Prehospital Advanced Diagnostics and Treatment of Acute Stroke
Prehospital Advanced Diagnostics and Treatment of Acute Stroke
The objective of this study is to investigate the effectiveness of prehospital diagnosis and,
 when appropriate, of intravenous thrombolytic treatment of ischemic stroke. At the same time,
 we will take the opportunity to do an explorative study with the aim to further improve the
 intervention by biomarkers, and outcome measures volumetric measured by MRI images.

 The intervention study aim to:

 -  Determine the time from symptom onset to thrombolytic treatment in the Mobila Stroke
 Unit (MSU) compared to the conventional model

 -  Determine the number of patients receiving thrombolytic treatment within the 4.5 hrs
 window in the MSU compared to the conventional model

 -  Determine if thrombolytic treatment in the MSU, when adjusted for time, results in
 better mRS- and Barthel outcome compared to treatment in the conventional model The
 explorative study aim to

 -  Determine if final IS infarction volume estimated by MRI, is independently correlated
 with time from symptom onset to thrombolytic treatment

 -  Define cut-off values for GFAP and RBP4 combined that with sufficient specificity and
 sensitivity can distinguish ICH from IS

 -  Determine the influence of time to treatment on pro-inflammatory markers after stroke

 Hypothesis Intervention study I. The Treat - NASPP MSU model is feasible and reduces onset to
 treatment time less than 15 min II. The number of patient treated with thrombolysis within
 4.5 hrs of symptom onset is significantly increased in the Treat-NASPP MSU model III.
 Treatment in the Treat-NASPP MSU model does not result in increased day 90 mRS and Barthel as
 compared to the conventional model when adjusted for time IV. Prehospital thrombolytic
 treatment of stroke does not increase the risk of secondary cerebral bleeding as compared to
 in-hospital thrombolytic treatment of stroke (cerebral bleeding worsening within 36 hrs less
 than 4 per cent, Norsk hjerneslagregister) Explorative study V. The final infarct volume,
 estimated by MRI, is significantly reduced when thrombolytic treatment is initiated already
 in the MSU VI. Biomarkers is a valid tool in the hyper acute phase of cerebral illness to
 exclude contraindication to thrombolysis VII. Reduced onset to treatment time results in
 lower levels of selected pro-inflammatory molecules
Treat-NASPP is a prospective controlled intervention study. The main aim of this study is to
 prospectively compare patients with ischemic stroke (IS) who are diagnosed and treated
 prehospitally in the MSU (intervention), with those who receive conventional pre- and
 inhospital diagnostics and treatment (control). At the same time we will do an explorative
 study with the aim to further improve diagnostic- (the biomarker study) and outcome measures
 (the biomarker study and MRI infarction volume study). The MSU will be staffed with an
 anaesthesiologist, a paramedic-nurse and a paramedic while on call. On the weeks the MSU is
 not operating, the data collection will take place from the conventional ambulance on
 weekdays from 8 am to 8 pm. Only ambulances staffed with the paramedic-nurse and paramedic
 that work as staff on the MSU will participate in the study. All emergency calls to the
 central EMS dispatch center (AMK 113) from the catchment region of Ostfold county will be
 screened for stroke symptoms by the EMS dispatcher according to normal procedures: they will
 use the FAST scale (one or more of the following neurological deficits: paralysis of arm or
 leg, facial paralysis, aphasia or dysarthria) and in regard to the inclusion criteria (listed
 below) the MSU will be dispatched when the inclusion criteria are fulfilled on weeks when the
 MSU is on call. The same inclusion criteria apply for the ordinary ambulance on weeks when
 the MSU is not on call. The intervention (prehospital CT and thrombolytic treatment) can only
 be administered in the MSU. The control (in-hospital CT and thrombolytic treatment) can only
 be administered in the hospital.

 MSU procedure On site the anesthesiologist will take the actual medical history and do a
 rapid screening using the ABCDE's of trauma care. If the patient is stable and further
 investigations can proceed including NIHSS scoring. The patient will get two venous lines,
 and blood samples will be collected. Blood samples for biomarkers (se details below) will be
 stored and delivered to the laboratory at the hospital for further analyses and storage in
 bio bank (related to REK 2014/1161). The patient will be taken into the stroke ambulance,
 where the CT scan is performed and blood tests are run in the point of care laboratory (POC).
 After completing the CT scan examination, the anesthesiologist will immediately get in
 contact with the on call neurologist (stroke team) at Ostfold Hospital. The anesthesiologist
 will provide the stroke team with clinical history, POC blood tests, NIHSS score, time of
 symptom onset and any known clinical contraindication of thrombolysis. The stroke team and
 the on call radiologist will interpret the CT scan by teleradiology and a treatment decision
 will eventually be made. If indication of thrombolytic treatment the stroke ambulance nurse
 will prepare and initiate iv. rtPa (Actilyse) as per protocol (appendix). The prehospital
 study data will be completed in an electronic study form by the anesthesiologist.

 Conventional ambulance management Conventional ambulance data collection will only take place
 when the MSU is not on duty. The conventional ambulance is then staffed with the same
 personnel (except the anaesthesiologis) as the MSU. After the paramedic or nurse-paramedic
 has taken the patient's actual medical history, performed a physical examination including
 NIHSS, established a venous line and eventually given the emergency treatment needed, the
 patient will be transported to the Østfold hospital. The paramedic will contact EMS
 dispatcher to inform patient inclusion in the study and the EMS dispatcher will contact the
 hospital stroke team. The paramedic will withdraw a blood sample for the biomarker study, and
 an additional blood sample will be taken at the hospital for standard analysis.

 Therapeutic decision In both the conventional and the MSU pathway a cerebral CT scan will be
 conducted as soon as possible after symptom onset. Images will in both pathways be registered
 in the hospital PACS system, and interpret by the on call stroke team (neurologist and
 radiologist). In the MSU pathway the anesthesiologist will decide which patients are eligible
 for CT scan, but in the conventional pathway the neurologist on call in the emergency
 department will make this decision. Prehospital clinical assessment will include the actual
 medical history, a stroke scale score, and ABCDE evaluation. The clinical information and
 scores will be completed in designated study forms, and in the specialized prehospital
 patient record system AMIS. Both paramedic/nurse in the conventional pathway and the
 anesthesiologist in the MSU will do a stroke scale score, and scores will be analyzed for
 research purposes.

 If a thrombolytic treated patient shows signs of clinical detoriation, expressed as an
 increase of 4 or more points on the NIHSS scale, an intracranial hemorrhage is to be
 suspected and the thrombolytic infusion must be stopped immediately. If in the MSU, a new
 cerebral CT scan should be conducted if the driving distance to the hospital exceeds 20
 minutes, and the CT findings should immediately be transferred and reported to the hospital.
 After identification of location and distribution of damage based on the CT image, treatment
 will either be initiated on site in accordance with in-hospital procedures, or the patient
 will be transported directly to location for neurosurgery (see attachment 3).

 Prehospital use of stroke scales: Stroke scales will be conducted in the MSU and the regular
 ambulance. All participants (anesthesiologists, paramedics and nurses) will attend a two-day
 course in stroke clinics, stroke treatment and the use of stroke scales. An online
 certification in NIHSS will be mandatory for participation.

 MR volumetric: MRI will be completed at day 1 in all included patients treated with
 thrombolysis, prehospital or in hospital. Final infarct volume will be estimated by using
 image-series according to standard MRI protocol at Ostfold hospital.

 Biomarker All serum- and plasma samples will be stored in the bio bank related to REK
 2014/2261. Venous blood for measurements of biomarkers will be drawn at very early time
 points after symptom onset (i.e. after arrival of the paramedics/anesthesiologists at the
 scene), and at different time points up to weeks after arrival at hospital from all patients
 enrolled. The total volume of blood drawn will not exceed 100 ml on any day. All samples will
 be drawn by personnel certified by Østfold hospital. One standard serum tube, one EDTA plasma
 tube and one citrate serum tube will be used for blood collection. Blood samples will be
 centrifuged within 2 hrs of blood collection using a standard centrifuge (10 min at
 1500-2000g). Serum/plasma will be transferred immediately in aliquots to Eppendorf tubes
 (each containing 0.5 ml) and stored at minus 80 degrees celcius. The Eppendorf tubes should
 be labeled appropriately indicating the patient number and the tubes collected per patient.
 Biomarkers will be analyzed in Professor Sandip Kanses lab, UiO, or shipped on dry ice to
 Professor Christian Forch, Department of Neurology, Schleusenweg 2-16, 60528 Frankfurt am
 Main, Germany. We will compare biomarker levels (index test) with CT findings (reference
 standard) and optimize cut-off points by using Receiver Operating Characteristics (ROC)
 analysis. Sensitivity and specificity will be calculated based on cross tabulations. The
 broad range of time points will be needed to monitor the rise and fall of biomarker
 concentrations, inflammatory response and diagnostic and prognostic windows in the wake of
 stroke.

 Data monitoring, harms and auditing An independent safety committee consisting of two
 experienced stroke neurologists will review all safety data after 10, 20, 50, 100, 150 and
 200 patients treated with thrombolysis. The committee will stop the study if they find
 evidence for an unacceptable increase of symptomatic cerebral bleedings (more than 4%) or
 deaths. Symptomatic cerebral haemorrhage is assessed as local or remote parenchymal
 haemorrhage combined with a neurological deterioration of four points or more on the NIHSS
 from baseline or from the lowest NIHSS value between baseline and 24 h, or a significant
 clinical worsening linked to the bleeding, or a bleeding leading to death.

 The over-all rate of cerebral bleeding complications and the mortality rate at seven days
 will be compared with data from the Norwegian stroke register.

 The main safety issues in the acute phase of stroke are linked to respiratory failure,
 cardiac arrhythmias and cerebral bleeding secondary to thrombolytic treatment.

 The anaestesiologists working in the MSU are highly qualified to take care of acute
 respiratory and cardiac failure. The MSU is technically equipped as an air ambulance
 helicopter.

 The main aim of our study is to provide early thrombolytic treatment to patients with
 cerebral infarction. The most serious complication of thrombolytic treatment is cerebral
 bleeding which may be fatal. Up to 10 % of all patients treated with thrombolysis will have a
 cerebral bleeding confirmed by CT, whereas only 2-4% of all patients will die or have a
 worsened outcome due to bleeding (called symptomatic bleeding). Cerebral bleedings following
 thrombolytic therapy will show up during the first few days, sometimes even in the very acute
 phase. Studies with thrombolytic therapy in MSU models have, however, not shown an increased
 risk of cerebral bleedings.

 In-hospital cerebral bleedings will be diagnosed and treated according to the standard
 routines. Patients are monitored both in the MSU and in the stroke unit with NIHSS scoring at
 close intervals for 24-36 hours. At the hospital a MRI cerebral scan will be performed as a
 routine at approximately 24 hours after symptom start.

 Statistical analysis The Treat-NASPP is designed in accordance with the Standards of
 Reporting of Diagnostic Accuracy initiative guidelines. For the prospective controlled
 intervention study our primary outcome will be i) OTT time, and ii) number of patients
 treated within 4.5 hours. Our secondary outcome will be mRS and Barthel at day 90 adjusted
 for OTT time.

 For the primary outcomes we will use the Mann-Whitney U test. For power calculation, we want
 to compare two continuous variables in two groups, or compare two means. 2-sample, 2-sided
 equality. If we estimate time saved by MSU-treatment (intervention) as compared to the
 conventional pathway (control) we find Mean group 1: 210 minutes (29) Mean group 2: 180
 minutes (we estimate 30 minutes saved in MSU) SD: 70 minutes Sampling ratio: 1 This gives us
 a number n=86 patients with thrombolytic treatment in each group. As we observed a mean
 reduction of time from onset of symptoms to diagnostics in the referred to NASPP study
 (unpublished data, REK 2013/2298) of 100 minutes, we consider this to be achievable.

 Biomarkers As we expect concentrations of biomarkers to have a skewed distribution (21, 30),
 we will use the Mann-Whitney U-test when comparing concentrations in patients with ischemic
 stroke and ICH. The ROC-curve analysis will be used to calculate the diagnostic accuracy of
 the biomarkers in distinguishing between IS and ICH.

 Sample size calculation for logistic regression is a complex problem, but based on the work
 of Peduzzi et al. (31) the following guideline for a minimum number of cases to include in
 the study can be suggested. Let p be the smallest of the proportions of negative or positive
 cases in the population and k the number of covariates (the number of independent variables),
 then the minimum number of cases to include is: N = 10 k / p. A statistician (Jo Røislien,
 see working group below) will be consulted for correct data analysis.

 Data storage Clinical data will be registered and stored at Ostfold Hospital Kalnes. Study
 data will be un-identified and registered using the secure server provided by Teknograd
 https://www.teknograd.no
Inclusion Criteria:

 -  All patients with suspected stroke met by emergency services within 4 hours after
 symptom onset Stroke symptoms: sudden weakness of leg or arm, especially on one side,
 facial asymmetry and/or sudden trouble walking, and speech disturbance (Norwegian
 Index of medical emergencies 27.03-27.06).

 Exclusion Criteria:

 -  Age under 18 years Pregnancy Female < 50 years and uncertainty of pregnancy
 Uncertainty regarding symptom onset time