Optimal Cerebral Perfusion Pressure Research Articles

Brain Tissue Oxygenation as an Adjunctive Monitor for Determining Optimal Cerebral Perfusion Pressure in Subarachnoid Hemorrhage Patients (P4.297)

Brain Tissue Oxygenation as an Adjunctive Monitor for Determining Optimal Cerebral Perfusion Pressure in Subarachnoid Hemorrhage Patients (P4.297)

Occurrence of CPPopt Values in Uncorrelated ICP and ABP Time Series.

Optimal cerebral perfusion pressure (CPPopt) is a concept that uses the pressure reactivity (PRx)-CPP relationship over a given period to find a value of CPP at which PRx shows best autoregulation. It has been proposed that this relationship be modelled by a U-shaped curve, where the minimum is interpreted as being the CPP value that corresponds to the strongest autoregulation. Owing to the nature of the calculation and the signals involved in it, the occurrence of CPPopt curves generated by non-physiological variations of intracranial pressure (ICP) and arterial blood pressure (ABP), termed here "false positives", is possible. Such random occurrences would artificially increase the yield of CPPopt values and decrease the reliability of the methodology.In this work, we studied the probability of the random occurrence of false-positives and we compared the effect of the parameters used for CPPopt calculation on this probability. To simulate the occurrence of false-positives, uncorrelated ICP and ABP time series were generated by destroying the relationship between the waves in real recordings. The CPPopt algorithm was then applied to these new series and the number of false-positives was counted for different values of the algorithm's parameters. The percentage of CPPopt curves generated from uncorrelated data was demonstrated to be 11.5%. This value can be minimised by tuning some of the calculation parameters, such as increasing the calculation window and increasing the minimum PRx span accepted on the curve.

Deriving the PRx and CPPopt from 0.2-Hz Data: Establishing Generalizability to Bedmaster Users.

The objective was to explore the validity of industry-parameterized vital signs in the generation of pressure reactivity index (PRx) and optimal cerebral perfusion pressure (CPPopt) values. Ten patients with intracranial pressure (ICP) monitors from 2008 to 2013 in a tertiary care hospital were included. Arterial blood pressure (ABP) and ICP were sampled at 240 Hz (of waveform data) and 0.2 Hz (of parameterized data produced by heuristic industry proprietary algorithms). 240-Hz ABP were filtered for pulse pressure and diastolic ABP within the limits of 20-150 mmHg. The PRx was calculated as Pearson's correlation coefficient using 10-s averages of ICP and ABP over a 5-min moving window with 80% overlap. For ease of comparison, we used the naming convention of BMx for PRx values derived from 0.2-Hz data. A 5-min median cerebral perfusion pressure (CPP) trend was calculated, PRx or BMx values divided and averaged into CPP bins spanning 5 mmHg. The minimum Y value (PRx or BMx) of the parabolic function fit to the resulting XY plot of 4 h of data was obtained, and updated every 1 min. Pearson's R correlations were calculated for each patient. Linear mixed-effects models were used with a random intercept to assess the overall correlation between the PRx (outcome) and the BMx (fixed effect) or the CPPopt-PRx (outcome) and the CPPopt-BMx (fixed effect). The overall correlation between the PRx and BMx was 0.78 based on the linear mixed effects models (p < 0.0001), and the overall correlation for the CPPopt-PRx and CPPopt-BMx based on the linear mixed effects models was 0.76 (p < 0.0001). One patient had low correlation of CPPopts derived from the PRx vs the BMx; this patient had the least number of hours of CPPopt data to compare. The BMx shows promise in CPPopt derivation against the validated PRx measure. If further developed, it could expand the capability of centers to derive CPPopt goals for use in clinical trials.

Is There a Relationship Between Optimal Cerebral Perfusion Pressure-Guided Management and PaO2/FiO2 Ratio After Severe Traumatic Brain Injury?

Severe traumatic brain injury (TBI) management has been associated with adult respiratory distress syndrome (ARDS) in previous literature. We aimed to investigate the relationships between optimal CPP-guided management, ventilation parameters over time and outcome after severe TBI. We performed retrospective analysis of recorded data from 38 patients admitted to the NCCU after severe TBI, managed with optimal cerebral perfusion pressure (CPPopt)-guided therapy, calculated using pressure reactivity index (PRx). All patients were sedated and ventilated with lung protective criteria (Peep > 5, tidal volume 6-8 ml/kg and airway pressure < 30 cmH2O). Daily mean CPPopt varied between a minimum of 84 mmHg and a maximum of 91 mmHg with an all period mean value of 88 mmHg. The mean value for the difference between CPP and CPPopt was -1.9 mmHg. Daily mean P/F ratio decreased and varied between 253 and 387 with an all-period mean of 294 mmHg. During the 10 days of recording data, five patients (13%) developed criteria of severe ARDS, but only two patients died due to severe ARDS (5%). PaO2/FiO2 (P/F) ratio did not correlate with CPPopt, but showed a strong correlation with tidal volume (p = 0.000) and driving pressure (p = 0.000). Although CPPopt-guided therapy may induce a decrease in P/F ratio over time during the first 10 days, we could not find an association with worst outcome, which may be influenced by lung protective ventilation strategies and preservation of cerebral autoregulation.

KidsBrainIT: A New Multi-centre, Multi-disciplinary, Multi-national Paediatric Brain Monitoring Collaboration.

Validated optimal cerebral perfusion pressure (CPP) treatment thresholds in children do not exist. To improve the intensive care unit (ICU) management of the paediatric traumatic brain injury (TBI) population, we are forming a new paediatric multi-centre collaboration to recruit standardised ICU data for running and reporting upon models for assessing autoregulation and optimal CCP (CPPopt). We are adapting the adult BrainIT group's approach to develop a new Paediatric Brain Monitoring and Information Technology Group (KidsBrainIT), which will include a repository to store prospectively collected high-resolution physiological, clinical, and outcome data. In the first phase of this project there are 7 UK Paediatric Intensive Care Units, 1 Spanish, 1 Belgium, and 1 Romanian Centre interested in participating. In subsequent phases, we plan to open recruitment to other centres both within Europe, US and abroad. We are collaborating with the Leuven Group and plan to use their LAx (low-frequency autoregulation index), DATACAR (dynamic adaptive target of active cerebral autoregulation), CPPopt and visualisation methodologies. We also plan to use the continuous diffuse optical monitoring and tomography technology developed in Barcelona as an acute surrogate end-point for optimising brain perfusion. This technology allows non-invasive continuous monitoring of deep tissue perfusion and oxygenation in adults but its clinical application in infants and children with TBI has not been studied previously. We report on the current status of setting up this new collaboration and also on pilot analyses in two centres which are the basis of our rationale for the need for a prospective validation study of CPPopt in children. Specifically, we demonstrated that CPPopt varied with time for each patient during their paediatric intensive care unit (PICU) stay, and the median overall CPPopt levels for children aged 2-6 years, 7-11 years and 12-16 years were 68.83, 68.09, and 72.17 mmHg respectively. Among survivors and patients with favourable outcome (GOS 4 and 5), there were significantly higher proportions with CPP monitoring time within CPPopt (p = 0.04 and p = 0.01 respectively). There is a need and an interest in forming a multi-centre PICU collaboration for acquiring data and performing analyses for determining validated CPPopt thresholds in the paediatric TBI population. KidsBrainIT is being formed to meet that need.

Multimodality neuromonitoring in severe pediatric traumatic brain injury.

Each year, the annual hospitalization rates of traumatic brain injury (TBI) in children in the United States are 57.7 per 100K in the <5 years of age and 23.1 per 100K in the 5-14 years age group. Despite this, little is known about the pathophysiology of TBI in children and how to manage it most effectively. Historically, TBI management has been guided by clinical examination. This has been assisted progressively by clinical imaging, intracranial pressure (ICP) monitoring, and finally a software that can calculate optimal brain physiology. Multimodality monitoring affords clinicians an early indication of secondary insults to the recovering brain including raised ICP and decreased cerebral perfusion pressure. From variables such as ICP and arterial blood pressure, correlations can be drawn to determine parameters of cerebral autoregulation (pressure reactivity index) and "optimal cerebral perfusion pressure" at which the vasculature is most reactive. More recently, significant advances using both direct and near-infrared spectroscopy-derived brain oxygenation plus cerebral microdialysis to drive management have been described. Here in, we provide a perspective on the state-of-the-art techniques recently implemented in clinical practice for pediatric TBI.

Brain-Heart Interactions in Traumatic Brain Injury.

The cardiovascular manifestations associated with nontraumatic head disorders are commonly known. Similar manifestations have been reported in patients with traumatic brain injury (TBI); however, the underlying mechanisms and impact on the patient's clinical outcomes are not well explored. The neurocardiac axis theory and neurogenic stunned myocardium phenomenon could partly explain the brain-heart link and interactions and can thus pave the way to a better understanding and management of TBI. Several observational retrospective studies have shown a promising role for beta-adrenergic blockers in patients with TBI in reducing the overall TBI-related mortality. However, several questions remain to be answered in clinical randomized-controlled trials, including population selection, beta blocker type, dosage, timing, and duration of therapy, while maintaining the optimal mean arterial pressure and cerebral perfusion pressure in patients with TBI.

On management of optimal cerebral perfusion pressure in severe traumatic brain injury patients

Background: The maintenance of patient-specific optimal cerebral perfusion pressure (CPPopt) is crucial for patients with traumatic brain injury (TBI).

Autoregulation in paediatric TBI-current evidence and implications for treatment.

Children who survive acute traumatic brain injury are at risk of death from subsequent brain swelling and secondary injury. Strict physiologic management in the ICU after traumatic brain injury is believed to be key to survival, and cerebral perfusion pressure is a prominent aspect of post brain injury care. However, optimal cerebral perfusion pressure targets for children are not known. Autoregulation monitoring has been used to delineate individualized optimal perfusion pressures for patients with traumatic brain injury. The methods to do so are diverse, confusing, and not universally validated. In this manuscript, we discuss the history of autoregulation monitoring, outline and categorize the methods used to measure autoregulation, and review the available validation data for methods used to monitor autoregulation. Impaired autoregulation after traumatic brain injury is associated with a poor prognosis. Observational data suggests that optimal neurologic outcome and survival are associated with optimal perfusion pressure defined by autoregulation monitoring. No randomized, controlled, interventional data is available to assess autoregulation monitoring after pediatric traumatic brain injury.

Time spent with impaired autoregulation is linked with outcome in severe infant/paediatric traumatic brain injury.

It could be shown in traumatic brain injury (TBI) in adults that the functional status of cerebrovascular autoregulation (AR), determined by the pressure reactivity index (PRx), correlates to and even predicts outcome. We investigated PRx, cerebral perfusion pressure (CPP) and intracranial pressure (ICP) and their correlation to outcome in severe infant and paediatric TBI. Seventeen patients (range, 1day to 14years) with severe TBI (median GCS at presentation, 4) underwent long-term computerised ICP and mean arterial pressure (MAP) monitoring using dedicated software to determine CPP and PRx and optimal CPP (CPP level where PRx shows best autoregulation) continuously. Outcome was determined at discharge and at follow-up using the Glasgow Outcome Scale. Favourable outcome was reached in eight patients, unfavourable outcome in seven patients. Two patients died. Nine patients underwent decompressive craniectomy to control ICP during Intensive Care Unit treatment. When dichotomised to outcome, no significant difference was found for overall ICP, CPP and PRx. The time with severely impaired AR (PRx>0.2) was significantly longer for patients with unfavourable outcome (64h vs 6h, p=0.001). Continuously impaired AR of ≥24h and age<1year was associated to unfavourable outcome. Children with favourable outcome spent the entire monitoring time at or above the optimal CPP. Integrity of AR has a similar role for outcome after TBI in the paediatric population as in adults. The amount of time spent with deranged AR seems to be associated with outcome; a factor especially critical for infant patients. The results of this preliminary study need to be validated in the future.

Further Controversies About Brain Tissue Oxygenation Pressure-Reactivity After Traumatic Brain Injury

Continuous monitoring of cerebral autoregulation is considered clinically useful due to its ability to warn against brain ischemic insults, which may translate to a relationship with adverse outcome. It is typically performed using the pressure reactivity index (PRx) based on mean arterial pressure and intracranial pressure. A new ORx index based on brain tissue oxygenation and cerebral perfusion pressure (CPP) has been proposed that similarly allows for evaluation of cerebrovascular reactivity. Conflicting results exist concerning its clinical utility. Retrospective analysis was performed in 85 patients with traumatic brain injury (TBI). ORx was calculated using three time windows of 5, 20, and 60min. Correlation coefficients and individual "optimal CPP" (CPPopt) were calculated using both PRx and ORx, and relation to patient outcome investigated. Correlation coefficients for all comparisons between PRx and ORx indicated poor association between these indices (range from -0.04 to 0.07). PRx was significantly lower in patients with good outcome (p=0.01), while none of the ORx indices proved to be significantly different in the two outcome groups. Higher mortality related to average CPP<CPPopt was found regardless of which index was used to calculate CPPopt. In the TBI setting, ORx does not appear to correlate with vascular pressure reactivity as assessed with PRx. Its potential use for individualizing CPP thresholds remains unclear.

Monitoring of Optimal Cerebral Perfusion Pressure in Traumatic Brain Injured Patients Using a Multi-Window Weighting Algorithm.

Methods to identify an autoregulation guided "optimal" cerebral perfusion pressure (CPPopt) for traumatic brain injury patients (TBI) have been reported through several studies. An important drawback of existing methodology is that CPPopt can be calculated only in ∼50-60% of the monitoring time. In this study, we hypothesized that the CPPopt yield and the continuity can be improved significantly through application of a multi-window and weighting calculation algorithm, without adversely affecting preservation of its prognostic value. Data of 526 severe TBI patients admitted between 2003 and 2015 were studied. The multi-window CPPopt calculation was based on automated curve fitting in pressure reactivity index (PRx)-CPP plots using data from 36 increasing length time windows (2-8 h). The resulting matrix of CPPopts was then averaged in a weighted manner. The yield, continuity, and stability of CPPopt were studied. The difference between patients' actual CPP and CPPopt (ΔCPP) was calculated and the association with outcome was analyzed. Overall, the multi-window method demonstrated more continuous and stable presentation of CPPopt in this cohort. The new method resulted in a mean (±SE) CPPopt yield of 94% ± 2.1%, as opposed to the previous single-window-based CPPopt yield of 51% ± 0.94%. The stability of CPPopt across the whole monitoring period was significantly improved by using the new algorithm (p < 0.001). The relationship between ΔCPP according to the multi-window algorithm and outcome was similar to that for CPPopt calculated on the basis of a single window. In conclusion, this study validates the use of a new multi-window and weighting algorithm for significant improvement of CPPopt yield in TBI patients. This methodological improvement is essential for its clinical application in future CPPopt trials.

Survey in expert clinicians on the validity of automated calculation of optimal cerebral perfusion pressure.

Optimal cerebral perfusion pressure (CPPopt) targeting in traumatic brain injury (TBI) patients constitutes an active and controversial area of research. It has been suggested that an autoregulation guided CPP therapy may improve TBI outcome. Prerequisites of a CPPopt intervention study would be objective criteria for the CPPopt detection. This study compared the agreement between automated and visual CPPopt detection. Twenty-five clinicians from 18 centers worldwide, familiar with brain monitoring and using dedicated software, reviewed ten 4-hour CPPopt screenshots at 48 hours after ictus in selected TBI patients. Each screenshot displayed the trends of cerebral perfusion pressure (CPP), intracranial pressure (ICP), cerebrovascular pressure reactivity (PRx) as well as the "CPP-optimal" curve and its associated value (automated CPPopt). The main objective was to evaluate the agreement between expert clinicians as well as the agreement between the clinicians and automated CPPopt. Twenty-two clinicians responded to our call (88%). Three screenshots were judged as "CPPopt not determinable" by >45% of the clinicians. For the whole group, the consensus between automated CPPopt and clinicians' visual CPPopt was high. Three clinicians were identified as outliers. All clinicians recommended to modify CPP when patients differed >±5 mmHg from their CPPopt. The inter-observer consensus was highest in cases with current CPP below the optimal value. The overall agreement between automated CPPopt and visual CPPopt identified by autoregulation experts was high, except for those cases when the curve was deemed by the clinicians not reliable enough to yield a trustworthy CPPopt.

Hypertension-Induced Enhanced Myogenic Constriction of Cerebral Arteries Is Preserved after Traumatic Brain Injury.

Traumatic brain injury (TBI) was shown to impair pressure-induced myogenic response of cerebral arteries, which is associated with vascular and neural dysfunction and increased mortality of TBI patients. Hypertension was shown to enhance myogenic tone of cerebral arteries via increased vascular production of 20-hydroxyeicosatrienoic acid (HETE). This adaptive mechanism protects brain tissue from pressure/volume overload; however, it can also lead to increased susceptibility to cerebral ischemia. Although both effects may potentiate the detrimental vascular consequences of TBI, it is not known how hypertension modulates the effect of TBI on myogenic responses of cerebral vessels. We hypothesized that in hypertensive rats, the enhanced myogenic cerebrovascular response is preserved after TBI. Therefore, we investigated the myogenic responses of isolated middle cerebral arteries (MCA) of normotensive and spontaneously hypertensive rats (SHR) after severe impact acceleration diffuse brain injury. TBI diminished myogenic constriction of MCAs isolated from normotensive rats, whereas the 20-HETE-mediated enhanced myogenic response of MCAs isolated from SHRs was not affected by TBI. These results suggest that the optimal cerebral perfusion pressure values and vascular signaling pathways can be different and, therefore, should be targeted differently in normotensive and hypertensive patients following TBI.

Benefit on optimal cerebral perfusion pressure targeted treatment for traumatic brain injury patients

PurposeThe maintenance of patient-specific optimal cerebral perfusion pressure (CPPopt) is crucial for patients with traumatic brain injury (TBI). The goal of the study was to explore the influence of CPP declination from CPPopt value on the TBI patients' outcome. MethodsThe CPP and cerebrovascular autoregulation (CA) monitoring of 52 TBI patients was performed. Patient-specific CPPopt has been identified and the associations between the patients' outcome and complex influence of time of CPP declination from CPPopt value, age, and the duration of CA impairment episodes has been analyzed. ResultsThe multiple correlation coefficient between the Glasgow outcome scale (GOS), duration of CA impairment events and percentage time, when 0<ΔCPPopt<10mmHg was r=−0.643 (P<0.001). The multiple correlation coefficients between GOS, age, and percentage time of ΔCPPopt when 0<ΔCPPopt<10mmHg was r=−0.587 (P<0.001). ConclusionThe CPPopt-targeted patient-specific management might be useful for stabilizing CA in TBI patients as well as for improving their outcome. Better outcomes were obtained by maintaining CPP in light hyperperfusion condition (up to 10mmHg above CPPopt) when CPPopt is in the range of 60–80mmHg, and keeping CPP within the range of CPPopt +/−5mmHg when CPPopt is above 80mmHg.

Increased risk of critical CBF levels in SAH patients with actual CPP below calculated optimal CPP

BackgroundCerebral pressure autoregulation can be quantified with the pressure reactivity index (PRx), based on the correlation between blood pressure and intracranial pressure. Using PRx optimal cerebral perfusion pressure (CPPopt) can be calculated, i.e., the level of CPP where autoregulation functions best. The relation between cerebral blood flow (CBF) and CPPopt has not been examined. The objective was to assess to which extent CPPopt can be calculated in SAH patients and to investigate CPPopt in relation to CBF.MethodsRetrospective study of prospectively collected data. CBF was measured bedside with Xenon-enhanced CT (Xe-CT). The difference between actual CPP and CPPopt was calculated (CPP∆). Correlations between CPP∆ and CBF parameters were calculated with Spearman’s rank order correlation coefficient (rho). Separate calculations were done using all patients (day 0–14 after onset) as well as in two subgroups (day 0–3 and day 4–14).ResultsEighty-two patients with 145 Xe-CT scans were studied. Automated calculation of CPPopt was possible in adjunct to 60% of the Xe-CT scans. Actual CPP < CPPopt was associated with higher numbers of low-flow regions (CBF <10 ml/100 g/min) in both the early phase (day 0–3, n = 39, Spearman’s rho = −0.38, p = 0.02) and late acute phase of the disease (day 4–14, n = 35, Spearman’s rho = −0.39, p = 0.02). CPP level per se was not associated with CBF.ConclusionsCalculation of CPPopt is possible in a majority of patients with severe SAH. Actual CPP below CPPopt is associated with low CBF.

The effect of resuscitation position on cerebral and coronary perfusion pressure during mechanical cardiopulmonary resuscitation in porcine cardiac arrest model

ObjectiveIt is unknown whether patient position is associated with the optimal cerebral (CePP) and coronary (CoPP) perfusion pressure. MethodsThis study utilized a randomized experimental design and anesthetized, intubated and paralyzed female pigs (n=12) (mean 42, SD 3kg). After 6min of untreated ventricular fibrillation, mechanical CPR with was performed for 3min in 0° supine position. The CPR was then performed for 5min in a position randomly assigned to either 1) head-up tilt (HUT) by three angles (30°, 45°, or 60°) or 2) head-down tilt (HDT) by three angles (30°, 45°, or 60°) and at 3) supine position between HUT and HDT positions. 4 Pigs were assigned to each angle of HUT or HDT position and 12 pigs were assigned to supine position. CePPs and CoPPs were measured and compared using MIXED procedure with pig as a random effect among angles and compared between angles with Tukey post-hoc analysis. ResultsWith 60°, 45°, 30° head-down, 0° (supine), and 30°, 45°, 60° head-up positioning, mean(SD) CePPs increased consistently as follows: 2.4(0.4), 9.3(1.6), 16.5(1.6), 27.0(1.5), 35.1(0.4), 39.4(0.6), and 39.9(0.3) mmHg, respectively. CoPPs were followings according to same angle: 12.9(2.5), 13.3(2.5), 12.8(0.4), 18.1(0.7), 30.3(0.4), 24.1(0.6), and 26.5(0.9) mmHg, respectively. The CePPs were peak at HUT(45°) and HUT(60°), but CoPP was peak in HUT(30°) and higher than HUT(45°) and HUT(60°). ConclusionCerebral perfusion pressure during mechanical CPR were similar and highest in the HUT(45° and 60°) positions whereas the peak coronary perfusion pressure was observed with HUT(30°).

The Combined Use of Cardiac Output and Intracranial Pressure Monitoring to Maintain Optimal Cerebral Perfusion Pressure and Minimize Complications for Severe Traumatic Brain Injury.

ObjectiveTo show the effect of dual monitoring including cardiac output (CO) and intracranial pressure (ICP) monitoring for severe traumatic brain injury (TBI) patiens. We hypothesized that meticulous treatment using dual monitoring is effective to sustain maintain minimal intensive care unit (ICU) complications and maintain optimal ICP and cerebral perfusion pressure (CPP) for severe TBI patiens.MethodsWe included severe TBI, below Glasgow Coma Scale (GCS) 8 and head abbreviation injury scale (AIS) >4 and performed decompressive craniectomy at trauma ICU of our hospital. We collected the demographic data, head AIS, injury severity score (ISS), initial GCS, ICU stay, sedation duration, fluid therapy related complications, Glasgow Outcome Scale (GOS) at 3 months and variable parameters of ICP and CO monitor.ResultsThirty patients with severe TBI were initially selected. Thirteen patients were excluded because 10 patients had fixed pupillary reflexes and 3 patients had uncontrolled ICP due to severe brain edema. Overall 17 patients had head AIS 5 except 2 patients and 10 patients (58.8%) had multiple traumas as mean ISS 29.1. Overall complication rate of the patients was 64.7%. Among the parameters of CO monitoring, high stroke volume variation is associated with fluid therapy related complications (p=0.043) and low cardiac contractibility is associated with these complications (p=0.009) statistically.ConclusionCombined use of CO and ICP monitors in severe TBI patients who could be necessary to decompressive craniectomy and postoperative sedation is good alternative methods to maintain an adequate ICP and CPP and reduce fluid therapy related complications during postoperative ICU care.

Autoregulation of the cerebral blood flow and the optimal cerebral perfusion pressure

Autoregulation of the cerebral blood flow and the optimal cerebral perfusion pressure

Enhanced Visualization of Optimal Cerebral Perfusion Pressure Over Time to Support Clinical Decision Making.

Cerebrovascular reactivity can provide a continuously updated individualized target for management of cerebral perfusion pressure, termed optimal cerebral perfusion pressure. The objective of this project was to find a way of improving the optimal cerebral perfusion pressure methodology by introducing a new visualization method. Four severe traumatic brain injury patients with intracranial pressure monitoring. Data were collected and pre-processed using ICM+ software. Sequential optimal cerebral perfusion pressure curves were used to create a color-coded maps of autoregulation - cerebral perfusion pressure relationship evolution over time. The visualization method addresses some of the main drawbacks of the original methodology and might bring the potential for its clinical application closer.