Original Contribution

Sublingual tissue perfusion improves during emergency treatment of acute decompensated heart failure^?,??

Christopher J. Hogan MD ^a,b,c,?, Kevin R. Ward MD ^a,b, Douglas S. Franzen MD ^a,b,

Bipin Rajendran BS ^a, Leroy R. Thacker PhD ^d,e

^aDepartment of Emergency Medicine, Virginia Commonwealth University Medical Center,

Medical College of Virginia Campus, Richmond, VA 23298-0401, USA

^bVirginia Commonwealth University Reanimation Engineering Science Center (VCURES),

Virginia Commonwealth University Medical Center, Richmond, VA 23298-0401, USA

^cDepartment of Surgery, Division of Critical Care/Trauma, Virginia Commonwealth University Medical Center,

Medical College of Virginia Campus, Richmond, VA 23298-0401, USA

^dDepartment of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298-0401, USA

^eCenter for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298-0401, USA

Received 27 April 2011; revised 3 June 2011; accepted 5 June 2011

Abstract

Objectives: The aim of this study was to measure sublingual perfused capillary density (PCD) to assess sublingual microvascular perfusion during emergency department (ED) treatment of acute decompensated heart failure .

Methods: This prospective, observational study enrolled ED patients with ADHF, measuring pre- and post-ED treatment PCD. Sidestream dark-field imaging was analyzed by 3 investigators blinded to patient identifiers and time points. Patient demographics, ADHF etiology, serum brain natriuretic peptide, and hemoglobin were measured along with a Visual analogue scale (VAS), which assessed patient baseline characteristics and response to ED treatment. A paired t test analyzed changes in PCD, mean arterial pressure (MAP), and patient assessment. Interrater variability was assessed with an intraclass correlation coefficient , with a P value b.05 considered significant for all testing.

Results: Thirty-six patients were enrolled with a mean time between pretreatment and posttreatment PCD (+-SD) of 138 +- 59 minutes and a hospital length of stay of 4.0 +- 4.1 days. During this time, PCD increased (difference, 1.3 mm/mm²; 95% confidence interval, 0.4-2.1; P = .004), as did the MAP (P = .002), patient VAS score (P b .001), and observer VAS score (P b .001). There was no correlation between the change in PCD and time (R² = .016, P = .47), MAP (R² = .013, P = .54), or VAS scores. The ICC was 0.954.

Conclusions: Sublingual tissue perfusion is diminished in ADHF but increases with treatment. It may represent a quantitative way to evaluate ADHF in the ED setting.

(C) 2012

^? This study was supported by a General Clinical Research Center Clinical Research Feasibility Fund (NCRR, NIH M01 RR00065).

^?? Preliminary parts of this study were presented in abstract form at the American Heart Association Resuscitation Research Symposium on November 12, 2010, in Chicago, IL. C.J.H. received an AHA Young Investigator Award for the presented abstract.

* Corresponding author. Department of Emergency Medicine, Department of Surgery, Division of Critical Care/Trauma, Virginia Commonwealth

University Medical Center, P.O. Box 980401, Richmond, VA 23238-0401, USA. Tel.: +1 804 828 5250; fax: +1 804 828 4994.

E-mail address: chogan@mcvh-vcu.edu (C.J. Hogan).

0735-6757/$ – see front matter (C) 2012 doi:10.1016/j.ajem.2011.06.005

Introduction

Acute decompensated heart failure accounts for over 1,000,000 emergency department (ED) visits annually, which results in a high rate of inpatient admission [1]. The ED diagnosis of ADHF centers on global assessment of cardiac function, namely, serum B-type Natriuretic Peptide measurement, physical examination, and chest radiographs, all of which have limitations [2-5].

One evolving concept is to approach heart failure from a tissue perfusion perspective, viewing the disease as a state of chronic hypoperfusion that is exacerbated in the acutely decompensated state. Previous studies assessing heart failure with global tissue Perfusion parameters (cardiac index and systemic oxygen delivery) demonstrated impaired systemic oxygen delivery [6] and utilization [7]. Sidestream dark-field imaging differs from this earlier perfusion work in ADHF because it measures perfusion on a regional microvascular level through quantitative analysis of perfused capillary den- sity (PCD), as opposed to a more global assessment. It is a noninvasive technology that has been shown to estimate heart failure severity [8] and Treatment response [9] in severe dis- ease and cardiogenic shock. Approaching ADHF in the ED setting from a regional microvascular perfusion perspective has not previously been reported, although the technology has been used in the ED sepsis population [10]. This study mea- sured PCD to assess the behavior of microvascular perfusion during ED treatment of ADHF as a potential objective means to evaluate the course of treatment.

Methods

This was an observational, prospective study that enrolled patients from October 2006 to January 2009. The study protocol was approved by our medical center’s Institutional Review Board, and written informed consent was obtained from all patients or their legally authorized representative before enrollment.

Patients were a random sample taken from those presenting to an urban ED that has an annual census of 75,000 patients. Patients presenting with complaints sugges- tive of ADHF were approached for enrollment after being screened by research personnel when the monitor cart was available. Inclusion criteria were designed to identify pa- tients who had a high likelihood of having isolated ADHF [11-13], namely, a serum BNP measurement greater than 100 ng/mL measured with an ADVIA Centaur BNP Assay (Bayer, Leverkusen, Germany) and a score of 8 or higher on the Boston Heart Failure Criteria (see Appendix 1) once the subject was evaluated by the ED attending physician and the chest radiograph was reviewed. The Boston Criteria was chosen because it can be applied in a uniform manner and has been previously validated [14,15].

Exclusion criteria limited factors that could alter micro- vascular flow dynamics: hypothermia (oral temperature

b35?C) or hyperthermia (oral temperature N38?C), a history or physical evidence of severe peripheral vascular disease, the presence of sepsis, hemorrhagic shock, or those who received ADHF treatment before enrollment.

Patients underwent PCD measurement with a MicroScan imaging system (MicroVision Medical, Amsterdam, The Netherlands), which recorded digital images of sublingual microcirculatory blood flow using technology that illumi- nates the tissue of interest with green light (540-550 nm), allowing erythrocytes within tissue arteries, arterioles, venules, and capillaries to be visualized (Fig. 1).

For each patient encounter, 2 separate, 20-second video sequences were recorded on the mucosal surface of the sublingual tissue and later analyzed by 3 independent scorers after the sequences were stripped of specific patient and time identifiers. Images were obtained in multiple areas of the sublingual tissue and were not recorded unless elimination of secretions, minimal tissue compression, adequate focus, and optimal contrast adjustment could be obtained. Repeat PCD measurements were made 2 hours after the initial assessment. PCD was calculated by measuring the total length of perfused capillaries divided by the image area. Capillaries were considered perfused if they had sluggish, continuous, or hyperdynamic flow by visual inspection. For purposes of analysis, capillaries were defined as vessels less than or equal to a width of 20 um based on previous studies utilizing sidestream dark-field imaging technology [8,9]. Each scorer independently identified and scored two 2- to 5-second steady-state segments using a semiautomated computer image analysis program (AVA 3.0, MicroVision Medical) that has been previously validated [9,16]. PCD values from each monitoring session were averaged for each scorer. For

final analysis, the average of the 3 scores was used.

Bedside mean arterial pressure (MAP) and both serum hemoglobin and BNP measurements were recorded during each imaging session. Medical history, including hyperten- sion, coronary artery disease, diabetes mellitus, and

Fig. 1 Sidestream dark-field imaging in ADHF, ranging from larger venules and arterioles to smaller capillaries in which single- file erythrocytes move through sublingual tissue.

hypercholesterolemia, were recorded for analysis along with Patient sex, age, and ethnicity. The heart failure etiology and ejection fraction (EF), if done, were determined from pre- vious records or subsequent inpatient workup. As patients underwent ED treatment, the medication class used and route of delivery were recorded for later analysis.

To evaluate ADHF severity in a uniform quantitative manner that reflects current clinical practice, 2 visual ana- logue scale (VAS) assessments were administered during each monitoring session (Appendix 2). The first part of the VAS asked patients to rate their present degree of dyspnea and level of activity using a 100-mm scale (0 mm, no dif- ficulty; 100 mm, severe dyspnea or decreased activity). The second part of the VAS was completed by the researcher administering the assessment to record how diaphoretic and dyspneic the subject appeared, using a 100-mm scale (0, no obvious distress; 100, severe dyspnea or diaphoresis). When possible, the same observer was used for all VAS admin- istrations for that specific subject.

Measurements

PCD (mm/mm²) was reported as an absolute number with median and 25th and 75th interquartile ranges (IQRs). Con- tinuous data, such as patient age, PCD, serum BNP (ng/dL), and hemoglobin (g/dL), were reported as means +- SD if found to be normally distributed; otherwise, median and IQR were reported. A medical record review after discharge pro- vided the ED length of stay, length of hospitalization, and death within 6 months of discharge.

Data analysis

For continuous data, normal distribution was determined by analysis with quantile plotting. To determine if PCD changed during ED treatment, the pretreatment and post- treatment values were analyzed with a paired Student t test (JMP version 8.0; SAS, Cary, NC), as was MAP. The VAS pretreatment and posttreatment scores were analyzed as ordinal data with Wilcoxon sign rank analysis (JMP version 8.0, SAS). To determine if changes in PCD correlated with changes in MAP, the length of time to reassessment, or change in VAS scores, logistic regression compared change in PCD to the pretreatment and postTreatment changes in these respective parameters (JMP version 8.0, SAS).

Reliability of PCD scores for the mean of k raters was assessed using Shrout and Fleiss’s [17] ICC(2,k), an intraclass correlation coefficient (ICC) that measures the reliability of the k ratings, assuming that all subjects are rated by same k raters who are assumed to be a random subset of all possible raters. An ICC N 0.9 was considered as excellent reliability, 0.8-0.9 as good reliability, and 0.7-0.8 as modest reliability (SAS version 9.2, SAS). A P b .05 was considered statistically significant for all tests.

Sample size calculations were based on previous data describing PCD in ADHF [18] suggesting a change of

2 mm/mm² was clinically significant and on data demon- strating an SD of 3.5 [19]. Thirty-six patients would be required for 90% power for a 2-sided test with an ? of .05.

Results

Sixty-seven patients were screened for enrollment, but 7 declined participation and 17 received EMS or ED treat- ment before enrollment. Enrollment continued until 36 patients met the discharge criteria and had complete data. Of the 43 patients enrolled, 2 were discharged with a diagnosis other than ADHF and 5 had incomplete data, leaving 36 patients for data analysis (Table 1 and Appendix 3). The 6-month mortality was 13%.

The time between the pretreatment and posttreatment PCD measurements was 138 +- 59 minutes, whereas the hospital length of stay once admitted was 4.0 +- 4.1 days. Patients underwent treatment with diuretics (89.9%), angio- tensin-converting enzyme inhibitors (5.4%), inotropes (16.2%), digoxin (2.7%) as well as with topical (70.0%),

intravenous (10.0%), and sublingual (20.0%) nitroglycerin. The mean pretreatment and posttreatment PCD (Fig. 2), MAP, as well as the patient- and observer-based VAS scores were normally distributed. ICC(2,k) for PCD was 0.954, indicating there was excellent reliability for raters’ PCD scores. PCD (Figs. 3 and 4) increased between the pretreat- ment and posttreatment measurements (P = .004), with a

2.5

	Table 1 Patient demographics
	Age (y), mean +- SD	61.2 +- 12.1
	Sex, n (%)
	Female	14 (39)
	Male	22 (61)
	Race, n (%)
Black		32 (89)
Hispanic		1 (3)
White		3 (8)
	ADHF etiology, n (%)
Hypertension		15 (41.3)
Ischemic		14 (38.9)
Pulmonary hypertension		4 (11.2)
Valvular		1 (2.9)
Unknown		2 (5.7)
ADHF classification, n (%)
Preserved LV function		6 (16.7)
Reduced LV function		30 (83.3)
	EF (%) (n = 34), mean +- SD Comorbidities, n (%)	30.2 +- 14.5
Diabetes mellitus		9 (25.7)
Hypertension		34 (97.1)
Coronary artery disease		20 (57.1)
Hypercholesterolemia		24 (68.6)
	Hemoglobin (g/dL), mean +- SD BNP (ng/dL), mean +- SD	12.0 +- 1.8 1530.9 +- 139

0.020

0.018

0.016

0.014

0.012

0.010

0.008

0.006

0.0225

0.02

0.0175

0.015

0.0125

0.01

0.0075

We also observed microvascular perfusion increased after ED treatment, a finding consistent with previous studies that measured PCD before, during, and after cardiogenic shock treatment. Nitroglycerin, in particular, has been shown to improve perfusion in the ADHF population [9,16], most likely due to its mediation of nitric oxide in endothelial dysfunction. PCD values we measured improved as patients received standard of care ADHF treatment, namely, diuretics, nitrates, and inotropes [13], and were monitored over a reasonable period for these interventions to take effect. Although there was variation in the follow-up assessment time, reassessment

time did not correlate with changes in PCD.

Symptomatic heart failure occurs from the combination of

Fig. 2 The pretreatment and posttreatment PCD measurement distributions, with the median denoted by the horizontal bar, and the 25th and 75th IQRs represented by the lower and upper boundaries of the rectangle, respectively.

difference of 1.32 m/mm² (95% confidence interval [CI], 0.4-2.1). The patient and observer VAS values decreased over this period (P b .001 for both), as did MAP (P = .002) (Table 2). The change in PCD (Figs. 5 and 6) did not correlate with changes in MAP (R² = .01, P = .54), time (R² = .02, P = .47), patient-scored VAS (R² = .09, P = .09),

or observer-scored VAS (R² = .04, P = .26) (Fig. 7A and B).

Discussion

With the exception of serum BNP, current ADHF assess- ment in the ED setting is still based on global parameters such as: physical examination findings, vital signs, chest radiographs, urine output, and Patient symptoms. These have moderate to poor accuracy in determining ADHF severity and response to treatment [2,4,20,21]. Serum BNP also has been studied for its ability to guide treatment with lackluster results [22]. Although ED-specific clinical decision rules have been developed [12], they still rely on global param- eters that are not fully refined [23].

It is in the ED setting that a quantitative ADHF assessor would prove most useful, as initiation of treatment early in the ADHF presentation has been found to impact outcomes [24-26], but modalities such as echocardiography or pul- monary artery catheters are not usually available. The eval- uation and treatment rendered in the ED has been found to impact the overall length of stay and costs as well [27].

As in previous studies evaluating severe heart failure and cardiogenic shock [8,28], we demonstrated diminished sublingual microvascular perfusion in ADHF patients. This is the first study to examine the ED population, which often represents a wide range of heart failure severity, ranging from mild fluid overload resulting in an observation unit short stay to fulminate cardiogenic shock requiring an ICU admission. This differs from previous studies that have investigated PCD in patients with more severe disease or cardiogenic shock in the intensive care unit setting [29].

diminished cardiac output, Peripheral vasoconstriction, fluid overload, and endothelial dysfunction, all of which make it a difficult and complex disease to evaluate and treat. Traditional assessors of disease severity focus on the former 3 processes from a global perspective, delineating clinical assessment into profiles based on evidence of congestion and hypoperfusion [30], which has not proven to be a reliable indicator of ADHF severity in advanced disease [31]. There is limited clinical data on endothelial dysfunction in ADHF [32,33], most likely from a lack of bedside assessors that could assess the behavior of the microvasculature. Our finding that an increased PCD did not correlate with the decreases in the VAS scores suggests that changes in the regional micro- vasculature may not be reflected in global assessment param- eters such as dyspnea or diaphoresis. Since global assessment is known to have poor accuracy in ADHF assessment, PCD may be a better assessor of disease severity and response to treatment despite not correlating with the current clinical parameters. Because these global assessors are currently the only clinical means to assess ADHF and its response to treatment, determining if PCD truly reflects disease severity and response to treatment may prove challenging. This study will help in the design of these future studies.

Sidestream dark-field imaging first made its debut in the trauma [34] and sepsis [35] populations, with limited use in the cardiogenic shock population [8]. This early work was limited by a lack of uniform measurement and reporting characteristics, as well as the cumbersome process of recording and analyzing the images. Since then, a consensus

Pre- and Post-Treatment PCD in the ED Treatment of ADHF

16

15

PCD (mm/mm2)

14

13

12

11

10

Pre-Treatment Post-Treatment

P = .004

Fig. 3 Pretreatment and posttreatment PCD with SE in patients undergoing ED treatment of ADHF. The change from pretreatment to posttreatment PCD is shown for each patient.

Pre- and Post-Treatment Capillary Perfused Density in ADHF

HF0048 HF0051

HF0052 HF0054

HF0055 HF0056 HF0057 HF0058

HF0060

HF0065

HF0061

HF0067

HF0071

HF0078 HF0082 HF0108 HF0109

HF0119 HF0121 HF0122 HF0123 HF0126 HF0129 HF0131 HF0132 HF0133 HF0143 HF0146 HF0149 HF0150 HF0151 HF0153 HF0154 HF0155

HF0156

HF0157

0.023

0.021

0.019

0.017

0.015

PCD (mm/mm2)

0.013

0.011

0.009

0.007

0.005

Pre-Treatment Post-Treatment

Fig. 4 The change from pretreatment to posttreatment PCD for each patient undergoing ED treatment of ADHF.

has emerged on how best to obtain, report and interpret sidestream darkfield imaging (SDI) data [36], and computer software has become available that has accelerated analysis [37]. Both of these advances have been incorporated into our analysis, in which 3 investigators independently selected images, isolated vessels less than 20 um, determined the absence or presence erythrocyte flow, and then used the imaging software to generate a PCD score while demon- strating excellent reproducibility.

PCD values in both the pretreatment and posttreatment periods (12.8 and 14.1 mm/mm², respectively) were lower than those found in the non-ADHF population, which had an average PCD of 14.8 mm/mm² [2,38]. Based on correlation analysis, the behavior of PCD appeared to be statistically

Table 2 Pretreatment and posttreatment values for PCD, MAP, and the patient- and observer-based VAS

independent of MAP, but overall, as MAP decreased between pretreatment and posttreatment, PCD increased. This increase in PCD may have resulted from decreased afterload, decreased endothelial dysfunction, or increased vessel dilation known to occur with ADHF treatment.

As opposed to peripheral circulation that may be subject to vasoconstriction, the sublingual PCD is of particular in- terest because it may represent blood flow in the central splanchnic region given that the tongue shares a common embryogenic origin with the gut and that previous studies have reported good correlation between sublingual and gastric mucosal carbon dioxide pressures [39]. More recent work in the cardiogenic shock and severe ADHF population has demonstrated significant alterations in microvascular

Pretreatment (+-SD)		Posttreatment (+-SD)	Difference (+-95% CI)	Significance
PCD (mm/mm2)	12.8 +- 3.8	14.1 +- 3.6	1.3 (0.4-2.1)	.004 a
MAP (mm Hg)	104.7 +- 24.2	97.0 +- 16.7	12.3 (6.5-18.1)	.002 a
Patient VAS (mm)	122.4 +- 45.3	34.5 +- 33.7	86.5 (68.0-105.1)	b.001 a
Observer VAS (mm)	60.0 +- 40.7	17.6 +- 26.5	35.0 (20.4-49.6)	b.001 a
a Statistically significant.

0.008 0.008

A

0.006 0.006

0.004 0.004

0.002 0.002

Delta PCD

Delta SDI

0 0

-0.002 -0.002

-0.004 -0.004

-0.006

50 100 150 200 250

ED Time (min)

-0.006

0.008

-150 -100 -50 0 50

Delta PT VAS

Fig. 5 Bivariate fit (R² = .016, P = .47) of change from pre- treatment and posttreatment PCD (?PCD) by time between measurements (ED time).

0.006

B

0.004

perfusion, and more importantly, these values appear to change with afterload reduction [9,16]. Our study is the first to examine the application of microvascular tissue perfusion measurement to the ED population, who often are evaluated and treated based on global assessment alone. SDI may represent a bedside technology that holds promise to assist clinicians in tailoring therapy to the individual.

Limitations

0.002

0

Delta SDI

-0.002

-0.004

-0.006

-100 -50 0 50

Delta OBS VAS

Although we argue that physical examination, chest radiographs, and patient symptoms are less than ideal assessors of ADHF, these markers are the currently the only guides clinically available. In our subject population,

Fig. 7 Bivariate fits of the (A) patient-scored VAS score (PT VAS, R² = .09, P = .09) and (B) observer-scored VAS score (?OBS VAS, R² = .04, P = .26) versus the change in PCD (?SDI) over the treatment period.

0.008

0.006

0.004

0.002

Delta PCD

0

-0.002

-0.004

-0.006

-20 -10 0 10 20 30 40 50

Delta MAP

we used the VAS to assess patient response to treatment and subjective physical examination findings to provide a quantitative measure, as has been used previously in the ADHF population [15], and found an improvement in patient symptoms during treatment. However, there is the possibility of measurement bias in each patient measuring their own VAS if each individual assessed their complaints differently. Our study was not designed to detect this phenomenon.

Another significant limitation was the lack of control over the ADHF treatment. This limited our ability to draw con- clusions about the effects of specific medications, although the overall effect of ED treatment demonstrated a significant improvement in PCD. However, sublingual nitroglycerin, which may have caused local vasodilation where PCD was measured, may have affected our results and is a limitation of this study. Future studies will investigate ADHF medica- tions, specifically nitroglycerin, to address thus limitation.

Fig. 6 Bivariate fit (R² = 0.013, P = .54) of change from pre- treatment and posttreatment PCD (?PCD) by pretreatment and posttreatment MAP measurements (?MAP).

Nitroglycerin also is of great interest because it has pre- viously been shown to improve microvascular perfusion in the cardiogenic shock population [9].

Our sample size calculations were based on a difference of 2 mm/mm², but the actual difference was 1.3 mm/mm². This may limit the validity of our conclusions, although the 95% CI around the mean difference demonstrated adequate significance. Because of the inner-city urban location of our medical center, the majority of patients were African American. This may matter because differences in response to various Medication classes among race has been previously reported [40], and we did not control for racial differences to account for this potential confounder. Because African Americans have a 53% higher ED visit rate for ADHF compared with whites but a 13% lower hospitalization rate [41], this technology may be particularly helpful in this subgroup of ADHF patients if found to be a predictor of which patients needs more aggressive treatment or hospital admission. Because the Boston heart failure criteria were validated in predominantly white heart failure patients [14] and our population was overwhelmingly African American, the accuracy of this scoring system may be limited. However, only 2 patients were excluded from the study because of an initial inaccurate heart failure diagnosis,

making the inclusion criteria we employed fairly accurate.

Although most parameters were measured during the monitoring period or hospitalization after enrollment, some EF values used in analysis were found upon chart review, values that were weeks or months old. We only used this measure to determine the etiology of ADHF. However, in the elapsed time between the lAST measurement and enrollment, it is possible that the EF may have significantly changed. Future studies will allow for a dedicated determination of EF and possibly other echocardiography parameters such as cardiac power.

Lastly, enrolling only 44 patients over 2 years may suggest selection bias. However, the SDI monitor was often in use by other concurrent studies that were applying this technology to other disease entities, limiting our ability to enroll on a regular basis. The lack of the monitor cart availability also impacted our 2-hour reassessments in some patients.

Conclusions

Sublingual tissue perfusion, as measured by PCD, is de- creased in ED patients with Acutely decompensated heart failure but increases after treatment. Measuring sublingual PCD has greater ease than previous technologies, and may represent a quantitative way to evaluate ADHF in the ED setting.

Appendix 1. Boston Inclusion Criteria

1

Dyspnea while climbing stairs

• Physical examination findings

Total Heart rate

1

2

If 91 to 110 beats per minute

If more than 110 beats per minute

Jugular venous distention

1. N6 cm H₂O
2. N6 cm H₂O plus hepatomegaly or edema

Chest examination

1. Basilar crackles
2. If crackles ascultated more than basilar
3. Wheezing

3 Third heart sound Total

• Chest radiograph 4 findings

3

3

3

2

Alveolar pulmonary edema

Interstitial pulmonary edema

Bilateral pleural effusion Cardiothoracic ratio greater than 0.50

Upper zone flow redistribution

Total

Grand total:

Note: Only a maximum of 4 points from each category allowed.

Appendix 2. Subject VAS

Patient: Please mark on the following scale how you feel: 1. Patient-reported dyspnea 0 mm 100 mm

“I can breath as I normally do” “I cannot breath at all” 2. Patient-reported level of activity 0 mm 100 mm

“I can move around as I “I am short of breath just normally do” sitting here” Observer: Rate the following observations: 3. Observer-reported dyspnea 0 mm 100 mm

No respiratory distress Needs intubation 4. Observer-reported diaphoresis 0 mm 100 mm

Skin is dry Dripping with sweat

Patient history	4	Dyspnea at rest
	4	Orthopnea
	3	Paroxysmal nocturnal
		dyspnea
	2	Dyspnea while walking
		on level area

Appendix 3. Individual characteristics of patients

Patient	EF (%)	Pre-Tx OBS VAS	Post-Tx OBS VAS	Pre-Tx PT VAS	Post-Tx PT VAS	Pre-Tx PCD	Post-Tx PCD	Died	Medications received
HF0048	17	86	32	123	14	12.6	18.2	N	NTG, FUR
HF0051	40	112	3	139	19	17.5	15.3	N	NTG, FUR, NAT
HF0052	20	–	–	–	–	7.1	8.2	N	NTG, FUR
HF0054	20	36	2	122	4	9.6	12.6	N	FUR
HF0055	35	84	4	162	37	7.3	9.0	N	NTG
HF0056	10	14	2	165	25	9.6	9.0	N	NTG, FUR
HF0057	–	–	–	–	–	8.4	10.4	N	FUR
HF0058	10	56	4	138	17	6.8	8.0	N	NTG, FUR, NAT
HF0060	35	139	19	108	16	6.5	10.0	N	NTG, DIG
HF0061	20	159	150	172	180	9.4	10.7	N	DOB, FUR
HF0065	25	61	65	164	57	10.9	13.3	N	FUR
HF0067	25	54	2	164	55	10.3	12.1	N	NTG, FUR
HF0071	15	14	38	72	88	12.2	12.4	N	NTG, FUR, NAT
HF0078	15	99	–	146	20	14.8	18.7	Y	FUR
HF0082	35	39	4	96	25	16.8	14.6	N	NTG, FUR
HF0108	30	8	6	63	9	12.8	14.5	N	FUR
HF0109	16	28	8	157	32	17.7	13.1	N	NTG, FUR, ACEI
HF0119	40	65	3	120	4	16.8	14.5	N	FUR
HF0121	59	62	56	120	27	17.8	18.9	N	NTG, FUR
HF0122	30	59	24	136	118	15.9	18.3	N	NTG, FUR
HF0123	35	35	17	110	34	16.0	19.4	N	NTG, FUR
HF0126	20	102	–	151	–	15.4	18.3	Y	FUR
HF0129	25	97	3	18	3	14.1	11.9	N	NTG, FUR, ACEI
HF0131	40	72	2	141	53	16.4	16.5	N	NTG
HF0132	60	99	43	111	118	10.3	13.5	N	NTG, FUR
HF0133	25	23	18	90	0	14.4	21.2	N	FUR
HF0143	60	97	120	0	0	13.0	15.5	N	NTG, FUR
HF0146	25	4	17	134	31	14.5	13.3	N	FUR
HF0149	25	13	0	59	28	16.3	17.9	N	FUR
HF0150	50	6	1	129	1	6.9	14.3	N	FUR
HF0151	60	9	12	174	16	13.0	12.7	N	FUR
HF0153	–	–	–	26	–	13.8	13.9	N	FUR, DOB
HF0154	40	59	4	101	96	15.2	15.7	Y	–
HF0155	15	96	–	180	–	10.7	11.5	Y	DOB
HF0156	20	76	1	149	73	12.8	12.0	N	NTG, FUR
HF0157	30	17	0	43	1	18.6	18.2	N	NTG, FUR
EF, pretreatment and posttreatment observer (Pre-TX OBS VAS and Post-Tx OBS VAS, respectively), pretreatment and posttreatment patient (Pre-TX PT VAS and Post-Tx PT VAS, respectively), pretreatment and post treatment PCD (Pre-Tx PCD and Post-Tx PCD, respectively), and mortality are listed. For medications received, nitroglycerin (NTG), furosemide (FUR), natrecor (NAT), digoxin (DIG), dobutamine (DOB), and angiotensin-converting enzyme inhibitor (ACEI) are listed.

References

1. Hugli O, Braun JE, Kim S, Pelletier AJ, Camargo J, Carlos A. United States emergency department visits for acute decompensated heart failure, 1992 to 2001. Am J Cardiol 2005;96:1537-42.
2. Collins SP, Lindsell CJ, Storrow AB, Abraham WT, ADHERE Scientific Advisory Committee, Investigators and Study Group. Prevalence of negative chest radiography results in the emergency department patient with decompensated heart failure. Ann Emerg Med 2006;47:13-8.
3. Collins SP, Ronan-Bentle S, Storrow AB. Diagnostic and prognostic usefulness of Natriuretic peptides in emergency department patients with dyspnea. Ann Emerg Med 2003;41:532-45.
4. Chang AM, Maisel AS, Hollander JE. Diagnosis of heart failure. Heart Fail Clin. 2009;5:25-35, vi.
5. Gheorghiade M, Follath F, Ponikowski P, et al. Assessing and grading congestion in acute heart failure: a scientific statement from the Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine. Eur J Heart Fail 2010;12:423-33.
6. Rady M, Jafry S, Rivers E, Alexander M. Characterization of systemic oxygen transport in end-stage chronic congestive heart failure. Am Heart J 1994;128:774-81.
7. Rocca HP, Weilenmann D, Follath F, et al. Oxygen uptake kinetics during low level exercise in patients with heart failure: relation to neurohormones, peak oxygen consumption, and clinical findings. Heart 1999;81:121-7.
8. De Backer D, Creteur J, Dubois MJ, Sakr Y, Vincent JL. Microvas- cular alterations in patients with acute severe heart failure and cardiogenic shock. Am Heart J 2004;147:91-9.
9. den Uil CA, Caliskan K, Lagrand WK, et al. Dose-dependent benefit of nitroglycerin on microcirculation of patients with severe heart failure. Intensive Care Med 2009;35:1893-9.
10. Trzeciak S, McCoy JV, Phillip Dellinger R, et al. Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med 2008;34:2210-7.
11. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American college of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and lung transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112:e154-235.
12. Lindsell CJ, Storrow AB, Peacock WF, Collins SP. A clinical pre- diction rule for an emergency department diagnosis of acute decom- pensated heart failure. Ann Emerg Med 2006;48:88.
13. Silvers SM, Howell JM, Kosowsky JM, Rokos IC, Jagoda AS. American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Ann Emerg Med 2007;49:627-69.
14. Di Bari M, Pozzi C, Cavallini MC, et al. The diagnosis of heart failure in the community. Comparative validation of four sets of criteria in unselected older adults: the ICARe Dicomano Study. J Am Coll Cardiol 2004;44:1601-8.
15. Nazerian P, Vanni S, Zanobetti M, et al. Diagnostic accuracy of emergency Doppler echocardiography for identification of acute left ventricular heart failure in patients with acute dyspnea: comparison with Boston Criteria and N-terminal prohormone brain natriuretic peptide. Acad Emerg Med 2010;17:18-26.
16. Den C, Lagrand W, Van der Ent M, Visser C, Spronk P. Effect of Intravenous nitroglycerin on the sublingual microcirculation in patients admitted to the intensive cardaic care unit. Critical Care 2008;12:S24.
17. Shrout P, Fleiss J. Intra-class correlations: uses in assessing rater reliability. Psychol Bull 1979;86:420-8.
18. Den C, Lagrand W, Klijn E, Visser C, Spronk PE, Simoons ML. Relationship between the sublingual microcirculation and lactate levels in patients with heart failure. Critical Care 2008;12:S24.
19. Hogan C, Ward K, Hess M. Microvascular tissue perfusion in stable versus decompensated heart failure. Acad Emerg Med 2005;12:56.
20. Ander DS, Jaggi M, Rivers E, et al. Undetected cardiogenic shock in patients with congestive heart failure presenting to the emergency department. Am J Cardiol 1998;82:888-91.
21. Teerlink JR. Dyspnea as an end point in clinical trials of therapies for acute decompensated heart failure. Am Heart J 2003;145:S26-33.
22. Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs standard medical therapy in Elderly Patients with Congestive Heart Failure (TIME- CHF) randomized trial. JAMA 2009;301:383-92.
23. Mebazaa A, Pang PS, Tavares M, et al. The impact of early Standard therapy on dyspnoea in patients with acute heart failure: the URGENT- dyspnoea study. Eur Heart J 2010;31:832-41.
24. Peacock WF, Fonarow GC, Emerman CL, Mills RM, Wynne J. Impact of early initiation of intravenous therapy for acute decompensated heart failure on outcomes in ADHERE. Cardiology 2007;107:44-51.
25. Maisel AS, Peacock WF, McMullin N, et al. Timing of immunore- active B-type natriuretic peptide levels and treatment delay in acute decompensated heart failure: an ADHERE (Acute Decompensated Heart Failure National Registry) analysis. J Am Coll Cardiol 2008;52: 534-40.
26. Peacock WF, Maisel AS, Jessie R, Fonarow G. Does time to IV diuretic matter in the emergency treatment of acute decompensated heart failure? Ann Emerg Med 2007;50:S75.
27. Rutten JHW, Steyerberg EW, Boomsma F, et al. N-terminal pro-brain natriuretic peptide testing in the emergency department: beneficial effects on hospitalization, costs, and outcome. Am Heart J 2008;156: 71-7.
28. den Uil CA, Lagrand WK, van der Ent M, et al. Impaired micro- circulation predicts poor outcome of patients with acute myocardial infarction complicated by cardiogenic shock. Eur Heart J 2010;31: 3032-9.
29. Boerma EC, Koopmans M, Konijn A, et al. Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict Resuscitation protocol: a double-blind randomized placebo controlled trial. Crit Care Med 2010;38:93-100.
30. Nohria A, Tsang SW, Fang JC, et al. Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admitted with heart failure. J Am Coll Cardiol 2003;41:1797-804.
31. Shah M, Ali V, Lamba S, Abraham WT. Pathophysiology and clinical spectrum of Acute congestive heart failure. Rev Cardiovasc Med 2001;2(Suppl 2):S2-6.
32. Sharma R, Davidoff MN. Oxidative stress and endothelial dysfunction in heart failure. Congest Heart Fail 2002;8:165-72.
33. Dixon LJ, Morgan DR, Hughes SM, et al. Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure. Circulation 2003;107:1725-8.
34. Ward KR, Tiba MH, Ryan KL, et al. Oxygen transport characterization of a human model of progressive hemorrhage. Resuscitation 2010: 987-93.
35. Trzeciak S, Rivers EP. Clinical manifestations of disordered micro- circulatory perfusion in severe sepsis. Crit Care 2005;9(Suppl 4): S20-6.
36. De Backer D, Hollenberg S, Boerma C, et al. How to evaluate the microcirculation: report of a round table conference. Crit Care 2007; 11:R101.
37. Dobbe JG, Streekstra GJ, Atasever B, van Zijderveld R, Ince C. Measurement of functional microcirculatory geometry and velocity distributions using automated image analysis. Med Biol Eng Comput 2008;46:659-70.
38. Hogan CJ, Ward KR, Kontos MJ, Franzen DR. Microvascular perfusion is significantly decreased in both stable and decompensated heart failure. AHA/Resuscitation Science Symposium. Chicago, IL, November 12; 2010.
39. Klijn E, Den Uil CA, Bakker J, Ince C. The heterogeneity of the microcirculation in critical illness. Clin Chest Med. 2008;29:643- 54, viii.
40. Yancy CW. Heart failure in African Americans: unique etiology and pharmacologic treatment responses. J Natl Med Assoc 2003;95:1-9 [quiz 10-2].
41. Green GB. Heart failure and the emergency department: epidemiology, characteristics, and outcomes. Heart Fail Clin. 2009;5:1-7, v.