Study protocol for DICE trial: Video-assisted thoracoscopic surgery decortication versus interventional radiology guided chest tube insertion for the management of empyema.

BACKGROUND: Empyema is a common thoracic surgery presentation, defined as pus in the pleural space. Despite the commonality of empyema, consensus on initial management remains ambiguous. Two standard of care treatment options include inserting a chest tube (thoracostomy) and the administration of intrapleural fibrinolytics, or an initial surgical approach, surgical decortication. Due to the complexity of this pleural space infection, often repeat interventions are required after initial management in order to achieve source control and resolution of clinical symptoms. This study aims to identify the most effective initial management option for empyema. STUDY
DESIGN: We present a study protocol for a randomized control trial (RCT) comparing adult individuals with empyema to one of two standard of care initial management options. Participants will be randomized into either interventional radiology guided chest tube insertion with intrapleural fibrinolytics (Dornase 5 mg and Alteplase 10 mg intrapleural twice daily for three days) or video-assisted thoracoscopic surgery (VATS) decortication.
METHODS: All adults with empyema meeting inclusion criteria will be invited to participate. They will be randomized into one of two intervention groups; interventional radiology guided chest tube insertion with fibrinolytics or initial VATS decortication. Each intervention will take place within 48 hours of randomization. The primary outcome will be the rate of re-intervention within 30 days. Re-intervention is defined as repeat chest tube insertion, VATS decortication, or decortication via thoracotomy. Secondary outcomes include a change in the size of empyema, length of stay, morbidity, as well as 30-day and 90-day mortality, as well as quality of life measurements. ANTICIPATED IMPACT: This study is aimed at identifying the most effective initial management option for individuals with empyema. Crown

Background

Empyema is a common thoracic surgery presentation with approximately 6.7 cases per 100,000 population occurring annually in Ontario, Canada [1]. Traditional treatment methods first included chest tube insertion or thoracostomy to penetrate its thick fibrous peel and obtain source control. The addition of intrapleural fibrinolytics has been incorporated into empyema management based on the multi-centre intra-pleural sepsis trial (MIST 2). This was a randomized control trial (RCT) examining four separate treatment arms; double placebo, placebo combined with intrapleural DNAse (5 mg), intrapleural t-PA (10 mg) with placebo, and intrapleural t-PA (10 mg) combined with DNase (5 mg) for six doses over three days [2]. This study demonstrated a statistically significant difference in the reduction of pleural empyema in the t-PA and DNase combined arm (P = 0.005) when compared with all the other arms [2]. This RCT has established the combination of t-PA and DNase as the gold standard therapy for fibrinolytics in those presenting with empyema.

MIST 2 trial was revolutionary in standardizing fibrinolytic agents, their dosing and length of treatment to improve empyema resolution compared to thoracostomy alone. There are limitations, however, in extrapolating information from this trial and applying it to clinical use. For example, the method of chest tube insertion was not clarified (e.g. percutaneous, bedside, under image guidance), nor whether the insertion was standardized across all investigators [2]. Literature overwhelmingly suggests that image guided thoracostomy with ultrasound decreases the complication rate (pneumothorax, infection, procedure failure, intercostal bleeding), compared with a blind chest tube insertion [[3], [4], [5]]. Therefore, if such benefits genuinely exist, it would be advantageous to consider it the standard of care to have Interventional Radiologists, experts in image-guided procedures, perform thoracostomy for empyema to improve patient outcomes.

Surgical decortication is another commonly accepted standard of practice. This includes the removal of the thick fibrous peel of an empyema, suctioning of pus, wash out of the pleural space, and drain (chest tube) placement. Typically, this can be accomplished with a minimally invasive approach using small incisions through the rib spaces, called Video-Assisted Thoracoscopic Surgery (VATS). A review of the literature reveals few randomized controlled trials (RCTs) that compare thoracostomy combined with MIST 2 trial fibrinolytics to VATS decortication. A search of databases in OVID MedLine, PubMed, and Cochrane Systematic Reviews revealed only one adult RCT that compared VATS decortication to thoracostomy with fibrinolytics. Wait et al., in 1997 used a small study population of twenty patients in each arm, randomizing participants to either bedside thoracostomy with streptokinase or VATS decortication [6]. This study demonstrated that in adults with a fibrinopurulent effusion, VATS decortication was associated with an increased rate of empyema resolution and a shorter length of stay [6]. The trial does not use the updated MIST 2 trial recommendations to add Dornase to the fibrinolytic regime. With advances in radiological imaging, ultrasound and fluoroscopic guidance to aid chest tube insertion would have been beneficial. This study suggested a benefit via a surgical approach, but the practical limitations in the study's non-surgical arm suggest that further investigations are required.

Rationale and background of study aims

As we examine the treatment options for empyema, emerging evidence may suggest VATS decortication is superior to non-operative alternatives. A Cochrane Systematic Review of eight trials (6 pediatric and 2 adult) examining treatment methods for empyema provided evidence suggesting there were similar complication rates between VATS decortication and chest tube drainage (although this does not specify with or without fibrinolytics). At the same time, those receiving VATS had a decreased length of hospital stay [7]. In addition, a recent study from the United States using the New York State Inpatient Database examined 4095 patients with a diagnosis of empyema. It evaluated their treatment with respect to chest tube insertion, VATS decortication, or decortication via thoracotomy [8]. Patients who received a chest tube compared with those who underwent a surgical approach had higher mortality during their initial hospital stay (chest tube:15.4%, VATS:4.7%, open: 6.0%, p < 0.001) [8]. Patients' readmission rate within thirty days was also significantly higher for the chest tube group (6.1%) compared with the surgical group (VATS 1.9% and open: 2.1%, p < 0.001), lending support that an initial surgical approach for empyema may be warranted [8]. A study from Ontario, Canada, examined the current state of empyema management in the province [9]. This was a retrospective review of 9014 adults who were discharged from hospital with a diagnosis of empyema between 1996 and 2015. They were stratified into either non-operative management (chest tube with or without fibrinolytics) or operative (VATS or open decortication) [8]. In calculating adjusted risk ratios, those treated non-operatively had a higher mortality risk as an inpatient (17.2% vs. 10.6%; RRadj 1.32–1.54) at 30 days compared with an operative approach, lending support to potentially increased mortality as well [9].

To examine routine practise at our own institution, a retrospective chart review of a single thoracic surgeon experience was conducted. All individuals referred for empyema between 2017 and 2019 were evaluated, which totalled 46 patients. Of these, 74% (34) underwent initial chest tube insertion, 21.7% (10) underwent initial surgical management and 4.3% (2) underwent no intervention. Of those whom the primary intervention was a chest tube insertion, 23.5% (8) required repeat or additional chest tube insertion, 35.3% (12) required surgical intervention and 41.2% (14) required no additional intervention. Of the 10 individuals who underwent initial surgical management, none required repeat interventions. Both procedures were associated with a low mortality rate of 2.2% (3) in this cohort, where two individuals passed away from significant co-morbidities opting for palliation, and one as a consequence of complications from bedside chest tube insertion.

Hypothesis and aim of the study

We speculate that initial surgical management with VATS decortication will result in a decreased number of repeat interventions in treating empyema within 30 days, an important quality of life measurement.

Primary objective

To identify the initial management option, either IR guided chest tube insertion with MIST 2 Trial fibrinolytics or VATS decortication, that will provide the fewest repeat interventions within 30 days. Repeat intervention is defined as repeat chest tube insertion or surgical intervention (VATS decortication or thoracotomy) after the initial intervention.

Secondary objective

To identify the initial management option that is associated with the largest change in size of empyema (measured by the volume change calculated by the region of interest on Osirix®), the lowest number of complications (myocardial infarction, pulmonary embolus, deep vein thrombosis, respiratory failure, etc.), the lowest 30-day and 90-day mortality, as well as the shortest length of hospital stay. Osirix is an image processing application specifically designed to navigate, visualize and measure multimodal and multi-dimensional images with capabilities from 2D-5D.

Methods and analysis

Settings and participants

The study design will be a single centre RCT occurring at the Kingston Health Sciences Centre (KHSC). All adults with empyema that meet all inclusion criteria will be invited to participate (See Fig. 1).

Fig. 1

Participant selection and randomization.

Inclusion criteria

Clinical evidence of infection including a fever or elevated serum levels of inflammatory markers such as an elevated white-cell count or C-reactive protein

CT Chest suggesting the presence of empyema

Diagnostic thoracentesis values: pH < 7.2, macroscopically purulent fluid, positive on culture for bacterial infection, or positive for bacteria on gram staining

Ability to undergo general anesthesia

Ability to tolerate single lung ventilation

Exclusion criteria

Younger than 18 years of age

Previous treatment with intrapleural fibrinolytic agents, Dornase, or both for empyema

Known sensitivity to intrapleural fibrinolytic agent or DNase

Pregnancy

Symptoms for ≥6 weeks or with a pleural peel on CT chest of ≥15 mm

Rapidly fatal underlying illness: e.g. sepsis, rapid deterioration requiring intubation, requiring vasopressors for hemodynamic support etc.

Previous pneumonectomy on the infected side

Expected survival of less than 3 months due to a pathologic condition other than that responsible for the pleural abnormalities

Enrollment

Patients suspected of an empyema will undergo a CT Chest as well as a diagnostic thoracentesis to confirm an exudative effusion. Fluid analysis must meet the above inclusion criteria. All participants will undergo a repeat CT chest before chest tube removal or in the absence of clinical improvement. Reassessment for residual empyema with a repeat CT chest is the standard of practice at our institution. It provides an objective measurement of any residual empyema and determines if any further interventions are warranted. This is combined with the participants’ clinical presentation to determine the overall clinical improvement.

Randomization

Participants will be randomized using block randomization in groups of ten using an online calculator. The study team will not be blinded as the participants will be allocated to one of two intervention groups, IR guided chest tube insertion with intrapleural fibrinolytics (Dornase 5 mg and Alteplase 10 mg twice daily for three days) or VATS decortication. Each intervention will occur within 48 h of randomization.

Study outcomes

The primary outcome will be the rate of repeat intervention within 30 days, an important quality of life measurement for patients with empyema. Repeat intervention is defined as repeat chest tube insertion, surgical intervention in the form of either VATS decortication or thoracotomy after chest tube insertion with fibrinolytics, or repeat surgical intervention. To measure this outcome, participants will be monitored daily by the study team while in hospital and up to 6 weeks post intervention. Once discharged, the electronic medical record will be used to access patient information to obtain information on new radiographic interventions, visitations to the hospital, or re-admission. A 30-day follow up phone conversation from initial intervention will be completed by the study team to obtain any additional information from the participants. Patients will also be interviewed by the study team at their 6-week thoracic surgery follow up clinic appointment. Health related quality of life will be measured by applying the World Health Organization Disability Assessment Schedule (WHODAS), to assess for differences in six domains of functioning. This will be administered at the time of randomization, discharge and at the 6-week follow up appointment (Appendix 2).

The change of the size of empyema will be calculated by a chest radiologist. The size and location of the empyema will be measured in three planes on CT imaging, comparing the initial empyema size on admission to the empyema size on discharge using Osirix®.

All data on patient complications will be collected. The length of hospital stay will be measured by calculating the days and minutes using the electronic medical record to obtain the date and time of admission or transfer and discharge. Mortality data will be collected from the online electronic medical record.

Follow up data will be collected. This includes any patient concerns captured on thoracic surgery assessment forms, vital signs in outpatient surgery follow up, mortality within 30 and 90 days as well as the cause of death. Patient satisfaction with the study will also be determined by a telephone interview 30 days post-initial intervention. Additional follow up will be conducted up to 6 weeks to allow for the time for patients to complete their six-week course of antibiotics and to be seen in thoracic surgery clinic. If patients do not present for the follow up visit, they will be contacted via telephone to ensure they are recovering favorably.

All adverse events and mortalities will be reported to the Health Sciences Affiliated Teaching Hospitals Research Ethics Board (HSREB).

Sample size and calculation

The most recent study from North America examining the association between initial empyema treatment modality and rate of re-intervention was by Semenkovich et al. They outlined that out of 4095 patients in New York State undergoing admission for empyema, those who received thoracostomy for treatment of empyema had a 44% failure rate requiring either VATS or open decortication after the initial intervention. In contrast, only 15% of patients who received VATS as the initial intervention required re-intervention in the form of an open decortication [8]. Currently, there is no Canadian data that addresses this issue, and data from our own institution correlates closely with our neighboring state of New York. Thus, we calculate a sample size of 70 patients (35 per arm) is required to detect a statistically significant difference at a power of 80% and an alpha of 0.05. We do not anticipate any difficulty recruiting this number of patients given the population data we have presented for our own institution earlier.

Recruitment

All adults diagnosed with empyema and meeting inclusion criteria will be invited to participate in the trial. Referrals from other services such as respirology, internal medicine, or peripheral centres being transferred for thoracic surgery care will also be invited to participate. Informed consent will be obtained in person by a research nurse not directly participating in the care of the patient, in order to prevent undue coercion. All patients will be provided with a copy of the informed consent form, and a patient information sheet. A copy of the consent form will be kept in their research portfolio.

Data collection, confidentiality and archiving of documents

All data collection will be performed by members of the research team. A document will be placed on the participant's chart identifying them as a study participant. A signed hard copy of the consent form will be securely stored in a locked filing cabinet in the Department of Surgery at the Kingston Health Sciences Centre (KHSC).

All data collected will be stored in electronic form in an excel spreadsheet. This will be kept on a hospital network computer and will be both encrypted and password protected and kept locked in the Department of Surgery at KHSC.

A separate electronic excel sheet linking participant hospital healthcare number with a study number will be stored on a hospital network computer and will also be both encrypted and password protected. This will be kept on a hospital computer, encrypted and password protected that will be locked in the Department of Surgery at KHSC.

Data will be securely kept for 10 years and then destroyed by the study team.

Statistical analysis plans

Data will initially be analyzed descriptively, including means, standard deviations and range checks for continuous data, and frequencies and percentages for the categorical data. The continuous data will also be assessed for the normality of the underlying distribution using the Shapiro-Wilk test. Comparisons between the two treatment groups will be made with the two-tailed Student's t-test for continuous data, or the Mann-Whitney U test in the event of non-normal distributions. The Pearson Chi-square test or Fisher's Exact Test will be used to compare categorical data between the two groups.

Ethics

This clinical trial was approved by the Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (HSREB) on June 30, 2020. This trial is registered through ClinicalTrials.gov; Clinical Trials ID NCT03584113.

Discussion

Empyema is a common thoracic surgery presentation, yet its optimal initial management remains unknown. Traditionally, two initial interventions have been commonly accepted and include chest tube insertion with intrapleural fibrinolytics, or VATS decortication. The initial treatment is often largely dependent upon the service managing the patient and centre-specific practices. Data from New York, our neighboring state, as well as our own hospital would suggest that initial intervention with chest tube insertion and fibrinolytics often leads to multiple repeat interventions and potential increased morbidity compared with initial VATS decortication [8]. Additionally, population-based data from Ontario also lends support that a non-operative approach to empyema is associated with an increased risk of 30-day mortality compared with initial operative intervention [9]. While retrospective population-based studies have highlighted the importance of considering an initial operative approach to empyema, there have been no randomized control trials which have compared the interventions thus far.

This study is unique in that not only does it compare two acceptable intervention strategies, but also standardizes each group ensuring that regardless of allocation, each participant is receiving optimal care within 48 hours. We propose a modern and precise approach to chest tube insertion with intrapleural fibrinolytics involving IR image-guided chest tube placement. This method of chest tube insertion differs from a blind bedside insertion technique and aims to reduce technical variability and limits this potentially confounding variable between the two groups. The insertion technique has been standardized between all interventional radiologists (Appendix 1).

Similarly, VATS decortication surgery will be standardized amongst thoracic surgeons at our institution (Appendix 1). Each intervention will be ensured to occur within 48 hours of randomization, preventing any delays in definitive treatment. Since our patient population is similar to that of Semenkovich et al. (2018), we anticipate that participants randomized into the VATS decortication arm may experience fewer repeat interventions, decreased morbidity, and a reduction in overall mortality compared to the non-surgical arm.

Empyema can have a major impact on the quality of life of patients. Multiple interventions, lack of empyema resolution, poor clinical improvement and prolonged hospitalizations can negatively affect the domains of functioning outlined by the WHO (cognition, mobility, self-care, getting along, life activities, & participation) [10]. We specifically chose the number of repeat interventions as the primary outcome to highlight its importance as an objective quality of life measurement for patients suffering from empyema. While other secondary outcomes will also be examined including change in size of empyema, length of stay, morbidity and mortality; emphasis is placed on identifying the treatment option that improves patient experience. Using the WHODAS questionnaire at the time of randomization, at discharge, and at 6-week follow up will also provide an in-depth longitudinal overview of patient quality of life outcomes and allows for comparison of the two intervention groups throughout treatment. Study participants will be followed for a total of 6 weeks to assess for any immediate complications. Long-term follow up will be determined at the discretion of their attending thoracic surgeon.

Interventions for the treatment of empyema, like any procedure, is associated with some risk. Chest tube insertion involves the risk of bleeding, infection, and iatrogenic injury to surrounding structures including lung and even liver, spleen, and hollow viscus organs if the tube inadvertently enters the intra-abdominal cavity. On the other hand, surgical risks include general anesthetic risk and procedural risk. General anesthetic risk includes myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism, and respiratory failure. Procedural risk includes bleeding, infection, and iatrogenic injury to surrounding structures. In contrast to patients undergoing elective thoracic surgery where lung function tests are obtained pre-operatively, this is not feasible in the acute setting with empyema management which contributes to uncertainty regarding the patient's post-operative recovery and respiratory status. Although the surgical risks may seem more significant compared to non-operative management, it is anticipated that the morbidity associated with increased hospital stay and repeat interventions in the non-operative arm will likely surpass those in the surgical group. A recent prospective study examined sixty-six patients with early-stage empyema who were followed and divided into two groups. Group A (28 participants) were stage I (exudative) managed conservatively by respirologists. Group B consisted of 38 participants of both stage I (exudative) and stage II (fibrinopurulent) empyema that were managed by thoracic surgery [11]. Group A patients were treated with non-surgical modalities including thoracostomy and fibrinolytics [11]. Group B was treated with VATS decortication [9]. Mean hospital stay for group A was 22 days, with 10.7% major morbidity (pulmonary embolism, renal failure and CVA), along with a 7.1% mortality rate [11]. In Group B the mean hospital stay was 4.1 days, there were no mortalities and no major morbidities [11]. While it is difficult to make definitive conclusions on outcomes since interventions were stratified based on complexity of pleural collections, we hypothesise that initial VATS decortication will produce similar results decreasing overall morbidity. This study may potentially present the basis for recommendations to treat empyema with early surgical intervention.

Limitations

The main limitation to this RCT is that it is a single-centred study. Therefore, our results may not be generalizable to other centres, particularly if thoracic surgery or interventaional radiology is not readily available. Additionally, we recognize that institutions hold varying practices where not all image-guided chest tubes are placed by IR. We feel that any image-guided chest tube placement is likely more accurate than blind insertion, hence this study is still generalizable to other centres. We believe that the results obtained from this RCT may guide future clinicians managing empyema, providing a valuable future reference.

Conclusion

Empyema is a common disease where there is a dichotomy in the optimal initial management. We seek to determine the primary intervention, either IR guided thoracostomy with fibrinolytics or VATS decortication, that will result in the fewest repeat interventions within 30-days, and improve the quality of life for patients with empyema. We hypothesise that initial VATS decortication for empyema will be superior to IR guided chest tube insertion group with intrapleural fibrinolytics, presenting a shift in paradigm in empyema management.

CRediT Author Statement

Wiley Chung (Corresponding Author): Conceptualization, Methodology, Investigation, Writing-Review & Editing, Supervision, Project Administration

Erin Williams (Primary Author): Conceptualization, methodology, validation, formal analysis, investigation, resources, Data curation, writing-Original Draft, Writing-Review & Editing, Supervision, Visualization, Funding Acquisition, Project Administration

Nader Hanna: Investigation, Resources, Data curation, Writing-Review & Editing, Formal Analysis

Alex Menard: Investigation, Writing-Review & Editing, Supervision

Benedetto Mussari: Investigation, Writing-Review & Editing, Supervision

Reza Nasirzadeh: Investigation, Writing-Review & Editing, Supervision

Emidio Tarulli: Investigation, Writing-Review & Editing, Supervision

Nader Hanna: Investigation, Resources, Data curation, Writing-Review & Editing, Formal Analysis

Jennifer Pereira: Investigation, Resources, Data Curation, Writing-Review & Editing

Gurmohan “Rob” Dhillon: Investigation, Writing-Review & Editing, Supervision

Kenneth Reid: Investigation, Writing-Review & Editing, Supervision

Dimitri Petsikas: Investigation, Writing-Review & Editing, Supervision

Paul Heffernan: Writing-Review & Editing

Declaration of competing interest

The authors declare no competing interests. This clinical trial did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

In the past 30 days, how much difficulty did you have in:
Understanding and communicating
D1.1	Concentrating on doing something for 10 min?	None	Mild	Moderate	Severe	Extreme or cannot do
D1.2	Remembering to do important things?	None	Mild	Moderate	Severe	Extreme or cannot do
D1.3	Analysing and finding solutions to problems in day-to-day life?	None	Mild	Moderate	Severe	Extreme or cannot do
D1.4	Learning a new task, for example, learning how to get to a new place?	None	Mild	Moderate	Severe	Extreme or cannot do
D1.5	Generally understanding what people say?	None	Mild	Moderate	Severe	Extreme or cannot do
D1.6	Starting and maintaining a conversation?	None	Mild	Moderate	Severe	Extreme or cannot do
Getting around
D2.1	Standing for long periods such as 30 min?	None	Mild	Moderate	Severe	Extreme or cannot do
D2.2	Standing up from sitting down?	None	Mild	Moderate	Severe	Extreme or cannot do
D2.3	Moving around inside your home?	None	Mild	Moderate	Severe	Extreme or cannot do
D2.4	Getting out of your home?	None	Mild	Moderate	Severe	Extreme or cannot do
D2.5	Walking a long distance such as a kilometre [or equivalent]?	None	Mild	Moderate	Severe	Extreme or cannot do

In the past 30 days, how much difficulty did you have in:
Self-care
D3.1	Washing your whole body?	None	Mild	Moderate	Severe	Extreme or cannot do
D3.2	Getting dressed?	None	Mild	Moderate	Severe	Extreme or cannot do
D3.3	Eating?	None	Mild	Moderate	Severe	Extreme or cannot do
D3.4	Staying by yourself for a few days?	None	Mild	Moderate	Severe	Extreme or cannot do
Getting along with people
D4.1	Dealing with people you do not know?	None	Mild	Moderate	Severe	Extreme or cannot do
D4.2	Maintaining a friendship?	None	Mild	Moderate	Severe	Extreme or cannot do
D4.3	Getting along with people who are close to you?	None	Mild	Moderate	Severe	Extreme or cannot do
D4.4	Making new friends?	None	Mild	Moderate	Severe	Extreme or cannot do
D4.5	Sexual activities?	None	Mild	Moderate	Severe	Extreme or cannot do
Life activities
D5.1	Taking care of your household responsibilities?	None	Mild	Moderate	Severe	Extreme or cannot do
D5.2	Doing most important household tasks well?	None	Mild	Moderate	Severe	Extreme or cannot do
D5.3	Getting all the household work done that you needed to do?	None	Mild	Moderate	Severe	Extreme or cannot do
D5.4	Getting your household work done as quickly as needed?	None	Mild	Moderate	Severe	Extreme or cannot do

Because of your health condition, in the past 30 days, how much difficulty did you have in:
D5.5	Your day-to-day work/school?	None	Mild	Moderate		Severe		Extreme or cannot do
D5.6	Doing your most important work/school tasks well?	None	Mild	Moderate		Severe		Extreme or cannot do
D5.7	Getting all the work done that you need to do?	None	Mild	Moderate		Severe		Extreme or cannot do
D5.8	Getting your work done as quickly as needed?	None	Mild	Moderate		Severe		Extreme or cannot do
Participation in society
In the past 30 days:
D6.1	How much of a problem did you have in joining in community activities (for example, festivities, religious or other activities) in the same way as anyone else can?	None	Mild	Moderate	Severe		Extreme or cannot do
D6.2	How much of a problem did you have because of barriers or hindrances in the world around you?	None	Mild	Moderate	Severe		Extreme or cannot do
D6.3	How much of a problem did you have living with dignity because of the attitudes and actions of others?	None	Mild	Moderate	Severe		Extreme or cannot do
D6.4	How much time did you spend on your health condition, or its consequences?	None	Mild	Moderate	Severe		Extreme or cannot do
D6.5	How much have you been emotionally affected by your health condition?	None	Mild	Moderate	Severe		Extreme or cannot do
D6.6	How much has your health been a drain on the financial resources of you or your family?	None	Mild	Moderate	Severe		Extreme or cannot do
D6.7	How much of a problem did your family have because of your health problems?	None	Mild	Moderate	Severe		Extreme or cannot do
D6.8	How much of a problem did you have in doing things by yourself for relaxation or pleasure?	None	Mild	Moderate	Severe		Extreme or cannot do

H1	Overall, in the past 30 days, how many days were these difficulties present?	Record number of days
H2	In the past 30 days, for how many days were you totally unable to carry out your usual activities or work because of any health condition?	Record number of days
H3	In the past 30 days, not counting the days that you were totally unable, for how many days did you cut back or reduce your usual activities or work because of any health condition?	Record number of days