Abscess
Conditions
Keywords
Wound Irrigation
Brief summary
The purpose of this study was to evaluate the safety and effectiveness of Irrisept compared to standard of care treatment of skin and soft tissue infections in the form of abscesses.
Detailed description
After being informed about the trial and potential risks, subjects completed an informed consent form prior to participation. After eligibility criteria was verified, an initial wound assessment examination was performed. Subjects were then randomized to the Irrisept or Standard of Care treatment group. At intervals of 48 hours (up to 96 hours) later, abscesses were assessed until healing occurred. If the subject required antibiotics, this was recorded, as well as results from the wound and Methicillin-resistant Staphylococcus Aureus (MRSA) cultures.
Interventions
DEVICEStandard of Care (SoC)
SoC consisted of irrigation with normal saline, using the same proprietary abscess irrigation tip as the Irrisept arm. SoC was used at the initial visit and at each subsequent 48-hour visit interval (up to 96 hours) until abscess healing.
DEVICEIrrisept Delivery System
Irrisept is a manual, self-contained irrigation device capable of producing 7-8 psi of pressure for effective wound cleansing and irrigation. Irrisept contents include the Chlorhexidine Gluconate (CHG) solution, a 450 mL bottle, and Irriprobe applicator or an abscess irrigation tip. The bottle design allows users to control the pressure of the solution through manual bottle compression. The device had an option for use with an Irriprobe applicator or an abscess irrigation tip. Irrisept was used at the initial visit and at each subsequent 48-hour visit interval (up to 96 hours) until abscess healing.
Sponsors
Irrimax Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Intervention model description
The randomization methodology was controlled by the site.
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Immunocompetent individuals, 12 years of age or older with an uncomplicated abscess 1. Uncomplicated abscess is defined as ≤8 cm of induration (defined as firmness to touch) at the greatest diameter. 2. ≤4 cm of surrounding erythema (surrounding redness). 2. Defined area of central fluctuance may or may not be present. 3. Patient must be able to answer questions. 4. Patient must be medically stable as defined by the emergency department physician. 5. Patient must participate voluntarily in the study.
Exclusion criteria
1. Currently receiving antibiotics or received antibiotics within the last 72 hours. 2. Evidence of systemic infection (fever, aches, chills, nausea). 3. Requires admission to the hospital for infection or for any other reason(s). 4. Abscess caused by a human or animal bite. 5. Prior history of hypersensitivity or allergy to Chlorhexidine Gluconate (CHG). 6. Immunodeficiency (examples: HIV positive, Crohn's disease, systemic lupus erythematosus, Addison's disease, psoriasis, splenectomy, leukemia, cancer (on chemotherapy)). 7. Currently on any immune-modifying medication (examples - prednisone, antivirals). 8. History of chronic skin infection (3 or more in the past year). 9. Chronic medical problem (for example, end-stage heart, liver, kidney or lung disease, diabetes mellitus, peripheral vascular disease, history of organ transplant). 10. Mental illness, including but not limited to, substance abuse, dementia, schizophrenia or mentally handicapped or challenged. 11. Incarcerated. 12. Patient is pregnant or thinks she may be pregnant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Abscess Wound Healing Determined By Pain Score | Abscess wound healing, assessed by pain, was reviewed at baseline and the 48-hour visit. | Pain assessments were used to determine if the use of pressurized irrigation with Irrisept in uncomplicated abscesses improved wound healing when compared to pressurized irrigation with SoC (normal saline). Pain was assessed using a Visual Analogue Scale (VAS). The scale was measured in centimeters (cm) which ranged between 0 cm (no pain at the far left) to 9.5 cm (most severe pain at the far right). Subjects marked their pain rating on the scale with an X. The distance from the beginning of the scale (far left) to the X was measured in cm. The mean VAS score was assessed at baseline and at the 48-hour follow-up visit. The overall mean improvement was compared between the 2 arms using two-tailed t-tests. |
| Number of Subjects That Used Oral Antibiotics | 24, 48, 72 & 96-hour visit intervals | Oral antibiotic use was used to determine if the use of pressurized irrigation with Irrisept in uncomplicated abscesses improved wound healing when compared to pressurized irrigation with SoC (normal saline). |
| Abscess Wound Healing Determined By Wound Improvement Score | Abscess wound healing, assessed by wound improvement, was reviewed at the 48-hour visit. | Wound improvement assessments were used to determine if the use of pressurized irrigation with Irrisept in uncomplicated abscesses improved wound healing when compared to pressurized irrigation with SoC (normal saline). Wound improvement was assessed via a clinician's discretion, according to a 5-point Likert scale: 1 = clinically resolved, no signs of active infection; 2 = markedly improved, resolving infection and healing; 3 = improved with some remaining signs of active infection; 4 = unchanged, stable without signs of worsening clinical infection and; 5 = worsening conditions. The results are shown using a chi-squared test, as an average Likert score compared between the 2 arms. |
| Abscess Wound Healing Determined By Exudation Score | Abscess wound healing, assessed by exudation, was reviewed at baseline and the 48-hour visit. | Exudation assessments were used to determine if the use of pressurized irrigation with Irrisept in uncomplicated abscesses improved wound healing when compared to pressurized irrigation with SoC (normal saline). Exudation was assessed via a clinician's discretion, according to a 5-point Likert scale: 1 = none; 2 = scant; 3 = minimal; 4 = moderate and; 5 = copious. The results are shown using a chi-squared test to compare the means at baseline and 48-hours. A two-tailed t-test was conducted for the mean improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Oral Antibiotic Use Required Due To Fluctuance | The need for oral antibiotics, assessed by fluctuance, was reviewed at baseline and the 48-hour visit. | The presence of fluctuance was assessed to determine if the use of Irrisept reduced or eliminated the need for oral antibiotics in uncomplicated abscesses. Clinicians recorded whether fluctuance was present for each subject initially and after 48 hours. |
| Oral Antibiotic Use Required, Determined By Erythema Area Size | The need for oral antibiotics, assessed by erythema, was reviewed at baseline and the 48-hour visit. | Erythema was assessed to determine if the use of Irrisept reduced or eliminated the need for oral antibiotics in uncomplicated abscesses. The mean circumference of the erythema area, measured in centimeters (cm), was assessed at baseline and 48-hours later. This was performed by the clinician drawing a circle with a marker around the area of redness surrounding the abscess. Mean improvement was compared between the 2 arms using two-tailed t-tests. |
| Oral Antibiotic Use Required, Determined By Induration (Abscess Area Size) | 48-hours after baseline | Induration or abscess size was assessed to determine if the use of Irrisept reduced or eliminated the need for oral antibiotics in uncomplicated abscesses. The need for oral antibiotics, assessed by the mean induration or abscess size (measured in cm), was reviewed at baseline and the 48-hour visit. Mean improvement was compared between the 2 arms using two-tailed t-tests. |
| Oral Antibiotic Use Required Due To Warmth | The need for oral antibiotics, assessed by warmth, was reviewed at baseline and the 48-hour visit. | Warmth was assessed to determine if the use of Irrisept reduced or eliminated the need for oral antibiotics in uncomplicated abscesses. Clinicians recorded whether the abscess was warm for each subject initially and after 48 hours. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Oral Antibiotic Use Required Due To Results of MRSA/Wound Culture | 0 days | The tertiary objective was to determine if the use of pressurized irrigation with Irrisept in uncomplicated abscesses improved wound healing in patients that have MRSA-positive wounds compared to pressurized irrigation with normal saline. No data was collected towards this objective; thus, the success or failure of this endpoint was not assessed. To be compliant with the CT.gov template, although the information is incorrect and no data was captured this outcome, data was entered for Irrisept subjects. |
Countries
United States
Participant flow
Recruitment details
From January 2010 to November 2011, patients with skin and soft tissue infections, in the form of abscesses, were recruited from Shands Emergency Department at the University of Florida.
Pre-assignment details
The planned sample size was 107 subjects enrolled in each arm. However, during the study, the site rearranged their ED and no longer treated abscesses. As a result, the study was terminated early after enrolling 35 subjects. Of those, 19 were on SoC and 16 were on Irrisept. A total of 30 subjects completed the study, with 12 subjects on Irrisept and 18 on SoC. For the 5 subjects that did not complete the study, 4 were on Irrisept and 1 on SoC.
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care (SoC) For subjects randomized to the control group, Standard of Care (SoC) (normal saline) was used at the initial visit and at each subsequent 48-hour visit interval (up to 96 hours) until abscess healing. | 18 |
| Irrisept For subjects randomized to the investigational group, Irrisept was used at the initial visit and at each subsequent 48-hour visit interval (up to 96 hours) until abscess healing. | 12 |
| Total | 30 |
Baseline characteristics
| Characteristic | Standard of Care (SoC) | Irrisept | Total |
|---|---|---|---|
| Age, Categorical Age - Known <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Age - Known >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Age - Known Between 18 and 65 years | 18 Participants | 12 Participants | 30 Participants |
| Region of Enrollment United States | 18 participants | 12 participants | 30 participants |
| Sex/Gender, Customized Female | 9 Participants | 6 Participants | 15 Participants |
| Sex/Gender, Customized Male | 8 Participants | 7 Participants | 15 Participants |
| Sex/Gender, Customized Unknown | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 12 / 18 | 6 / 12 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Abscess Wound Healing Determined By Exudation Score
Exudation assessments were used to determine if the use of pressurized irrigation with Irrisept in uncomplicated abscesses improved wound healing when compared to pressurized irrigation with SoC (normal saline). Exudation was assessed via a clinician's discretion, according to a 5-point Likert scale: 1 = none; 2 = scant; 3 = minimal; 4 = moderate and; 5 = copious. The results are shown using a chi-squared test to compare the means at baseline and 48-hours. A two-tailed t-test was conducted for the mean improvement.
Time frame: Abscess wound healing, assessed by exudation, was reviewed at baseline and the 48-hour visit.
Population: 5 scale units were analyzed. These include: 1 = none; 2 = scant; 3 = minimal; 4 = moderate and; 5 = copious.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care (SoC) | Abscess Wound Healing Determined By Exudation Score | Baseline | 2.31 score on a scale | Standard Deviation 1.21 |
| Standard of Care (SoC) | Abscess Wound Healing Determined By Exudation Score | 48-Hour Follow-up Visit | 2.00 score on a scale | Standard Deviation 1 |
| Irrisept | Abscess Wound Healing Determined By Exudation Score | Baseline | 2.40 score on a scale | Standard Deviation 1.43 |
| Irrisept | Abscess Wound Healing Determined By Exudation Score | 48-Hour Follow-up Visit | 2.10 score on a scale | Standard Deviation 1.44 |
Primary
Abscess Wound Healing Determined By Pain Score
Pain assessments were used to determine if the use of pressurized irrigation with Irrisept in uncomplicated abscesses improved wound healing when compared to pressurized irrigation with SoC (normal saline). Pain was assessed using a Visual Analogue Scale (VAS). The scale was measured in centimeters (cm) which ranged between 0 cm (no pain at the far left) to 9.5 cm (most severe pain at the far right). Subjects marked their pain rating on the scale with an X. The distance from the beginning of the scale (far left) to the X was measured in cm. The mean VAS score was assessed at baseline and at the 48-hour follow-up visit. The overall mean improvement was compared between the 2 arms using two-tailed t-tests.
Time frame: Abscess wound healing, assessed by pain, was reviewed at baseline and the 48-hour visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care (SoC) | Abscess Wound Healing Determined By Pain Score | Baseline | 5.27 units on a scale | Standard Deviation 2.79 |
| Standard of Care (SoC) | Abscess Wound Healing Determined By Pain Score | 48-Hour Follow-up | 3.80 units on a scale | Standard Deviation 3.08 |
| Irrisept | Abscess Wound Healing Determined By Pain Score | Baseline | 6.33 units on a scale | Standard Deviation 2.42 |
| Irrisept | Abscess Wound Healing Determined By Pain Score | 48-Hour Follow-up | 3.91 units on a scale | Standard Deviation 3.3 |
Primary
Abscess Wound Healing Determined By Wound Improvement Score
Wound improvement assessments were used to determine if the use of pressurized irrigation with Irrisept in uncomplicated abscesses improved wound healing when compared to pressurized irrigation with SoC (normal saline). Wound improvement was assessed via a clinician's discretion, according to a 5-point Likert scale: 1 = clinically resolved, no signs of active infection; 2 = markedly improved, resolving infection and healing; 3 = improved with some remaining signs of active infection; 4 = unchanged, stable without signs of worsening clinical infection and; 5 = worsening conditions. The results are shown using a chi-squared test, as an average Likert score compared between the 2 arms.
Time frame: Abscess wound healing, assessed by wound improvement, was reviewed at the 48-hour visit.
Population: 5 scale units were analyzed. These include: 1 = clinically resolved, no signs of active infection; 2 = markedly improved, resolving infection and healing; 3 = improved with some remaining signs of active infection; 4 = unchanged, stable without signs of worsening clinical infection and; 5 = worsening conditions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care (SoC) | Abscess Wound Healing Determined By Wound Improvement Score | 2.88 score on a scale | Standard Deviation 0.93 |
| Irrisept | Abscess Wound Healing Determined By Wound Improvement Score | 2.50 score on a scale | Standard Deviation 0.62 |
Primary
Number of Subjects That Used Oral Antibiotics
Oral antibiotic use was used to determine if the use of pressurized irrigation with Irrisept in uncomplicated abscesses improved wound healing when compared to pressurized irrigation with SoC (normal saline).
Time frame: 24, 48, 72 & 96-hour visit intervals
Population: There were 4 timepoints for assessing abscess wound healing with the use of oral antibiotics: 24, 48, 72 \& 96 hours.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard of Care (SoC) | Number of Subjects That Used Oral Antibiotics | Number of Subjects Requiring Oral Antibiotics at 24-hour Follow-up | 1 participants |
| Standard of Care (SoC) | Number of Subjects That Used Oral Antibiotics | Number of Subjects Requiring Oral Antibiotics at 48-hour Follow-up | 2 participants |
| Standard of Care (SoC) | Number of Subjects That Used Oral Antibiotics | Number of Subjects Requiring Oral Antibiotics at Follow-up : 72-hour Follow-up | 1 participants |
| Standard of Care (SoC) | Number of Subjects That Used Oral Antibiotics | Number of Subjects Requiring Oral Antibiotics at Follow-up : 96-hour Follow-up | 0 participants |
| Irrisept | Number of Subjects That Used Oral Antibiotics | Number of Subjects Requiring Oral Antibiotics at Follow-up : 96-hour Follow-up | 1 participants |
| Irrisept | Number of Subjects That Used Oral Antibiotics | Number of Subjects Requiring Oral Antibiotics at 24-hour Follow-up | 0 participants |
| Irrisept | Number of Subjects That Used Oral Antibiotics | Number of Subjects Requiring Oral Antibiotics at Follow-up : 72-hour Follow-up | 0 participants |
| Irrisept | Number of Subjects That Used Oral Antibiotics | Number of Subjects Requiring Oral Antibiotics at 48-hour Follow-up | 1 participants |
Secondary
Oral Antibiotic Use Required, Determined By Erythema Area Size
Erythema was assessed to determine if the use of Irrisept reduced or eliminated the need for oral antibiotics in uncomplicated abscesses. The mean circumference of the erythema area, measured in centimeters (cm), was assessed at baseline and 48-hours later. This was performed by the clinician drawing a circle with a marker around the area of redness surrounding the abscess. Mean improvement was compared between the 2 arms using two-tailed t-tests.
Time frame: The need for oral antibiotics, assessed by erythema, was reviewed at baseline and the 48-hour visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care (SoC) | Oral Antibiotic Use Required, Determined By Erythema Area Size | Baseline | 4.01 centimeters (cm) | Standard Deviation 2.44 |
| Standard of Care (SoC) | Oral Antibiotic Use Required, Determined By Erythema Area Size | 48-hour Follow-up | 3.41 centimeters (cm) | Standard Deviation 4.85 |
| Irrisept | Oral Antibiotic Use Required, Determined By Erythema Area Size | Baseline | 3.25 centimeters (cm) | Standard Deviation 2.34 |
| Irrisept | Oral Antibiotic Use Required, Determined By Erythema Area Size | 48-hour Follow-up | 1.70 centimeters (cm) | Standard Deviation 1.27 |
Secondary
Oral Antibiotic Use Required, Determined By Induration (Abscess Area Size)
Induration or abscess size was assessed to determine if the use of Irrisept reduced or eliminated the need for oral antibiotics in uncomplicated abscesses. The need for oral antibiotics, assessed by the mean induration or abscess size (measured in cm), was reviewed at baseline and the 48-hour visit. Mean improvement was compared between the 2 arms using two-tailed t-tests.
Time frame: 48-hours after baseline
Population: Induration was assessed at baseline and the 48-hour follow-up visit. The length and width (in centimeters) of the abscess was used to measure the wound area (induration). For each subject, the difference in area between the two timepoints was used to find the mean improvement for both arms.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care (SoC) | Oral Antibiotic Use Required, Determined By Induration (Abscess Area Size) | Baseline | 12.263 centimeters (cm) | Standard Deviation 10.03 |
| Standard of Care (SoC) | Oral Antibiotic Use Required, Determined By Induration (Abscess Area Size) | 48-Hour Follow-up | 8.843 centimeters (cm) | Standard Deviation 8.53 |
| Irrisept | Oral Antibiotic Use Required, Determined By Induration (Abscess Area Size) | Baseline | 10.238 centimeters (cm) | Standard Deviation 8 |
| Irrisept | Oral Antibiotic Use Required, Determined By Induration (Abscess Area Size) | 48-Hour Follow-up | 5.875 centimeters (cm) | Standard Deviation 4.14 |
Secondary
Oral Antibiotic Use Required Due To Fluctuance
The presence of fluctuance was assessed to determine if the use of Irrisept reduced or eliminated the need for oral antibiotics in uncomplicated abscesses. Clinicians recorded whether fluctuance was present for each subject initially and after 48 hours.
Time frame: The need for oral antibiotics, assessed by fluctuance, was reviewed at baseline and the 48-hour visit.
Population: Fluctuance was assessed at baseline and the 48-hour follow-up visit. Chi-square tests for answers yes or no were run at the baseline and 48-hour follow-up visits.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Standard of Care (SoC) | Oral Antibiotic Use Required Due To Fluctuance | Baseline | No | 10 Participants |
| Standard of Care (SoC) | Oral Antibiotic Use Required Due To Fluctuance | Baseline | Yes | 8 Participants |
| Standard of Care (SoC) | Oral Antibiotic Use Required Due To Fluctuance | 48-hour Follow-up | Yes | 4 Participants |
| Standard of Care (SoC) | Oral Antibiotic Use Required Due To Fluctuance | 48-hour Follow-up | No | 14 Participants |
| Irrisept | Oral Antibiotic Use Required Due To Fluctuance | 48-hour Follow-up | No | 10 Participants |
| Irrisept | Oral Antibiotic Use Required Due To Fluctuance | Baseline | Yes | 5 Participants |
| Irrisept | Oral Antibiotic Use Required Due To Fluctuance | Baseline | No | 7 Participants |
| Irrisept | Oral Antibiotic Use Required Due To Fluctuance | 48-hour Follow-up | Yes | 2 Participants |
Secondary
Oral Antibiotic Use Required Due To Warmth
Warmth was assessed to determine if the use of Irrisept reduced or eliminated the need for oral antibiotics in uncomplicated abscesses. Clinicians recorded whether the abscess was warm for each subject initially and after 48 hours.
Time frame: The need for oral antibiotics, assessed by warmth, was reviewed at baseline and the 48-hour visit.
Population: Warmth was assessed at baseline and the 48-hour follow-up visit. Chi-square tests for answers yes or no were run at the baseline and 48-hour follow-up visits.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Standard of Care (SoC) | Oral Antibiotic Use Required Due To Warmth | Baseline | No | 4 Participants |
| Standard of Care (SoC) | Oral Antibiotic Use Required Due To Warmth | 48-Hour Follow-up | Yes | 9 Participants |
| Standard of Care (SoC) | Oral Antibiotic Use Required Due To Warmth | 48-Hour Follow-up | No | 9 Participants |
| Standard of Care (SoC) | Oral Antibiotic Use Required Due To Warmth | Baseline | Yes | 14 Participants |
| Irrisept | Oral Antibiotic Use Required Due To Warmth | Baseline | Yes | 8 Participants |
| Irrisept | Oral Antibiotic Use Required Due To Warmth | Baseline | No | 4 Participants |
| Irrisept | Oral Antibiotic Use Required Due To Warmth | 48-Hour Follow-up | No | 8 Participants |
| Irrisept | Oral Antibiotic Use Required Due To Warmth | 48-Hour Follow-up | Yes | 4 Participants |
Other Pre-specified
Oral Antibiotic Use Required Due To Results of MRSA/Wound Culture
The tertiary objective was to determine if the use of pressurized irrigation with Irrisept in uncomplicated abscesses improved wound healing in patients that have MRSA-positive wounds compared to pressurized irrigation with normal saline. No data was collected towards this objective; thus, the success or failure of this endpoint was not assessed. To be compliant with the CT.gov template, although the information is incorrect and no data was captured this outcome, data was entered for Irrisept subjects.
Time frame: 0 days
Population: 0
Post Hoc
Worsening Symptoms Causality
Causality for each worsening event was determined by using the following categories: 'related', 'possibly related', 'unlikely related', 'unrelated' or 'unknown'.
Time frame: Baseline and up to 48-hours later
Population: There was a total of 42 AEs for which causality assessments were made; 28 AEs were from subjects on SoC and 14 were from subjects on Irrisept.
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Standard of Care (SoC) | Worsening Symptoms Causality | Unlikely Related Worsening Symptom | 14 Total Number of Worsening Symptoms |
| Standard of Care (SoC) | Worsening Symptoms Causality | Possibly Related Worsening Symptom | 10 Total Number of Worsening Symptoms |
| Standard of Care (SoC) | Worsening Symptoms Causality | Unrelated Worsening Symptom | 3 Total Number of Worsening Symptoms |
| Standard of Care (SoC) | Worsening Symptoms Causality | Unknown Relation Worsening Symptom | 1 Total Number of Worsening Symptoms |
| Standard of Care (SoC) | Worsening Symptoms Causality | Related Worsening Symptom | 0 Total Number of Worsening Symptoms |
| Irrisept | Worsening Symptoms Causality | Unknown Relation Worsening Symptom | 0 Total Number of Worsening Symptoms |
| Irrisept | Worsening Symptoms Causality | Related Worsening Symptom | 0 Total Number of Worsening Symptoms |
| Irrisept | Worsening Symptoms Causality | Unrelated Worsening Symptom | 5 Total Number of Worsening Symptoms |
| Irrisept | Worsening Symptoms Causality | Possibly Related Worsening Symptom | 2 Total Number of Worsening Symptoms |
| Irrisept | Worsening Symptoms Causality | Unlikely Related Worsening Symptom | 7 Total Number of Worsening Symptoms |