a b s t r a c t

Background: Cerebral regional oxygen saturation (rSO₂) can be measured immediately and noninvasively just after arrival at the hospital and may be useful for evaluating the futility of resuscitation for a patient with out- of-hospital cardiopulmonary arrest (OHCA). We examined the best practices involving cerebral rSO₂ as an indicator of the futility of resuscitation.

Methods: This study was a single-center, prospective, observational analysis of a cohort of consecutive adult OHCA patients who were transported to the University of Tokyo Hospital from October 1, 2012, to September 30, 2013, and whose cerebral rSO₂ values were measured.

Results: During the study period, 69 adult OHCA patients were enrolled. Of the 54 patients with initial lower cerebral rSO₂ values of 26% or less, 47 patients failed to achieve return of spontaneous circulation (ROSC) in the receiver operating characteristic curve analysis (optimal cutoff, 26%; sensitivity, 88.7%; specificity, 56.3%; positive predictive value, 87.0%; negative predictive value, 60.0%; area under the curve [AUC], 0.714; P =

.0033). The AUC for the initial lower cerebral rSO₂ value was greater than that for blood pH (AUC, 0.620; P =

.1687) or lactate values (AUC, 0.627; P = .1081) measured upon arrival at the hospital as well as that for initial higher (AUC, 0.650; P = .1788) or average (AUC, 0.677; P = .0235) cerebral rSO₂ values. The adjusted odds ratio of the initial lower cerebral rSO₂ values of 26% or less for ROSC was 0.11 (95% confidence interval, 0.01- 0.63; P = .0129).

Conclusions: Initial lower cerebral rSO₂ just after arrival at the hospital, as a static indicator, is associated with non-ROSC. However, an initially lower cerebral rSO₂ alone does not yield a diagnosis performance sufficient for evaluating the futility of resuscitation.

(C) 2014

1. Introduction

Out-of-hospital cardiopulmonary arrest (OHCA) has a very poor prognosis, with approximately 120000, 280000, and 380000 victims

? Contributors: T Fukuda, as the principal investigator, made substantial contribu- tions to idea formation, study design and completion, data collection, management, and

analysis, interpretation of results, and drafting and revising the manuscript. N Ohashi, M Nishida, M Gunshin, K Doi, T Matsubara, S Nakajima, and N Yahagi participated in idea formation, data collection and management, and reviewing the manuscript critically for important intellectual content. T Fukuda performed the statistical analysis. All authors approved the final version for publication.

?? Funding sources: This study was supported in part by a grant from the University

of Tokyo Hospital.

? Conflict of interest statement: We declare that we have no conflicts of interest.

* Corresponding author. Department of Emergency and Critical Care Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Tel.: +81 3 3815 5411; fax: +81 3 3814 6446.

E-mail address: [email protected] (T. Fukuda).

annually in Japan, Europe, and the United States, respectively [1-3]. Of these victims, approximately 60% in Europe and 55% in the United States are transferred to hospitals, whereas almost all OHCA patients in Japan are transferred to hospitals [4-8]. In Japan, nonphysicians are legally prohibited from terminating resuscitation except in specific situations [4,9-12].

Although the rate of survival after OHCA has been increasing with advances in care throughout the “Chain of survival,” it is still low [13,14]. In our previous study, which was conducted using a nationwide administrative database in Japan, we found the following outcomes for OHCA patients transferred to hospitals: approximately 75% died within 24 hours after arrival at the hospital, approximately 17% survived more than 24 hours but died during hospitalization, and approximately 8% survived until discharge [4].

Although futile medical care should be avoided, it is very difficult to judge the futility of resuscitation in patients with OHCA. Even if a patient does not leave the hospital alive or develops neurological

http://dx.doi.org/10.1016/j.ajem.2014.02.039

0735-6757/(C) 2014

Near-infrared spectroscopy“>sequelae, it does not necessarily indicate that the medical care is futile. However, resuscitation efforts for patients who do not achieve sustained return of spontaneous circulation may be consid- ered futile. In addition, in Japan, where resuscitation is attempted for almost all patients with OHCA, it is extremely important to be able to identify such patients. The earlier the futility of resuscitation in patients with OHCA can be established, the better it is. A definitive judgment just after hospital arrival is ideal in Japan.

Cerebral regional oxygen saturation (rSO₂) is measurable upon arrival at the hospital, and its measurement result can be obtained immediately. In addition, cerebral rSO₂ is noninvasive and may be available to judge the futility of resuscitation for patients with OHCA. Although the use of cerebral rSO₂ as a prognostic indicator of OHCA has been studied [15-19], the best practices for use of cerebral rSO₂ as a prognostic indicator of OHCA have not been established thus far.

Because rSO₂ is affected by the ratio of composition of arteries and veins at the measurement site, even if a patient is measured again using the same timing, the value varies depending on the measure- ment site. Therefore, rSO₂ has been used as a dynamic indicator (relative change) rather than a static indicator (absolute value). One purpose of this study was to examine whether cerebral rSO₂ can be used as a static indicator. In addition, it is assumed that the values of cerebral rSO₂ measured at several sites may not be equal when cerebral rSO₂ is used as a static indicator. This study also aimed to examine whether the lowest, highest, or average value is the best for judging if resuscitation will be futile.

1. Methods
   1. Study design and participants

This study was a single-center, prospective, observational analysis of a cohort of consecutive patients aged 18 years or older with OHCA who were transported to the University of Tokyo Hospital from October 1, 2012, to September 30, 2013, and whose cerebral rSO₂ values were measured. Approval for the study was obtained from the Institutional Review Board of the University of Tokyo. The require- ment of prior informed patient consent was waived because of the emergency setting. Unless there were no relatives, including the patient himself, who could receive an explanation, subsequent informed patient consent was obtained.

Study setting

The University of Tokyo Hospital is a tertiary emergency medical center located in the central portion of the 23 wards of Tokyo. As of January 2013, the central portion of the 23 wards of Tokyo consists of 5 wards (Bunkyo, Chiyoda, Chuo, Minato, and Taito), an area of 63.55 km² with a population of approximately 799000 people living in 446000 households [12,20]. In this population, 699000 individuals are older than 18 years. Of the 55 hospitals in this area, 25 hospitals are designated emergency hospitals, and 6 hospitals serve as tertiary emergency medical centers. There are 15 fire departments and 26 branch offices in the central portion of the 23 wards of Tokyo. Ambulances are deployed from 24 of 41 fire stations. All of the emergency medical services (EMS) personnel perform cardiopulmo- nary resuscitation (CPR) in conformity with the Japanese CPR guidelines, which are based on the American Heart Association and the International Liaison Committee on Resuscitation guidelines [21-23]. In most cases, an ambulance crew consists of 3 EMS personnel, including at least 1 emergency lifesaving technician who has completed extensive training [10,11,24-26]. Some of these emergency lifesaving technicians are authorized to secure an infusion line, administer epinephrine, perform endotracheal intubation, perform defibrillation, and lead CPR. Advance directives, Living wills, or do-not-attempt-resuscitation orders are not generally accepted in

Japan [9-11]. The EMS providers in Japan are not allowed to terminate resuscitation out of the hospital except in specific situations such as decapitation, Rigor mortis, livor mortis, or decomposition. Most patients who have an OHCA treated by EMS personnel are transported to a tertiary emergency medical center [4,9-11].

Data collection

The data were collected prospectively with Utstein-style prehos- pital EMS records and hospital medical records. The prehospital EMS records included information such as the witness status; the bystander CPR status; the initial cardiac rhythm; and a series of EMS times for the call receipt, ambulance arrival at the scene, contact with patients, and hospital arrival. The hospital medical records included information such as Patient sex, age, blood pH, lactate value, cerebral rSO₂ values on hospital arrival, and whether ROSC was achieved.

Cardiopulmonary arrest was defined as the end of cardiac mechanical activity, which was determined by the absence of signs of circulation [27,28]. Bystander CPR was defined as CPR performed before EMS personnel reached the patient, regardless of the witness status [1,21,27]. Sustained ROSC was defined as ROSC with subsequent admission to the intensive care unit or ROSC without repetitive cardiopulmonary arrest for 20 consecutive minutes [27].

Near-infrared spectroscopy

A near-infrared spectroscopy (NIRS) device (INVOS 5100C; Covidien, Boulder, CO) can measure cerebral rSO₂ noninvasively in real time. Each probe of the NIRS device consists of an adhesive strip housing a single near-infrared light transmitter and 2 sensors. The transmitted near-infrared light penetrates the skin, skull, and brain cortical tissue. The 2 sensors detect light scattered by the tissue into 2 parabolic curves measuring hemoglobin saturation of the blood from the skin and skull in one sensor and from the skin, skull, and frontal cortex tissue in the other sensor. Frontal cortex hemoglobin saturation is calculated by the subtraction of the 2 signals. Thus, cerebral rSO₂ can be measured by the NIRS device without vascular pulsation, even in patients with hypotension, hypothermia, and/or circulatory arrest. The limits of detection for the device include hemoglobin-oxygen saturation of less than 15% or more than 95% and a cortical tissue depth of more than 2 cm [29,30]. Cerebral rSO₂ values in normal healthy individuals range from 55% to 80%.

Cerebral rSO₂ measurement

The NIRS device was set ready to operate before patient arrival. Advanced life support in conformity with the Japanese CPR guidelines, based on the American Heart Association and the International Liaison Committee on Resuscitation guidelines, was provided for each patient with cardiopulmonary arrest on hospital arrival. Cardiopulmonary arrest patients were met by at least a 7-member resuscitation team in the emergency department (ED). The team consisted of 1 attending physician in the ED, 2 residents, 1 nurse, and 3 EMS personnel. The resuscitation team concentrated on the CPR, and the other extra medical staff measured cerebral rSO₂ using the NIRS device. The patient’s skin was thoroughly cleaned, and 2 disposable probes were carefully applied bilaterally to the patient’s forehead. The cerebral rSO₂ values stabilized within several seconds after placement of the NIRS probes. The cerebral rSO₂ values were continuously monitored until either CPR was terminated or sustained ROSC was achieved. Both lower and higher cerebral rSO₂ values obtained from the 2 probes were recorded. If only 1 of 2 cerebral rSO₂ values were recorded, it was adopted as both the lower and the higher value. After admission to the intensive care unit, the clinical staff performed routine post-cardiac arrest care irrespective of the cerebral rSO₂ values.

Exclusion criteria for cerebral rSO₂ measurement included the following: (1) patients younger than 18 years, (2) patients who had achieved ROSC on hospital arrival, (3) patients with facial injuries who could not have probes attached, and (4) only the 7-member

Table 1

Characteristics of patients with OHCA in the study

Characteristic Total

(N = 69)

Non-ROSC (n = 53)

ROSC P

(n = 16)

resuscitation team being present as they were required for CPR.

Age (y), mean (SD) 66.1 (14.1) 67.6 (14.8) 61.0 (10.6) .0995

Male	48 (69.6)	34 (64.2)	14 (87.5)	.0752
Witnessed	30 (43.5)	17 (32.1)	13 (81.3)	.0005

2.6. Study end points	With bystander CPR	28 (40.6)	22 (41.5)	6 (37.5)	.7747
	Shockable initial rhythm	12 (17.4)	7 (13.2)	5 (31.3)	.0952
The primary end point was sustained ROSC with subsequent	Prehospital advanced airway
admission to the intensive care unit.	management Including supraglottic airway	14 (20.3)	12 (22.6)	2 (12.5)	.3767
	Only endotracheal intubation	3 (4.3)	3 (5.7)	0 (0.0)	.3305
2.7. Statistical analysis	Prehospital epinephrine	13 (18.8)	11 (20.8)	2 (12.5)	.4593
The descriptive data were summarized using the mean +- SD for	administration Cerebral oxygen saturation (%), mean (SD)

the continuous variables and the proportions for the categorical variables. Continuous variables were compared using analysis of variance. Categorical variables were compared using the ?² test. Receiver operating characteristic curve (ROC) analysis was performed to evaluate the predictive accuracy of not achieving ROSC. The odds ratio (OR) and 95% confidence intervals (CIs) based on the determined cutoff values were set to assess the risk of not achieving ROSC. Multivariate logistic regression analysis was used to examine the association between initial lower cerebral rSO₂ values of 26% or less and ROSC. The adjusted OR of initial lower cerebral rSO₂ values of 26% or less for ROSC and its 95% CI were calculated after adjustment for potential confounders, including age, sex, witness status, bystander CPR status, initial cardiac rhythm, prehospital advanced airway management, prehospital epinephrine administration, time from emergency call to ambulance arrival on the scene, and time from emergency call to hospital arrivals. All statistics were conducted using JMP Pro 10.0.2 (SAS institute, Inc, Cary, NC). All tests were 2-tailed, and P b .05 was regarded as statistically significant.

1. Results

During the study period, 71 adult OHCA patients had cerebral rSO₂ measured. Of these patients, 2 were excluded because of lack of blood pH or lactate measurements. Of the remaining 69 patients, we obtained both initial lower and higher cerebral rSO₂ values for 63

The data are expressed as n (%) of the population or the mean (SD) unless otherwise indicated. There was a significant difference in the proportion of witnessed patients (P = .0005), initial lower cerebral rSO₂ (P = .0002), initial average cerebral rSO₂ (P = .0141), and time from call to hospital arrival (P = .0402) between the 2 groups.

Initial lower cerebral rSO2	20.6 (10.1)	18.2 (6.8)	28.5 (14.7)	.0002
Initial higher cerebral rSO2	27.3 (17.1)	25.8 (17.0)	32.4 (16.9)	.1728
Initial average cerebral rSO2	23.9 (12.3)	22.0 (10.5)	30.5 (15.6)	.0141
Blood pH, mean (SD)	6.83 (0.17)	6.81 (0.18)	6.88 (0.14)	.1676
Lactate (mmol/L), mean (SD)	14.2 (4.9)	14.8 (4.4)	12.5 (6.1)	.1040
Call to scene arrival (m),	8.7 (6.5)	9.1 (7.1)	7.4 (3.8)	.3701
mean (SD)
Call to hospital arrival (m),	38.7 (11.7)	40.3 (12.3)	33.5 (7.5)	.0402
mean (SD)

patients (91.3%), and for 6 patients (8.7%), we obtained only 1 of 2 initial cerebral rSO₂ values (Fig.).

Table 1 shows the demographic characteristics of the cohort. Overall, the average patient age was 66.1 years. In addition, 48 patients (69.6%) were male, and 16 patients (23.2%) achieved ROSC. Patients who did not achieve ROSC were significantly less likely to have their event witnessed (32.1% vs 81.3%; P = .0005), had longer time from emergency call to hospital arrivals (40.3 vs 33.5 minutes, P = .0402), and had smaller initial lower cerebral rSO₂ values (18.2% vs 28.5%; P = .0002). There were no significant differences in the age,

69 Eligible for analysis

63 Obtained both initial lower and higher cerebral rSO₂ values 6 Obtained only one of two initial cerebral rSO₂ values

2 Excluded

(Blood pH or Lactate value unknown)

71 Consecutive adult OHCA patients whose initial cerebral rSO₂ were measured from October 1, 2012 to September 30, 2013

Fig. Study profile.

Table 2

Receiver operating characteristic curve analysis of non-ROSC prediction

	Cutoff	AUC (95% CI)	P	OR (95% CI)	Sensitivity (95% CI)	Specificity (95% CI)	PPV (95% CI)
Cerebral oxygen saturation
Initial lower cerebral rSO2	26.0%	0.714 (0.535-0.844)	.0033	10.07 (2.74-37.06)	88.7% (82.8-93.4)	56.3% (36.9-71.9)	87.0% (81.3-91.7)
Initial higher cerebral rSO2	28.0%	0.650 (0.488-0.784)	.1788	4.64 (1.42-15.14)	73.6% (67.3-78.8)	62.5% (41.6-79.8)	86.7% (79.2-92.8)
Initial average cerebral rSO2	23.0%	0.677 (0.506-0.811)	.0235	4.22 (1.30-13.68)	71.7% (65.4-79.9)	62.5% (41.5-79.9)	86.4% (78.7-92.7)
Blood pH	6.886	0.620 (0.459-0.759)	.1687	4.28 (1.29-14.21)	66.0% (59.6-70.9)	68.8% (47.4-84.9)	87.5% (79.0-93.9)
Lactate	8.2 mmol/L	0.627 (0.436-0.786)	.1081	7.35 (1.75-30.91)	92.5% (87.5-96.5)	37.5% (21.0-51.1)	83.1% (78.6-86.7)

The AUC was greater for the prediction of non-ROSC when initial lower cerebral rSO₂ values (0.714; P = .0033) were used than when other indicators were used. The optimal cutoff of initial lower cerebral rSO₂ was 26.0%. The OR of initial lower cerebral rSO₂ of 26% or less for not achieving ROSC was 10.07 (95% CI, 2.74-37.06).

sex, bystander CPR status, initial cardiac rhythm, prehospital advanced airway management, prehospital epinephrine administra- tion, time from call to scene arrival, blood pH, lactate value, and initial higher cerebral rSO₂ values between the 2 groups.

Table 2 shows the ROC analyses used to predict non-ROSC. The area under the curve (AUC) was greater for the prediction of non- ROSC when initial lower cerebral rSO₂ values (0.714; P = .0033) were used than when initial higher cerebral rSO₂ values (0.650; P =

.1788) or initial average cerebral rSO₂ values (0.677; P = .0235) were used. In addition, the AUC was greater than when blood pH (0.620; P = .1687) or lactate values (0.627; P = .1081) were used. The optimal cutoff of initial lower cerebral rSO₂ values was 26.0%. The use of an initial lower cerebral rSO₂ of 26.0% or less to predict non-ROSC had a sensitivity of 88.7%, a specificity of 56.3%, a positive predictive value (PPV) of 87.0%, and a negative predictive value (NPV) of 60.0%. The OR of an initial lower cerebral rSO₂ of 26.0% or less for not achieving ROSC was 10.07 (95% CI, 2.74-37.06).

Table 3 shows the results of the multivariate logistic regression analysis for ROSC. The presence of a witness was an independent factor associated with a better chance of achieving ROSC after OHCA (adjusted OR, 19.37; 95% CI, 2.86-213.04; P = .0017). Conversely, having an initial lower cerebral rSO₂ of 26% or less reduced the possibility of ROSC after OHCA after adjustment for potential confounders (adjusted OR, 0.11; 95% CI, 0.01-0.63; P = .0129).

1. Discussion

In this single-center prospective cohort study of OHCA patients whose cerebral rSO₂ values were measured, we found that initial lower cerebral rSO₂ as a static indicator may help predict the medical futility of resuscitation. The ROC analysis revealed that the initial lower cerebral rSO₂ more accurately identified patients with OHCA who could not achieve sustained ROSC than initial higher or average cerebral rSO₂. However, the AUC for initial lower cerebral rSO₂

regarding the prediction of non-ROSC was not always high enough to be used alone.

The rSO₂ values may vary depending on the measurement site because of the principles underlying its measurement, even if a patient is measured at the same time. Thus, it was unclear whether rSO₂ was available as a static indicator. In our study, 2 initial cerebral rSO₂ values of OHCA patients, which were measured at the same time just after arrival at the hospital, were classified as a higher value and a lower value. As a result, the initial higher cerebral rSO₂ value presented poor precision as a predictive indicator of non-ROSC and was inconvenient to use (AUC, 0.650; P = .1788), whereas the initial lower cerebral rSO₂ value could be used as a predictive indicator (AUC, 0.714; P = .0033). When there was a great difference between the initial higher and lower cerebral rSO₂ values, the higher value might have been directly affected by the composition of arteries just under the measurement site, and the lower value might reflect the saturation of the brain tissues more accurately.

Our study findings revealed that rSO₂ could be used as a static indicator for the prediction of ROSC by using the lower initial cerebral rSO₂ value.

However, the AUC was not sufficiently high, and the termination of resuscitation should not be determined based on initial lower cerebral rSO₂ values alone.

Actually, when the initial lower cerebral rSO₂ values are used as a criterion to judge the termination of resuscitation, it is more important that the specificity and PPV are high, rather than the use of sensitivity to predict non-ROSC. Although this examination was also performed after the cutoff value was changed (Table 4), the specificity and PPV achieved at most levels of 62.5% and 87.8%, respectively.

To use initial cerebral rSO₂ as a criterion to judge the futility of resuscitation, it is necessary for both the specificity and PPV to be almost 100%. Thus, the initial lower cerebral rSO₂ values should not be used alone. It may be necessary to use such values in combination with other indicators to predict non-ROSC.

Table 3

Return of spontaneous circulation-contributing factors after OHCA

Adjusted OR (95% CI) P

Table 4

Diagnostic accuracy of initial lower cerebral rSO₂ for non-ROSC by each cutoff

Age (for 1 increment of year) Sex (male) Witnessed	1.01 (0.95-1.07) 8.73 (0.88-159.57) 19.37 (2.86-213.04)	.8345 .0654 .0017	Cutoff	Sensitivity (95% CI)	Specificity	PPV (95% CI)	NPV (95% CI)
With bystander CPR	0.60 (0.08-4.01)	.5999	15.0%	66.0%	62.5%	85.4%	35.7%
Shockable initial rhythm	1.30 (0.12-14.06)	.8231		(59.7-71.4)	(41.4-80.1)	(77.1-92.2)	(23.6-45.8)
Prehospital advanced airway management	0.07 (0.01-1.01)	.0511	19.0%	81.1%	62.5%	87.8%	50.0%
(including supraglottic airway)				(74.9-86.2)	(42.0-79.2)	(81.1-93.2)	(33.6-63.4)
Prehospital epinephrine administration	0.20 (0.01-2.19)	.1962	26.0%	88.7%	56.3%	87.0%	60.0%
Call to scene arrival (for 1 increment of minute)	1.02 (0.77-1.26)	.8659		(82.8-93.4)	(36.9-71.9)	(81.3-91.7)	(39.4-76.7)
Call to hospital arrival (for 1 increment of minute)	0.99 (0.87-1.12)	.8978	36.0%	98.1%	31.3%	82.5%	83.3%
Initial lower cerebral rSO2 (<=26%)	0.11 (0.01-0.63)	.0129		(93.9-99.7)	(17.3-36.4)	(79.0-83.8)	(46.0-97.0)

(95% CI)

The presence of a witness was an independent factor associated with a better chance of achieving ROSC after OHCA (adjusted OR, 19.37; 95% CI, 2.86-213.04; P = .0017). On the other hand, having an initial lower cerebral rSO₂ of 26% or less reduced the possibility of ROSC after OHCA after adjustment for potential confounders (adjusted OR, 0.11; 95% CI, 0.01-0.63; P = .0129).

With respect to the diagnostic accuracy of initial lower cerebral rSO₂ for non-ROSC by each cutoff, the specificity of 62.5% was highest with a cutoff of 19.0% or less, and the PPV of 87.8% was highest with a cutoff of 19.0%.

50.0%	100.0%	12.5%	79.1%	100.0%
	(97.6-100.0)	(4.4-12.5)	(77.2-79.1)	(35.1-100.0)

This study has several limitations. First, we measured the initial cerebral rSO₂ value only at 2 sites. Considering that the higher value of the measurements in the 2 sites was not useful as a predictive indicator for prognosis, higher precision can be obtained when the lowest value of all of the values measured at more sites is used. Second, in this study, when the measurement value was obtained only from 1 of 2 sites, one of the values was considered as the numerical value of both the higher value and the lower value; this was observed in 6 (8.7%) of 69 patients, which might slightly distort the results. Third, among patient characteristics, underlying diseases were not taken into account. It is unknown whether the cerebral rSO₂ value is similarly available in patients with a history of organic brain disease. To overcome these limitations, it will be necessary to measure the initial cerebral rSO₂ value at several sites in future studies, taking the underlying diseases of OHCA patients into account. Fourth, this study was a single-center and small-scale study. These results may not be generalized to other hospital settings because of several potential biases in our hospital setting. Fifth, none of the clinical staff were blinded to the cerebral rSO₂ values and other clinical information collected. This may have affected their attitudes toward resuscitation efforts. Finally, as with all epidemiological studies, the data integrity, validity, and ascertainment bias are potential limitations. To minimize these potential sources of biases, a future larger scale, multicenter, blinded study is required.

1. Conclusions

Cerebral rSO₂ can be measured immediately and noninvasively just after arrival at the hospital and might be used as a static indicator for the prediction of non-ROSC when the initial lower value is used. However, cerebral rSO₂ alone does not result in a diagnosis performance that is sufficient for judging the futility of resuscitation. Thus, cerebral rSO₂ should be used in combination with other indicators.

Acknowledgments

The authors thank all of the EMS personnel and participating physicians and nurses at The University of Tokyo Hospital.

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