients with cerebrospinal injuries was reported in old publications from 1966. Until now, transport time has improved significantly, but there is still plenty of room for optimization.

Fig. 4. Distance and traffic in association with mortality. A, The distance from location of onset and the neurosurgical department did not play a significant role in relation to patient mortality. B, Transport during rush hour did not affect patient mortality.

Fig. 5. Distance maps and distribution of high-volume neurosurgical centers in the area. A, The black crosses symbolize patients who were transported directly to our neurosurgical center. The red circles symbolize referring hospitals. The distance is in kilometers. B, Distribution of the 4 university hospitals in the area and their distance from our center as well as the travel time by ambulance. There are another 3 Level I trauma centers in this area, increasing the number to 7 within a radius of 90 km around our center.

As shown in the examples of cardiac ischemia, stroke, and traumatic brain injury above, the essential points for optimal Patient transport as well as the weaknesses which have to be overcome are analyzed and can be transferred to optimize patient transfer in cases with aSAH.

We suggest the following points which would lead to a faster onset- to-hospital time:

Citizen information campaign improving awareness of SAH and its symptoms like thunderclap headache should be initiated (as example, see http://www.youtube.com/watch?v=ecrSILW61UY&sns=em). Most of all, they are able to recognize the symptoms of an SAH and steer the ambulance and the arriving physician in the right direction.
  • Increase awareness of emergency response teams toward SAH to triage pa- tients efficiently and initiate direct transport to a neurosurgical department.
  • Immediate CCT scan by arrival of a patient in a non-neurosurgical hospital to facilitate fast transfer to a neurosurgical department.
  • extended use of mobile CT scanners on ambulances.
  • Establish teleradiological network between hospitals.
  • Use of helicopters for fast transport from rural areas.
  • Disclosure

    All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrange- ments) or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript.

    Ethical approval

    The study was approved by the Heinrich Heine University Institutional Ethics Committee, study number 5277.

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