Clinical trial NCT04143776: Renal- and Pulmonary Function in Relation to Abdominal Hypertension After Abdominal Reconstruction
Official title: Renal- and Pulmonary Function in Relation to Abdominal Hypertension After Abdominal Reconstruction: The REPARE-study
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: Hernia, Ventral
Hernia Incisional
Acute Kidney Injury
Restrictive Lung Disease
Intraabdominal Hypertension
Keywords: hernia
abdominal reconstruction
intraabdominal pressure
acute kidney injury
restrictive lung disease
Lead sponsor: Bispebjerg Hospital
Sponsor class: OTHER
First posted: 2019-10-29
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients diagnosed with medium to giant incisional hernia undergoing planned open incisional hernia repair.

Brief summary: An incisional hernia is technically challenging to operate and is the most frequent long-term complication after open surgery, resulting in impaired quality of life and reduced physical ability. Large hernias contain large amounts of abdominal volume, which similarly are missing from the abdominal cavity. Due to adaptations of the abdominal wall muscles and decreased space in the abdominal cavity, abdominal wall reconstruction lead to increased tension and thereby increased intraabdominal pressure.

Reduced renal and lung function after surgery is one of the leading causes of prolonged hospitalization, increased costs and mortality. Elevated intraabdominal pressure is a known risk factor for kidney injury, but relationships between hernia surgery, increased intraabdominal pressure, renal and lung function are still unclear.

Therefore, in patients undergoing surgery for incisional hernia, we will investigate the extent and consequences of elevated intraabdominal pressure, as well as its relation to renal injury and reduced lung function. We will also investigate the relationship between hernia dimensions and the development of increased intraabdominal pressure, as well as identifying patients at particular risk of developing elevated intraabdominal pressure.

From April 2020 to October 2021, we will include 100 patients at Bispebjerg Hospital, Denmark, diagnosed with medium to giant incisional hernia, who will undergo scheduled surgery. Patients are followed from before to 30 days after surgery. They will be examined with CT scans before and after surgery. Blood tests, pulmonary function tests and measurement intraabdominal pressure will be performed before and until 3 days after surgery. Thirty days after surgery, lung function tests and blood tests are repeated at a final examination at the out-patient clinic. During follow-up, differences in hospital stay, complications, reoperations, and mortality will be investigated.

Participation in the project is not associated with any side effects and risks. The study is expected great scientific gain, as the results can help identify particularly vulnerable patients in need of extended observation and treatment. The results obtained by the project are sought to be published in relevant scientific journals and conferences. The project is expected to extend over a 3-year period, which will include commissioning, data collection, analytical processing, dissemination of results and conduction of PhD thesis.

Detailed description: Introduction Incisional hernia is the most common long-term complication following abdominal surgery with an estimated incidence of 10.3% within 24 months. Large incisional hernias are associated with patient discomfort, reduced quality of life and are surgically challenging with increased risks of postoperative complications. Constant contraction of the lateral abdominal wall muscles may cause displacement of a greater proportion of the abdominal contents through the hernia defect, thereby reducing volume in the abdominal cavity (loss of domain).

Abdominal wall reconstruction in patients with loss of domain may lead to increased abdominal pressure with pressures persistently being measured above 12 mm Hg. Abdominal hypertension results in direct compression on intraabdominal vessels, which can result in oedema, reduced cardiac output and hypoxia due to hypoperfusion and reduced venous return. If intraabdominal pressures exceeds 20 mm Hg abdominal compartment syndrome occurs, leading to multiorgan failure.

Intraabdominal hypertension is additionally a known risk factor in development of acute kidney injury (AKI). A pooled incidence of AKI is estimated to 13.4% after major abdominal surgery. Development of AKI is independently recognized to be associated to increased mortality, length of stay and costs in hospitalized patients. Patients with AKI are at increased risk of developing acute coronary syndrome, heart failure and infection. Additionally, patients developing AKI after general surgery are estimated to have an eight-fold increased risk of 30-day mortality. Thus, treatment of AKI is vital, complex and time-consuming.

Intraabdominal pressures above 16 mm Hg lead to pulmonary parenchymal compression, resulting in alveolar atelectasis, pulmonary infection, decreased oxygen transport across the pulmonary capillary and decreased carbon dioxide excretion. Furthermore, elevated intraabdominal pressure to the diaphragmatic pleura may hamper diaphragmatic movement, resulting in restricted respiratory compliance with reduced forced vital capacity (FVC) but retained ratio of the forced expiratory volume within 1 second above FVC (FEV1/FVC). This condition is comparable with restrictive lung disorders.

It is possible to limit postoperative acute kidney injury and respiratory complications following intermittent intraabdominal hypertension using decompressive treatment and fluid therapy. Elevated intraabdominal pressure may ideally be limited with additional surgical procedures. However, there are few reports the relationship between abdominal wall reconstruction, intraabdominal hypertension, renal- and pulmonary function. In addition, predictive factors regarding patient characteristics, hernia dimensions and surgical procedures are still unclear. In the preoperative evaluation prior to abdominal wall reconstruction, it is important to know risks and consequences of elevated abdominal pressure. Furthermore, it is important to identify patients needing close monitoring, additional decompressing management or prophylactic surgical procedures in order to decrease costs, morbidity and mortality.

In three reports, this study evaluates intraabdominal pressure after abdominal reconstruction and its relationship to renal- and pulmonary function.

Materials and methods This is a prospective observational single-center cohort study scheduled to start in April 2020. In total, 100 patients diagnosed with medium to giant incisional hernia will be included at the surgical out-patient clinic after written and oral informed consent behind closed doors at Bispebjerg Hospital. Study follow-up is 30 days after surgery. Participants will stay admitted at the surgical department at least 3 days after surgery and subsequently discharged after sufficient postoperative recovery. All participants are invited at the out-patient clinic at postoperative day (POD) 30 for a final evaluation and data collection.

Upon inclusion, following patient characteristics are collected for all participants through a case report form:

* Age
* Gender
* Smoking status
* Height
* Weight
* ASA score
* Charlson comorbidity index
* Hernia age
* Chronic obstructive pulmonary disease
* Chronic kidney disease
* Planned procedure for abdominal reconstruction
* Number of previous abdominal operations
* Use of abdominal binder

All participants will undergo preoperative CT scans of abdomen and thorax with maximized inspiration as a part of the standardized hernia protocol with collection of following data:

* Calculated lung area in frontal plane
* Site of incisional hernia
* Maximal horizontal fascial defect
* Maximal vertical fascial defect
* Hernia volume
* Abdominal volume An additional postoperative CT scan of abdomen and thorax with maximized inspiration are performed at POD 30 to estimate changes in abdominal volume and lung area.

Additionally, preoperative venous blood samples are collected and analysed for:

* Leucocytes
* C-reactive protein
* Creatinine
* Urea
* Potassium
* Sodium
* Estimated glomerular filtration rate

On POD 1, 2, 3 and 30 venous blood samples are collected and monitored for above mentioned parameters.

In all participants, a standardized bladder catheter will be placed prior surgery and maintained until POD 3. Intraabdominal pressure is indirectly measured through the bladder pressure by use of the UnoMeter™ Abdo-Pressure™ IAP monitoring system (ConvaTec Denmark A/S). This is a precise, reproducible and validated method of monitoring the intraabdominal pressure. In accordance with recommendations from previous studies, a zero reference point is marked on the patient in the midaxillary line at the iliac crest. At each measurement the patient is placed in neutral position. No restrictions will be set on the surgical procedure or postoperative treatment. The use of component separation technique or botulinum toxin A injections will be noted. The intraabdominal pressure is measured prior surgery, after extubation, on POD 1, 2 and 3. Urine output and fluid balance are monitored at POD 1, 2 and 3.

Pulmonary function test is performed using Spirobank II Basic Spirometer. FVC and FEV1 is measured upon inclusion, on POD 1, 2, 3 and 30. Severity of pulmonary restriction is graded according to guidelines set by The American Thoracic Society. During general anaesthesia, changes in the inspiratory bronchial peak pressure (IBPP) will be monitored before and after primary fascial closure with Primus® anaesthesia workstation (Dräger Denmark A/S).

AKI is defined by guidelines set by the KDIGO AKI Guideline Work Group, including any of two following:

* increase in S-creatinine by ≥0.30 mg/dl (≥26.5 μmol/l) within 48 hours, or
* increase in S-creatinine to ≥1.5 times baseline, known or assumed to have occurred within 7 days
* decrease in urine output \<0.5 ml/kg//hour for 6 hours.

Furthermore, AKI severity is staged according to following criteria:

1. S-creatinine 1.5 to 1.9 times baseline or ≥0.3 mg/dl (≥26.5 μmol/l) increase or urine output \<0.5 ml/kg//hour for 6 hours to 12 hours.
2. S-creatinine 2.0 to 2.9 times baseline or urine output \<0.5 ml/kg//hour for ≥12 hours.

3 S-creatinine 3.0 times baseline or increase to ≥4.0 mg/dl (≥353.6 μmol/l) or urine output \<0.3 ml/kg//hour for ≥24 hours or anuria for ≥12 hours.

An epidural catheter will be placed preoperatively and maintained until POD 3. In case of inability to place an epidural catheter, bilateral transversus block will be applied. Anaesthesia will be induced using propofol, remifentanil and suxamethonium. Due to the short-lived action of suxamethonium, residual relaxation when surgery starts is absent. This will be verified using the Train-Of-Four standard muscle stimulation-relaxation evaluation.

At follow-up, following data is registered for each participant:

* Length of hospital stay
* Postoperative complications according to the Clavien-Dindo classification
* Need for intubation or treatment at the intensive care unit
* Occurrence of death within 30 days

Statistical considerations A pilot study of 30 patients underwent abdominal reconstruction for incisional hernia with pre- and postoperative measurement of intraabdominal pressure. In this study, abdominal hypertension of grade 1 or higher was found in 70% of the patients. A statistical power calculation shows that at least 88 patients must be included at an expected incidence of 70%, confidence interval of 95%, spread of +/- 10% at a selected type 1 error level of 5%. It is known that the incidence of lung complications after surgery for incisional hernia is 20% and that the incidence of AKI is 1,4%. Based on the above, it is expected that inclusion of 100 patients will be able to show clinically significant causal relationships between intraabdominal hypertension, AKI, and pulmonary complications. This is done by univariate Chi-Square test and multivariable logistic regression analysis, adjusted for the relevant confounders. In addition, associations between changes in creatinine and urea will be correlated to intraabdominal pressure by linear regression analysis, as will the results of lung function tests and volume determinations by CT scan to examine correlation to changes in intraabdominal pressure.

Side effects, risks and disadvantages Placement of a bladder catheter for measurement of intraabdominal pressure is a part of the standardized hernia protocol. The bladder catheter is usually removed on POD 1, but will instead be maintained until POD 3. This is considered to be associated with a small risk of catheter-associated urinary tract infection, which will be treated according to national guidelines. Measurement of intraabdominal pressure is safe and not associated with any additional risk. On POD 1-3, venous blood samples will be drawn from each participant. This is associated with little to no pain and a considerable small risk of a small haematoma. Study participants undergo one additional CT scans within the study period. The participants are thus subjected to extra ionizing radiation. The effective participant dose is approximately 2.6 mSv per scan. By this, participants are subjected to radiation at a level which is estimated to increase the life-time risk of radiation-induced cancer by less than 0.01%. This is not considered clinically relevant. There are no other side effects, risks and disadvantages associated with participation in the study.

Respect for physical and mental integrity as well privacy This is a public research study which is reported through the regional joint notification to the Danish Data Protection agency. Information about participants is protected via the law on handling of personal information and the Danish health Act. Information about previous surgery, concurrent diseases and contact information is passed from the participants' medical charts. This information will be used to identify possible study participants. After study completion, no more information is gathered from the patient's medical chart. In case of need for further information, Sinor Soltanizadeh can contact the participant after the study is finalized. This study has been reported to the Danish National Data Protection Agency.

Economy Study initiator and primary investigator Sinor Soltanizadeh does not receive any other financial support than the salary paid by departments of which he is working full-time. The study is not company sponsored. Sinor Soltanizadeh is not associated with private sources of funding with interests in the study. No financial support is expected for this study, as the study will be departmentally funded. If support is given, the Ethical Committee of the Capital Region (RegionH) will be notified and study material including patient information will be updated.

Remuneration and other services Remuneration and other services are not paid to study participants.

Information accessibility Further information about the study is available to participants by direct inquiry to Sinor Soltanizadeh by telephone or e-mail.

Publication of results Results - positive, negative or inconclusive - will be published in relevant scientific peer-review journals, as well as presented to relevant scientific conferences. In case publication in a journal is not achieved, results will be publicly available via http://www.clinicaltrials.gov/.

Research ethics outline The overall aim of this study is to estimate the incidence of AKI and pulmonary impairment, and investigate consequences thereof in patients undergoing abdominal reconstruction. Additionally, to determine prognostic factors of developing AKI and pulmonary impairment. The participants will contribute to understanding the development AKI and pulmonary impairment. It is clinically relevant to minimize the risk of AKI, and knowledge gained from present study will help to understand preventive measures in certain patients. Participants are expected to gain from this study by a more thorough monitoring of their renal function and pulmonary function and gain access to earlier necessary treatment.

Participation in this study is considered to be associated to minimal risks and side effects. The autonomy as well as the integrity of the participant is not compromised in any way by participating in the study.

In conclusion, this study is considered to be in concordance with ethical standards, as the possible gain from participation exceeds the risks associated.

Recruitment of participants Patients are recruited at the out-patient clinic of Bispebjerg Hospital at the time of first contact. In case a patient fulfils in- and exclusion criteria, they are informed about the study and given oral and written participant information. Patients will be informed of their right to have an assessor present at the time of information. The information will be given in a private room where the door is closed in order to avoid disturbance. Patients are offered one week of consideration time before deciding whether or not to participate in the study, and will be offered a new interview for after the consideration time. In case patients themselves declare they need no time to reflect, oral and written consent can be given immediately after the first information is given.

Eligibility criteria: Inclusion Criteria:

* Horizontal fascial defects of \>8 cm defined by preoperative CT scan
* Planned elective open incisional hernia repair

Exclusion Criteria:

* Pregnancy
* Previous bladder resection or reconstruction
* Chronic catheter use
* Inability to provide informed consent

Primary outcomes:
measure: Intraabdominal hypertension after abdominal reconstruction
timeFrame: Before surgery, on postoperative day 1, 2 and 3.
measure: Pulmonary function in intraabdominal hypertension after abdominal reconstruction
timeFrame: Before surgery, on postoperative day 30.
measure: Surgical complications and intraabdominal hypertension after abdominal reconstruction
timeFrame: From surgery to postoperative day 30.
Secondary outcomes:
measure: Intraabdominal hypertension after abdominal reconstruction
timeFrame: Before surgery, on postoperative day 1, 2 and 3.
measure: Pulmonary function in intraabdominal hypertension after abdominal reconstruction
timeFrame: Before surgery, during surgery, on postoperative day 1, 2, 3 and 30.
measure: Surgical complications and intraabdominal hypertension after abdominal reconstruction
timeFrame: From surgery to postoperative day 30. Predicting factors are assessed preoperatively.
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Digestive Disease Center, Bispebjerg Hospital
Study officials:
affiliation: Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen
name: Sinor Soltanizadeh, MD
role: PRINCIPAL_INVESTIGATOR
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