P. Mellado, J. Diedler, and T. Steiner
Introduction
Since the first human electroencephalogram (EEG) was recorded in 1929 by Hans Berger, enormous advances have been made in EEG recording technology and data analysis [1, 2]. The recording period was extended and long-term EEG monitoring became technically feasible when computer applications were introduced in the 1970s and digital EEG recording systems established. However, the use of long-term EEG monitoring was mostly limited to epilepsy monitoring units and only subse- quently found its way to the intensive care unit (ICU).
Yet, an old comparison to cardiology still holds true: While it is an unchallenged standard to continuously monitor heart function in all ICU patients with abnormal cardiac function, brain activity is often not monitored in patients with acute brain damage, mainly because brain function has been more difficult to monitor. A single or even repeated EEG represents only a small sample of data. For example, seizures in the ICU setting are usually brief and paroxysmal and can easily be missed when EEG recording is performed intermittently. Fortunately, over the past 15 years, rapid advances in computer technology and digital data transmission and analysis have made it possible to introduce continuous EEG monitoring in the ICU.
The goal of continuous EEG monitoring is to enable intensive care physicians to predict impending central nervous system (CNS) injury at a time when intervention is still possible. The challenge for the future will be to demonstrate that intensified monitoring of brain function by continuous EEG will result in better outcomes.
Indications for Continuous EEG in the ICU Detection of Seizures
The underlying rationale for continuous EEG monitoring in the ICU is to detect sec- ondary insults that may lead to further injury of the already damaged and vulnerable brain, thus enabling intensive care physicians to promptly initiate treatment [3]. Here, seizures are of utmost importance. In the intensive care setting, there are two main types of seizures: 1. classical convulsive seizures, which may result in generalized con- vulsive status epilepticus, a life-threatening entity; and 2. subtle, clinically invisible, non-convulsive seizures, with non-convulsive status epilepticus as a maximal form.
The annual incidence of generalized convulsive status epilepticus ranges between 3.6 and 6.6 per 100,000 and of non-convulsive status epilepticus between 2.6 and 7.8 per 100,000 [4]. Mortality and morbidity of both types of seizures are influenced by the underlying etiology; this will be discussed in more detail later.
However, there is a general consent that seizures and status epilepticus, both con- vulsive and non-convulsive, are potentially life-threatening complications in patients with acute brain injuries. Today, there is little doubt that unrecognized and untreated non-convulsive seizures and non-convulsive status epilepticus exacerbate neuronal injury [5]. For example, DeGiorgio et al [6] have shown that neuron-spe- cific enolase is elevated in patients with convulsive or non-convulsive seizures.
Importantly, enzyme levels were highest in those with non-convulsive seizures. This observation clearly suggests that seizure activity without clinical convulsions can produce neuronal injury [6].
Non-convulsive seizures and non-convulsive status epilepticus in patients with reduced consciousness
Although non-convulsive seizures and non-convulsive status epilepticus were first described more than 100 years ago, this diagnosis is often missed in ICU patients.
Continuous EEG monitoring is the only reliable means to rule out non-convulsive seizures or non-convulsive status epilepticus in stuporous or comatose patients, and without continuous EEG monitoring early diagnosis and appropriate treatment are often delayed. Thus, it has become clear that the majority of seizures in ICU patients are clinically not visible and will be missed without continuous EEG recording [7].
In a study of 124 critically ill neurological patients, 35 % presented with non-con- vulsive seizures and 76 % of those were even in non-convulsive status epilepticus [8].
Another prospective study of 198 patients with altered levels of consciousness showed that 37 % of patients had non-convulsive seizures [9]. Finally, in a study of 236 comatose patients who were admitted to a medical ICU, excluding all patients with any clinical suspicion of seizure, continuous EEG still detected non-convulsive status epilepticus in 8 % [10].
A retrospective study of 570 patients monitored by continuous EEG identified 110 patients with seizures (19 %), and 101 of the 110 (92 %) had exclusively non-convul- sive seizures. In the same study, the authors found that in 95 % of non-comatose patients, the first non-convulsive seizure was detected within the first 24 hours of continuous EEG monitoring; however, in comatose patients, the first seizure was detected after 24 hours in 20 %, and after 48 hours of continuous EEG monitoring in 13 %. The authors concluded that a period of 24 hours was usually sufficient to detect non-convulsive seizures in patients who were not comatose and one of 48 hours or more in comatose patients. Without EEG monitoring, the diagnosis of non- convulsive seizures would have been missed [11].
Early diagnosis is crucial
As discussed above, it is well known that early recognition of status epilepticus is crucial for effective treatment and results in better outcomes. A study conduced by Lowenstein and Alldredge showed that the efficacy of first-line therapy in status epi- lepticus decreased from 80 % when therapy was initiated within 30 minutes after onset to 40 % when treatment started after 2 hours [12].
Focusing on non-convulsive status epilepticus, Young et al. showed that, in patients with non-convulsive status epilepticus lasting less than 10 hours, 60 % returned home and 10 % died. However, if the non-convulsive status epilepticus lasted longer than 20 hours, none of the patients returned home and 85 % died [13].
The same study found that the mortality of patients with non-convulsive status epi- lepticus depended on the time needed for a proper diagnosis to be made: only 36 %
of patients in whom status epilepticus was diagnosed within 30 minutes died com- pared to 75 % of those in whom diagnosis was delayed for more than 24 hours [13].
Detection of non-convulsive seizures/non-convulsive status epilepticus after status epilepticus
Continuous EEG monitoring is crucial for detecting non-convulsive seizures and non-convulsive status epilepticus in patients with status epilepticus who do not quickly regain consciousness following cessation of convulsions [14]. A study including 164 patients with generalized convulsive status epilepticus found that 48 % of patients had non-convulsive seizures and 14 % were in non-convulsive status epi- lepticus after clinical convulsions stopped. In this study, the mortality was signifi- cantly higher in those with non-convulsive seizures or non-convulsive status epilep- ticus than in those without [15]. Another study, comprising 33 patients with refrac- tory status epilepticus who were treated with intravenous midazolam, showed that 18 % had seizures within the first 6 hours after treatment, 56 % had seizures more than 6 hours after initiation of therapy, and 68 % had seizures after treatment was completed. Of these seizures, 89 % were clinically subtle or purely non-convulsive seizures [16].
Detection of seizures after acute brain damage
Although various studies have been conducted, the exact incidence of non-convul- sive seizures and non-convulsive status epilepticus following specific brain injuries such as traumatic brain injury (TBI), hemorrhagic or ischemic stroke, and sub- arachnoid hemorrhage (SAH) still remains unclear. There are two main reasons for this: first, until recently, none of the studies employed continuous EEG monitoring in these specific entities; second, electrographic manifestations of non-convulsive seizures or non-convulsive status epilepticus in critically ill patients are quite differ- ent from those in patients with epilepsy (see EEG patterns in the ICU).
The clinical incidence of early posttraumatic seizures ranges between 2 and 12 % [17]. One prospective study, including 94 moderately-severe TBI patients monitored by continuous EEG, detected seizures in 22 %, 52 % of which were non-convulsive seizures and one-third non-convulsive status epilepticus [18].
In patients with intracerebral hemorrhage (ICH), the clinical incidence of early seizures has been reported to be between 4.9 % and 17 % [19]. In a recent, pro- spective ICU study monitoring 63 patients with ICH by continuous EEG, seizures were detected in as many as 28 % of the patients. In 18 patients presenting with seizures, these were not clinically visible in 16, and were non-convulsive status epi- lepticus in 8 [20]. In this study, seizures were observed in 34 % of patients with lobar hemorrhage and, surprisingly, in 21 % with deep subcortical hemorrhage.
The authors observed that non-convulsive seizures were associated with an increased amount of midline shift and the outcome tended to be worse [20]. How- ever, in another prospective study of 9 patients with ICH who were admitted to a stroke unit and monitored by continuous EEG, only one developed electrical epi- leptic activity [21].
The reported incidence of early clinical seizures in patients with acute ischemic stroke varies between 4.4 % and 13.8 % [19]. One prospective study using continuous EEG monitoring in 46 patients with ischemic stroke detected non-convulsive sei- zures or convulsive seizures in 6 % [20]. In another prospective study, 91 consecutive patients with ischemic stroke admitted to a stroke unit were monitored with contin- uous EEG, 16 of whom (17 %) developed electrical epileptic activity [21].
Early clinical seizures after SAH have been reported in 1.1 to 16 % of patients [19]. A study including 26 patients with SAH who were stuporous or comatose and were monitored by continuous EEG showed that eight of them (30 %) had non-con- vulsive status epilepticus. All eight patients were receiving prophylactic anticonvul- sive therapy [22].
Monitoring treatment
Once ongoing seizures are detected, continuous EEG is essential to monitor the effects of therapeutic interventions, particularly when the therapeutic goal is to titrate medications to a burst-suppression pattern, a frequent endpoint in the man- agement of refractory, generalized status epilepticus. Recently, recommendations of the European Federation of Neurological Societies on the management of status epi- lepticus were published [4]. These guidelines recommend titrating the treatment towards a burst suppression pattern for at least 24 hours in patients with refractory status epilepticus [4].
Continuous EEG monitoring of non-convulsive seizures and non-convulsive status epilepticus and outcome
Young and al. found in a multivariate analysis that the two variables associated with mortality in 49 patients with non-convulsive status epilepticus were seizure duration and delay to diagnosis [13]. Another retrospective study involving 105 patients who underwent continuous EEG monitoring in an ICU found that continuous EEG was essential for the diagnosis and treatment of non-convulsive seizures and refractory status epilepticus. However, only a minority of patients had a favorable neurological outcome [23]. We already know that the prognosis of non-convulsive status epilepti- cus in the ICU setting is poor: in different patient series the overall mortality was 30 % to 50 % [13, 22], and refractory non-convulsive status epilepticus after severe TBI and SAH has been associated with 100 % mortality [4, 22]. Therefore, the chal- lenge of demonstrating that the aggressive, early termination of non-convulsive sta- tus epilepticus in these patients can result in better outcomes remains.
Moreover, further studies are needed to determine which EEG patterns typically summarized as non-convulsive seizures in critically ill patients indicate impending brain damage and whether changing the therapeutic strategy when such EEG pat- terns are recorded will improve clinical outcome.
Detection of Ischemia
Continuous EEG monitoring has been widely used in the last 30 years to detect acute cerebral ischemia during carotid artery surgery or intracranial endovascular treat- ment. However, continuous EEG was only recently introduced to monitor the course of spontaneous acute ischemic stroke [24].
EEG is a highly sensitive tool to detect brain ischemia. Cortical layers 3 and 5, which are particularly sensitive to oxygen deficits, contribute most to the generation of electrical dipoles detected by EEG. Cerebral ischemia results in EEG changes as has been demonstrated by positron emission tomography (PET) and Xenon-com- puted tomography (CT) study of cerebral blood flow (CBF) [25, 26].
EEG patterns usually begin to change when reversible neuronal dysfunction occurs. At this time CBF decreases to 25 to 30 ml/100 g/minute, a level at which ther- apeutic interventions could be instituted to prevent permanent brain damage [27].
Cell death occurs when CBF drops to 10 ml/100 g/minute. EEG signs of ischemia
include loss of beta activity, followed by activity in theta and delta ranges and finally flattening of the EEG with burst suppression or continuous suppression [18]. These EEG signs can be detected far sooner and are more sensitive than clinical examina- tions, which are often of limited use in ICU patients [28].
EEG monitoring also helps to demonstrate the recovery of brain function follow- ing reperfusion. A study comparing EEG and CBF with Xenon CT CBF measure- ments showed a hemispheric slowing of EEG activity that correlated with moderate- to-severe reduction of CBF. Upon application of hypervolemic therapy, EEG patterns improved and ischemia was resolved [29]. Another study in ischemic stroke patients showed that a pattern of regional attenuation without delta activity predicted mas- sive infarction with malignant edema [28].
Continuous EEG may also be used to detect reversible ischemia in SAH. A study in 32 patients with low-grade SAH using quantitative, continuous EEG showed that the loss of relative alpha variability preceded angiographic vasospasm or changes in transcranial Doppler findings by at least 2 days; sensitivity was 100 % [30]. In another study, 42 grade IV-V SAH patients were monitored by quantitative, continu- ous EEG for 7 days. It was shown that a reduction of more than 50 % of the alpha/
delta ratio from the baseline could predict cerebral ischemia with an 89 % sensitivity and 84 % specificity [31].
Despite promising data, the utility of EEG parameters to detect ischemia in the ICU setting has yet to be demonstrated. Further research studies of ischemic stroke should combine continuous EEG and advanced imaging techniques such as PET and perfusion CT and magnetic resonance imaging (MRI). Improvements in real-time ischemia detection systems and software with automatic alarms are needed to estab- lish wider application of continuous EEG monitoring in ischemic stroke [32].
Other Indications Prognosis
Continuous EEG monitoring provides prognostic information. For example, Nei et al. showed that, in patients in status epilepticus, the occurrence of periodic epileptic discharges was associated with a poor outcome [33]. In another continuous EEG study including 89 patients after moderate-to-severe TBI, a Glasgow Coma Scale score lower than 9 and a persistently impaired variability of relative alpha predicted poor outcome or death (positive predictive value of 86 %) [34].
Continuous EEG influences therapeutic management
Few studies have been carried out on the effect of continuous EEG monitoring in the ICU on therapeutic management. In a study of 124 critically ill neurological patients, continuous EEG monitoring had an impact on clinical decisions in 51 % of cases and made a significant contribution in 31 % [8]. In another study including 15 neuro-critical care patients, continuous EEG influenced therapeutic management on almost 50 % of monitoring days [35]. Further research is required to determine whether continuous EEG monitoring results in better outcomes.
EEG Patterns in the ICU Generalized Status Epilepticus
Treiman identified five EEG patterns that occur in a predictable sequence during the course of secondarily generalized status epilepticus (Table 1) [36]. However, other investigators have not found this sequential EEG pattern [33, 37]. It is well known that in later stages of generalized status epilepticus, electroclinical dissociation, termed ‘subtle’ status epilepticus, may develop [36]. During this period, the patient may demonstrate slight twitching of the limbs, facial muscles or jerking eye move- ments. This last sign is correlated with phase 4 and 5 of the EEG of Treiman.
Table 1. Sequence of EEG patterns in secondary generalized status epilepticus. Modified from [36]
1. EEG changes of discrete seizures with interictal slowing 2. Merging seizures with waxing and waning ictal discharges.
3. Continuous ictal discharges.
4. Continuous ictal discharges with ‘flat’ periods.
5. Periodic epileptiform discharges on a ‘flat’ background
Non-convulsive Seizures and Non-convulsive Status Epilepticus
Identifying EEG seizures in patients with severe brain lesions is challenging even for experienced EEG experts. The classic ictal patterns of seizure may not be evident in patients with diffuse brain injury and profound EEG background suppression [38].
Moreover, no widely accepted criteria to diagnose non-convulsive seizures or non- convulsive status epilepticus have been defined yet. For example, it is controversial whether certain EEG patterns, such as periodic lateralized epileptiform discharges (PLEDs), bilateral independent PLEDs (BIPLEDs), periodic epileptiform discharges (PEDs), focal or generalized, and generalized triphasic waves (TWs), are ictal or interictal [37, 39 – 41]. Moreover, the dichotomy of EEG patterns into ictal or nonic- tal clearly represents an oversimplification [7].
Furthermore, EEG patterns seen in metabolic encephalopathies cannot always be distinguished from non-convulsive status epilepticus and EEG patterns can be abol- ished by benzodiazepines [42]. Until last year, no generally accepted nomenclature existed to describe the EEG patterns encountered in ICU patients monitored by con- tinuous EEG, and there is no consensus regarding which patterns are associated with ongoing neuronal injury and require intervention [43].
As a first step towards standardizing terminology, a group of experts has pro- posed a new classification for rhythmic and periodic EEG patterns encountered in critically ill patients [43]. This approach will facilitate multicenter research projects that, for instance, should aim at determining which EEG patterns are associated with ongoing neuronal damage.
Stimulus-induced Rhythmic, Periodic, or Ictal Discharges
Recently, a new EEG phenomenon in critically ill patients was recognized, ‘stimulus- induced rhythmic, periodic, or ictal discharges’ (SIRPIDs) [44]. SIRPIDs were observed in 33 of 150 (22 %) patients monitored by continuous EEG. All of these periodic, rhythmic or ictal-appearing discharges were consistently induced by alert- ing stimuli such as examination, chest percussion, or loud noise. Furthermore, 18 of
these patients fulfilled the criteria for ictal discharges with rhythmic patterns and temporal evolution. There was no significant difference in the incidence of clinical sei- zures in patients with or without SIRPIDs; however, clinical status epilepticus was more common in patients with focal or ictal-appearing SIRPIDs than in those with- out. Recording video or documenting patient stimulation was necessary to distinguish SIRPIDs from spontaneous seizures. Indeed, further research is necessary to deter- mine the pathophysiologic, prognostic, and therapeutic significance of SIRPIDs [44].
Staffing and Technical Requirements for Implementing Continuous EEG Monitoring in the ICU
Staffing Requirements
A well-trained continuous EEG monitoring team is fundamental for the successful implementation of any continuous EEG monitoring program on the ICU. EEG experts should be available 24 hours per day to guarantee proper interpretation of the generated data. Furthermore, specialized training of the ICU nursing and physi- cian staff is indispensable, as are frequent visits by the EEG technician.
Data Analysis
The ongoing analysis of continuous EEG data is a major task due to the sheer vol- ume of information generated and the need for near real-time interpretation of EEG patterns. Visual unprocessed EEG analysis performed by experienced readers at rel- atively low review rates represents the classic and standard method of assessing EEGs and is an excellent means of recognizing seizures and detecting changes in a standard EEG. However, standard visual analysis of a continuously recorded EEG in the ICU setting is impractical: it is far too time-consuming since an experienced electroencephalographer would have to be constantly available for continuous real- time interpretation of EEG patterns.
Nowadays, technological advances in digital EEG data acquisition, storage, com- puter processing, transmission, and display of large amounts of data have made con- tinuous EEG monitoring in the ICU technically feasible [45, 46].
Usually, the classic 16-channel EEG plus an electrocardiogram channel are recorded. Electrodes are placed using the international 10 – 20 system, sometimes with modifications. More electrodes provide greater spatial coverage but are techni- cally more difficult to maintain and may provide redundant data. In digital EEG, data from a wide variety of placements can be recorded and retrospective montag- ing is also possible.
Continuous EEG data collected over long periods of time can be transformed into a more ‘user-friendly’ summary format that can be interpreted by non-electroen- cephalographers in real-time. The computer analysis technique transforms the con- tinuous EEG data into power spectra by fast Fourier transformation (FFT), creating quantitative EEG (qEEG) parameters [47]. To date, most qEEG tools use amplitude- integrated EEG (AEEG) or frequency-domain methods to simplify the EEG. The qEEG can be displayed graphically as compressed spectral arrays (CSAs), a kind of picture that is easy to interpret, and that could be useful as a means for non-expert caregivers to screen cerebral function at the bedside [45]. CSA has not been formally tested in the ICU setting [32]. Furthermore, it is not known which of the qEEG tools are best for recognizing seizures or ischemia. Comparison of currently available and
developing methodologies will facilitate the creation of more sensitive and specific quantitative assessment tools.
Numerous specialized EEG signal processing software packages are available for screening large continuous EEG datasets to detect possible electrographic seizure activity for ambulatory patients with epilepsy; however, as already discussed, EEG patterns of seizure activity in critically ill patients are different from those in ambu- latory patients.
Surprisingly, little systematic research has been conducted to evaluate the sensi- tivity and specificity of the currently available qEEG tools to detect seizures and ischemia in the ICU. Good clinical practice requires that the underlying EEG signal must be available for review by an experienced electroencephalographer to confirm the significance of any changes suggested by methods that have simplified the EEG data stream. One group recommends reviewing the electrographic data at least twice a day and even more frequently if clinically warranted [32].
The ongoing development of new methods to display and analyze continuous EEG data will result in the widespread adoption of continuous EEG monitoring tech- nology in the ICU. For an overview of the currently available techniques to display and analyze continuous EEG data see the excellent reviews published by Scheuer and Wilson [45] and Kull and Emerson [46].
Recording Electrodes
One of the main limiting factors of continuous EEG monitoring in the ICU setting is the recording electrode [48]. From the vast array of electrodes used, the only elec- trode that, once placed, never requires further adjustment for weeks is the chronic silver-silver/chloride (Ag-Ag/Cl) sphenoidal (Sp) electrode. This electrode has been recently modified to permit subdermal placement. Importantly, this new electrode is also MRI and CT compatible [48].
Concomitant Video Monitoring
The use of digital video/continuous EEG has been shown to be particularly helpful in identifying subtle ictal phenomena (facial twitching or rhythmic eye movements) and artifacts that mimic seizures. One study found that all artifacts were easily and quickly recognized on video recordings but were quite difficult to identify without this technique [49]. Valid interpretation of continuous EEG and artifact recognition in the absence of video monitoring is only possible if the ICU staff accurately notes any external manipulation of the patient.
Artifacts
EEG artifacts are recorded electrical phenomena that do not arise from the brain.
An EEG recorded in the ICU setting is often contaminated by artifacts arising from monitoring equipment, life support systems, and personnel. Traditionally, artifacts have been divided into exogenous and biologic/physiologic artifacts:
There are a large number of sources of exogenous artifacts in the ICU, some of them mimicking seizures or other important EEG patterns, including electronic devices that generate alternating current fields and structures that generate static charges such as dripping intravenous fluids and water commonly found moving in ventilator tubing. Dislodged EEG electrodes and electrodes that have dried out, with
serious mismatches in impedance between electrodes, are also responsible for arti- facts, as are vibrating beds, pumps, monitors, ventilators, and pacemakers. Even the movement of the patient by doctors or nurses may be a source of electric artifacts.
Completely disconnected electrodes occasionally may record activity that looks sim- ilar to that of a comatose patient with moderate to severe diffuse slowing and atten- uation. Therefore, electrodes should be secured with collodion and checked at least twice per day and after any manipulation or transport of the patient [50]. Drug- induced artifacts on the EEG are also well-recognized, the most frequent being beta activity due to benzodiazepines. Electromagnetic fields from cellular phones, radios or beepers produce artifacts in general digital monitoring of patients, and future investigations must study such effects on continuous EEG monitoring.
Biologic/physiologic artifacts include EEG changes induced mainly by the patient’s heart beats or respiration. Finally, it must be considered that sedating med- ications, which severely alter brain activity and hence EEG patterns, are routinely used in the ICU.
The Future: Multimodal Neuromonitoring in the ICU
The monitoring standards of patients with catastrophic intracranial diseases are changing and an active search for secondary insults such as ischemia, hypoxia, or seizures is an important target in order to improve the outcome of these critically ill patients.
Today, in addition to the traditional monitoring of intracranial pressure (ICP) and cerebral perfusion pressure (CPP), it is possible to measure global oxygen deliv- ery via jugular bulb oximetry or to continuously record focal brain tissue oxygen tension and brain temperature using intracranial probes. Intracerebral microdialysis provides further information about glucose metabolism in the brain. In most centers CT and MRI scans of the brain are available 24 hours a day. Finally, we can continu- ously monitor regional CBF with an intracranial probe using laser Doppler or ther- mal diffusion techniques.
Software with which these data can be fully integrated is being developed. The integrative use of all or a specific selection of some of these techniques, in combina- tion with general monitoring of a patient, has been termed multimodal neuromoni- toring. However, only continuous EEG can directly show seizures. And, as discussed above, every patient with a catastrophic intracranial disease is at risk of developing seizures and should be monitored by continuous EEG.
The issue of monitoring techniques that may be of special use in which intracra- nial disease, and more importantly, in which specific patient, must be addressed in future multicenter trials.
Conclusion
Continuous EEG recording is strongly recommended for patients with acute intra- cranial diseases who are at risk of developing seizures. As a result of recent techno- logical improvements, continuous EEG and video monitoring for over 48 hours or longer is now feasible.
Although previously thought to be uncommon, non-convulsive seizures and non- convulsive status epilepticus are being identified more frequently. In fact, anyone
who works with critically ill neurologic patients and does not see this entity on a regular basis is missing the diagnosis [7]. Prompt diagnosis and treatment of non- convulsive status epilepticus is crucial, and delayed treatment has been associated with poor outcome.
We currently face four major challenges in further establishing continuous EEG monitoring in the ICU setting:
1. Standardized terminology must be used.
2. Continuous EEG monitoring must be transformed into a more user-friendly but also highly sensitive and specific method.
3. The incidence of non-convulsive seizures and non-convulsive status epilepticus following catastrophic intracranial disease must be determined.
4. Most importantly, we must determine whether continuous EEG monitoring leads to therapeutic decisions that significantly influence the outcome of our patients.
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