Prevention of Lung Edema After Thoracic Surgery
Information source: University Hospital, Geneva
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Lung Injury, Acute; Thoracotomy; Anesthesia; Intensive Care, Surgical; Extravascular Lung Water
Intervention: inhalation of salbutamol (5 mg) (Drug); ipratropium (Drug)
Phase: N/A
Status: Completed
Sponsored by: University Hospital, Geneva Official(s) and/or principal investigator(s):
Christoph Ellenberger, MD, Principal Investigator, Affiliation: University Hospital of Geneva
Summary
Background :
Acute lung injury (ALI) occasionally occurs after pulmonary resection and carries a bad
prognosis with a high mortality rate ranging from 20 to 100%.
Objectives :
1. to evaluate pre-, intra- and postoperative changes in hemodynamics, oxygenation indices
as well as intra- and extravascular lung water using simple thermodilution technique and
continuous arterial pressure analysis
2. to test the efficacy of inhaled beta2 - adrenergic agonist versus anticholinergic agents
to reduce lung edema in patients undergoing thoracic surgery and in pigs subjected to
lipolysacharide-induced ALI.
Design of the research protocol:
- Prospective controlled trial including surgical patients with high risk factors for ALI
(n=60) allocated to receive inhaled drugs (randomised, double-blind, cross-over mode).
- Main measurements:
Intra-thoracic blood volume, intra- and extra-vascular lung water, hemodynamic parameters
(CO, systolic arterial pressure/flow variations, dPmax, MAP, CVP), oxygenation indices
(PaO2/FIO2), ventilatory parameters, clinical outcome data, histochemical and pathological
data.
Glossary CO = cardiac output; dPmax = maximal arterial pressure slope; SAP-V = systolic
arterial pressure variations; Flow–V = Flow variations; MAP = mean arterial pressure; CVP =
central venous pressure; PaO2=arterial oxygen pressure; FIO2= oxygen inspiratory fraction
Clinical Details
Official title: Does Inhaled Salbutamol Prevent Lung Edema After Thoracic Surgery? A Randomized Controlled Study
Study design: Treatment, Randomized, Double-Blind, Active Control, Crossover Assignment, Efficacy Study
Primary outcome: reduction in extravascular lung water
Secondary outcome: changes in oxygenation indices, hemodynamics and radiological lung injury score
Detailed description:
Material and Methods Patient selection Consecutive patients who require elective lung
resection for cancer at the University Hospital of Geneva will be screened for the presence
of risk factors for postoperative ALI or hydrostatic lung edema: age > 60 yrs, history of
chronic alcohol consumption (>60g/day), prior radiation or chemotherapy, cardiac
insufficiency (left ventricular ejection fraction < 40%, or a history of past acute heart
failure), coronary artery disease (history of myocardial infarct, Q wave on the ECG, positive
stress test or coronary angiogram), recent pneumonia (within 6 weeks of hospital admission),
reduced diffusion capacity for carbon monoxide (DLCO < 60% of predicted values) and predicted
postoperative lung perfusion of < 55% of total lung perfusion. Patients with at least 3 risk
factors for postoperative lung edema will be considered eligible for the study. Patients
undergoing pneumonectomy or presenting with intracardiac shunts, valvular diseases or aortic
abdominal aneurysm will all be excluded as these conditions preclude valid measurements of
extravascular lung water volumes. In addition, chronic treatment with inhaled
bronchodilators, a history of any adverse reaction to bronchodilators and liver or kidney
insufficiencies will be considered exclusion criteria.
This randomized double blind, cross-over study has been approved by the local university
hospital ethics committee and written informed consent has been obtained from all selected
patients.
The same team of pneumonologists, thoracic surgeons and anesthesiologists/intensive care
physicians will be involved in the perioperative medical management. In addition to history
and clinical examination, a standardized preoperative assessment includes chest radiography,
ECG, pulmonary function testing as well as computed tomography scans and positron emission
tomographies of the chest, abdomen and brain. Quantitative lung perfusion/ventilation
scanning, brain imaging, maximal aerobic capacity and myocardial stress testing will be
performed when appropriate in intermediate-to-high risk surgical candidates.
Operative and anesthetic management Routinely, antimicrobial prophylaxis with cefazoline will
be administered for 24 hours and an epidural catheter was inserted at the 4th-5th or at the
5th-6th vertebral interspace. Thoracic epidural anesthesia (TEA) will be initiated
preoperatively with the administration of bupivacaïne 0. 25% and continued postoperatively
with a lower dosage (bupivacaine 0. 1%) that was combined with opiates (fentanyl 2 mcg/ml).
Each patient will be equipped with a 4-French femoral artery catheter and an internal jugular
venous line that will be connected to a pulse contour cardiac output monitor (PV2024L;
Pulsion Medical Systems AG, Munich, Germany).
After anesthesia induction, a left sided double-lumen endotracheal tube will be inserted and
pressure support ventilation will be adjusted to optimize gas exchanges and minimize lung
hyperinflation with low tidal volume (5-6 ml/kg), high inspiratory oxygen fraction (50-80%)
and positive end expiratory pressure levels (PEEP, 4-12 cm H2O). Periodically, lung
recruitment maneuvers will also be performed to re-open alveolar collapsed areas. Anesthesia
will be maintained by infusing propofol targeted to achieve bispectral
electroencephalographic values between 40 and 60. Lung resection with systematic lymph node
dissection will be performed through an anterolateral muscle-sparing thoracotomy.
During surgery, intravenous crystalloids (Ringer-lactate solution) will be infused at a rate
of 2-3 ml/kg/h and blood losses will be compensated with colloids
(poly(0-2-hydroxy-ethyl)amidon, HAES 6%) and with red blood cell concentrates if the
hemoglobin levels decreased below 80-90 g/L. At the end of surgery, all patients will be
extubated in the operating theater after reversing the residual neuromuscular blockade with
anticholinesterase agents. An active physiotherapy program including incentive spirometry,
deep diaphragmatic breathing exercises and mobilization will be started in the
high-dependency care unit (HDU). A maximal fluid balance of 500 ml per day will be targeted
during the first 48 hours after surgery, by limiting fluid intakes including i. v.
crystalloids (glucose-saline 0. 45% 1 ml/kg/h), i. v. colloids (1/1 compensation of fluid
losses through thoracic drains and oral beverages (500 ml on the day of surgery and
1’000-1’200 ml over the next two days).
Study design Within the first 36 hours after surgery, patients will received in random order
nebulized salbutamol and nebulized ipratropium bromide at 4 consecutive sessions conducted at
least 6 hours apart (figure 1). The treatment order will be generated from random number
tables by an independent observer and concealed in sealed envelopes. The investigators,
attending physicians and nurses will be blinded to the treatment group.
Over 10 minutes, either salbutamol (5 mg diluted in 5 ml normal saline) or ipratropium
bromide (0. 5 mg diluted in 5 ml normal saline) will be administered via a Cirrus nebulizer
and a compressor (Wokingham, UK).
Measurements In addition to arterial blood sampling, complete sets of hemodynamic
measurements will be performed as shown in figure 1: (a) preoperatively, before and 30 min
after initiation of TEA, (b) 2 and 8 hours after surgery (postoperative day 0, [POD0]),
before and 30 min after administration of salbutamol or ipratropium (6 hours apart in random
order), (c) on the morning of the first postoperative day (POD1) on two consecutive sessions
(6 hours apart in random order), before and 30 min after administration of salbutamol or
ipratropium bromide.
Cardiac output (CO) and volumetric pulmonary variables will be obtained by the simple
transpulmonary indicator dilution technique. Three consecutive measurements with less than
10% variations will be averaged. A fifteen milliliters bolus of 0. 9% saline at 4°C will be
injected through the central venous catheter into the right atrium and the change in
temperature will be measured with the femoral artery thermistor tipped catheter. Using the
mean transit time methods, intrathoracic blood volume, extravascular lung water and global
end-diastolic volume will be calculated and indexed for the patient body weight (ITBVI, EVLWI
and GEDVI, respectively). Heart rate (HR), stroke volume (SV) and maximal change in arterial
pressure will be determined by beat-to-beat analysis of the arterial pressure wave. The
systemic vascular resistance index (SVRI) will be calculated using standard formula. The
ratio of EVLWI to ITBVI will be calculated as an index reflecting the permeability of the
alveolar–capillary barrier.
Arterial oxygen pressure (PaO2 in mmHg) will be measured using a blood gas analyzer (ABL-510
analyzer, Radiometer, Copenhagen, Denmark) and will be related to the inspiratory O2 fraction
to express the oxygenation index (PaO2/FIO2). In addition, chest radiograph scores (number of
quadrants with >50% involvement with an alveolar filling process) will be recorded on POD0
(arrival in HDU) and POD1 (end of the study).
Outcomes The primary outcome measure will be a reduction in EVLWI within the first 24 hours
after lung surgery. Secondary outcomes will be the PaO2/FIO2 ratio, hemodynamic data and
radiological lung injury score.
Statistical analysis A sample size of 20 subjects provides the power (80%) to detect a 20%
difference in EVLWI for a two-sided significance level of = 0. 05; in a preliminary study,
we found a mean value of 9. 1 ml/kg for EVLWI with a standard deviation (SD) of 2. 2 ml/kg.
Results will be reported as M(SD), median (interquartile) or numbers (percentages). A p value
of < 0. 05 was considered significant in all analyses. All data will be analyzed with the SPSS
statistical software (version 9. 0, SPP, Chicago, IL). ANOVA for repeated measurements will be
used to compare baseline values (preoperative, POD0 and POD1) followed by Bonferroni post-hoc
tests. Paired and unpaired Student t tests will be used to assess and to compare the effects
of bronchodilators. Furthermore, the correlation between changes in EVLWI, CI, ITBVI and
PaO2/FIO2 will be analyzed by linear regression.
Eligibility
Minimum age: N/A.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
Patients with at least 3 risk factors for postoperative lung edema
- age > 60 yrs
- history of chronic alcohol consumption (>60g/day)
- prior radiation or chemotherapy
- cardiac insufficiency (left ventricular ejection fraction < 40%, or a history of past
acute heart failure)
- coronary artery disease (history of myocardial infarct, Q wave on the ECG, positive
stress test or coronary angiogram)
- recent pneumonia (within 6 weeks of hospital admission)
- reduced diffusion capacity for carbon monoxide (DLCO < 60% of predicted values)
- predicted postoperative lung perfusion of < 55% of total lung perfusion
Exclusion Criteria:
- pneumonectomy
- intracardiac shunts
- valvular diseases
- aortic abdominal aneurysm
- chronic treatment with inhaled bronchodilators
- a history of any adverse reaction to bronchodilators
- liver or kidney insufficiencies
Locations and Contacts
University Hospital of Geneva, Geneva CH-1211, Switzerland
Additional Information
Starting date: September 2004
Ending date: June 2007
Last updated: July 9, 2007
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