the lessMAS trial

the l avage with e xogenous s urfactant s uspension in M econium A spiration S yndrome l e s s M A S trial A MULTICENTRE RANDOMISED CONTROLLED TRIAL OF THERAPEUTIC LUNG LAVAGE IN VENTILATED INFANTS WITH MECONIUM ASPIRATION SYNDROME Chief Investigators: A/Prof. Peter A. Dargaville Dr. John F. Mills Prof. Colin J. Morley Dr. Beverley Copnell Department of Neonatology Royal Children’s Hospital, Melbourne Murdoch Childrens Research Institute Version 2.0, December 2003 Tabl e of con ten ts Trial summary ................................................................................................................................ 3 Background.................................................................................................................................... 4 2.1 INTRODUCTION ..................................................................................................................................................................4 2.2 LUNG LAVAGE IN ANIMAL MODELS OF MAS..........................................................................................................4 2.3 LUNG LAVAGE IN HUMAN INFANTS WITH MAS ....................................................................................................4 2.4 METHOD OF LAVAGE........................................................................................................................................................5 2.4.1 Total lavage volume.....................................................................................................................................................5 2.4.2 Aliquot volume .............................................................................................................................................................5 2.4.3 Surfactant concentration.............................................................................................................................................5 2.4.4 Conduct of the lavage procedure ..............................................................................................................................5 2.5 PRELIMINARY HUMAN DATA IN SUPPORT OF THE LESSMAS TRIAL..............................................................6 2.5.1 Experience of therapeutic lung lavage at Royal Children's Hospital, Melbourne ..............................................6 2.5.2 Safety data from the RCH cases.................................................................................................................................7 2.5.3 Potential efficacy..........................................................................................................................................................7 2.6 STUDY POPULATION.........................................................................................................................................................8 2.6.1 Disease severity ...........................................................................................................................................................8 2.6.2 Timing of lavage...........................................................................................................................................................8 3. LessMAS TRIAL PROTOCOL........................................................................................................... 9 3.1 TRIAL OBJECTIVE...............................................................................................................................................................9 3.2 STUDY POPULATION.........................................................................................................................................................9 3.3 RECRUITMENT ....................................................................................................................................................................9 3.3.1 Entry criteria ..................................................................................................................................................................9 3.3.2 Exclusion criteria...........................................................................................................................................................9 3.4 CONSENT...............................................................................................................................................................................9 3.5 RANDOMISATION............................................................................................................................................................10 3.6 MASKING............................................................................................................................................................................10 3.7 INTERVENTION – THERAPEUTIC LUNG LAVAGE ...................................................................................................10 3.7.1 Setting..........................................................................................................................................................................10 3.7.2 Stabilisation of the infant prior to lavage ...............................................................................................................10 3.7.3 Sedation and muscle relaxation during therapeutic lung lavage.........................................................................10 3.7.4 Preparation for lavage................................................................................................................................................10 3.7.5 Lavage equipment and lavage fluid preparation ...................................................................................................11 3.7.6 Lavage method ...........................................................................................................................................................11 3.7.7 Post-lavage management ..........................................................................................................................................12 3.7.8 Post-lavage investigations .......................................................................................................................................12 3.8 NO LAVAGE........................................................................................................................................................................12 3.9 POST-INTERVENTION MANAGEMENT ......................................................................................................................13 3.9.1 Criteria for extubation and use of nasal CPAP.......................................................................................................13 3.10 DATA COLLECTION AND HANDLING........................................................................................................................13 3.10.1 Data collection in hospital...............................................................................................................................................13 3.10.2 Data collection after discharge .......................................................................................................................................14 3.11 OUTCOME VARIABLES ...................................................................................................................................................14 3.11.1 Primary outcome measure ................................................................................................................................................14 3.11.2 Secondary outcome measures ........................................................................................................................................14 3.11.3 Measures of safety...........................................................................................................................................................14 3.11.4 Outcomes in the first two years of life ...........................................................................................................................14 3.11.5 Sub-analyses .....................................................................................................................................................................14 3.12 SAMPLE SIZE...........................................................................................................................................................................15 3.13 TRIAL PLAN.............................................................................................................................................................................15 3.14 FEASIBILITY............................................................................................................................................................................15 3.15 SAFETY AND ADVERSE EVENTS.......................................................................................................................................15 3.16 INTERIM ANALYSIS..............................................................................................................................................................15 3.17 FUNDING...................................................................................................................................................................................15 4. REFERENCES.................................................................................................................................16 Appendix A..........................................................................................................................................17 1. 2. lessMAS trial protocol Version 2, December 2003 2 the l avage with e xogenous s urfactant s uspension in M econium A spiration S yndrome l e s s M A S trial Trial summary 1. RESEARCH QUESTION Does therapeutic lung lavage with dilute surfactant reduce the duration of respiratory support in ventilated infants with meconium aspiration syndrome (MAS)? BACKGROUND Lung lavage using a suspension of dilute surfactant has been shown to be well-tolerated and effective in animal models of MAS; large quantities of meconium are removed from the lung, and post-lavage lung function is improved. In human infants with MAS, lung lavage appears to be safe, and potentially efficacious. Experimental data support the use of a single, large-volume lavage (two aliquots of 15 mL/kg), using surfactant diluted to a concentration of 5 mg/mL. This lavage should be performed as early as possible in ventilated infants with moderate to severe MAS. RESEARCH DESIGN A multicentre, randomised controlled trial, to be conducted at Australasian and selected international Neonatal Intensive Care Units. SELECTION CRITERIA Inclusion criteria: Term infants less than 24 hours of age with respiratory failure secondary to MAS, requiring mechanical ventilation at a mean airway pressure of at least 12 cm H O, and with an 2 alveolar-arterial oxygen difference of at least 450 mm Hg. Exclusion criteria: Severe encephalopathy or major congenital anomaly or, such that withdrawal of active treatment is being considered; known or suspected structural cardiac disease; and extreme cardiorespiratory instability precluding large volume lung lavage. RANDOMISATION Eligible infants will be randomly allocated, using sequentially numbered opaque sealed envelopes, with stratification by study centre, to either "Lung Lavage" or "No Lavage". INTERVENTION As soon as possible after randomisation, infants randomised to the "Lung Lavage" group will receive lung lavage using two aliquots of 15 mL/kg of dilute SurvantaTM (5 mg/mL). Each aliquot will be instilled rapidly down the endotracheal tube, and then recovered by tracheal suctioning. Recruitment manoeuvres will then be used to re-establish lung volume. Once the lavage is complete, infants will be managed exactly as for the "No Lavage" group, in whom all normal neonatal intensive care treatments will be administered. OUTCOMES Primary outcome measure: duration of respiratory support (cumulative hours of endotracheal intubation and nasal CPAP) Secondary outcomes: mortality, pneumothorax, duration of intubation, oxygen therapy and hospitalisation Measures of safety: change in oxygenation, pH, pCO2 and base excess after lavage Outcomes in the first 2 years: hospitalisations in the first year, developmental outcome at 2 years SAMPLE SIZE 66 infants (33 per group) lessMAS trial protocol Version 2, December 2003 3 2. 2.1 INTRODUCTION Background Meconium aspiration syndrome (MAS) is a complex disease of the newborn lung that may result in considerable respiratory morbidity. In Australasia the incidence of MAS is approximately 1.5 per 1000 livebirths; around 0.45 per 1000 infants are ventilated with MAS [1]. Analysis of data reported to the Australian and New Zealand Neonatal Network (ANZNN) between 1995 and 2000 showed that the incidence of MAS requiring mechanical ventilation does not appear to be changing [1]. Of concern, over this period, there was an increase in the duration of respiratory support for ventilated infants with MAS. This occurred despite increased utilisation of high frequency ventilation, nitric oxide and exogenous surfactant therapy. When inhaled, meconium causes a wide range of pathophysiological disturbances, including airway obstruction, epithelial disruption and surfactant inhibition [2]. Despite this, the current therapeutic emphasis in MAS is on providing supportive care, with little effort made to remove meconium from the lung to halt or slow disease progression. Recently, however, therapeutic lung lavage has been investigated as a means of cleansing the lung of meconium, and a body of evidence now exists supporting the potential efficacy of this therapy in MAS. 2.2 LUNG LAVAGE IN ANIMAL MODELS OF MAS In animal models of MAS, lung lavage using total fluid volumes of 10-60 mL/kg has resulted in considerable improvement in oxygenation and/or pulmonary mechanics, associated with removal of significant amounts of meconium from the airspaces [3-7]. Saline, surfactant and perfluorocarbon have each been studied as potential lavage fluids. Comparative data suggest that exogenous surfactant, either full-strength [3] or diluted [4-7], is a more effective lavage fluid than saline or perfluorocarbon, both in terms of pulmonary function post-lavage, and removal of meconium from the lung. 2.3 LUNG LAVAGE IN HUMAN INFANTS WITH MAS In human infants, the history of lavage as a therapy for MAS extends back to the early 1970s, when saline lavage was used in the delivery room to improve clearance of meconium from the airways of meconium-stained babies [8]. Reports of lung lavage in infants with established MAS have since appeared [9,10], using volumes of 20-40 mL/kg saline, followed by a bolus of natural surfactant. Improvement in oxygenation and carbon dioxide clearance was noted in each case. More recently, lavage with suspensions of dilute surfactant has been evaluated in human infants with MAS [11-13], and two small randomised trials of dilute surfactant lavage have been conducted [11,13]. The study by Wiswell et al [13] is the only controlled trial. This trial used repeated 8 mL/kg aliquots of diluted synthetic surfactant (KL4, marketed as SurfaxinTM ) with a total lavage volume of 48 mL/kg. There was an improvement in oxygenation and reduction in ventilator days in the lavage group, although the differences between groups were not statistically significant. A larger randomised controlled trial of SurfaxinTM lavage in MAS is being conducted (Wiswell, personal communication 2001). The lessMAS trial investigators consider that a separate RCT should be conducted in Australasia, for the following reasons: 1. The SurfaxinTM trial uses a product that does not have FDA approval for any indication, and is unlikely to be available in Australasia for some years at least. 2. The total lavage volume, aliquot volume, and lavage technique in the SurfaxinTM trial are not considered optimal by the lessMAS trial investigators (see below). 3. It is highly desirable that more than one adequately powered randomised controlled trial is conducted for this, or any other, therapy. lessMAS trial protocol Version 2, December 2003 4 2.4 METHOD OF LAVAGE In formulating a lavage protocol suitable for use in human infants, answers to the following questions were sought: a) What is the appropriate total lavage volume to optimise meconium removal from the lung? b) What is the appropriate aliquot volume to be instilled into the lung at one time? c) What concentration of surfactant should be used in the lavage fluid? d) How should the lavage procedure be conducted to minimise any adverse physiological effects? The answers to these questions, which have to a large extent been resolved through local experimentation and investigation, are set out as follows. 2.4.1 Total lavage volume In neonatal piglets, a total lavage volume of 30 mL/kg in two aliquots removed 60% of meconium pigment instilled into the lung immediately prior to the lavage; further aliquots of 15 mL/kg each removed less than 10% additional pigment [7]. A total lavage volume of 30 mL/kg has thus been chosen for the lessMAS trial. The Trial Investigators consider that lavage volumes > 30 mL/kg will result in significant deposition of extra fluid without much additional meconium removal. 2.4.2 Aliquot volume In the piglet model of MAS, an aliquot volume of 15 mL/kg recovered more centrifugeable meconium solids and meconium pigment compared with lavage using 3 mL aliquots [7]. Postlavage oxygenation and pulmonary mechanics were improved as a result. Aliquots greater than 15 mL/kg cannot be rapidly instilled into the lungs of a ventilated subject; fluid invariably refluxes up the endotracheal tube, and is wasted. Lavage with aliquots of 15 mL/kg, performed exactly according to the protocol below, has been well tolerated in human infants with MAS [14]. The lessMAS trial will therefore use an aliquot volume of 15 mL/kg. 2.4.3 Surfactant concentration Meconium inhibits surfactant function in a dose-dependent manner [15]; in vitro such inhibition can be readily overcome by increasing surfactant phospholipid concentration to 3 mg/mL. High plasma protein concentration has been noted in the alveolar space in MAS [16], and will also contribute to surfactant inhibition. In vitro studies have shown that increasing surfactant concentration from 1.25 mg/mL to 6.25 mg/mL virtually eliminates inhibition by plasma protein [17]. Taking these data into consideration, the lessMAS study will use a surfactant concentration of 5 mg/mL, equivalent to a 1 in 5 dilution of full-strength SurvantaTM . Two factors preclude the use of higher concentrations than 5 mg/mL, the increasing viscosity of phospholipid suspensions at high concentrations, and the relatively high cost of surfactant. 2.4.4 Conduct of the lavage procedure The ideal lavage procedure should cleanse the lung as effectively as possible, with as little physiological disturbance as possible, and retention of as little fluid in the lung as possible. The lessMAS investigators consider that the important principles in conducting optimal therapeutic lung lavage are as follows: • Lavage should only be performed by personnel who have received instruction and training in the technique of lavage. • Lavage must be conducted rapidly, with each aliquot instilled and recovered within 60-80 secs. • The infant must be disconnected from the ventilator for suction (i.e. not suctioned "in-line"). Cineradiographic studies in our laboratory clearly show that meconium and retained lung fluid efflux more effectively when the lung is allowed to deflate. The use of "in-line" suctioning in previous studies [12,13] may have limited the efficacy of lavage, and accentuated the postlavage desaturation related to fluid retention. • Efforts must be made to re-recruit lung volume after each lavage aliquot. lessMAS trial protocol Version 2, December 2003 5 2.5 PRELIMINARY HUMAN DATA IN SUPPORT OF THE LESSMAS TRIAL 2.5.1 Experience of therapeutic lung lavage at Royal Children's Hospital, Melbourne To date, the lessMAS study investigators have performed lung lavage with dilute surfactant in seven ventilated infants with severe MAS [14]. Details of the demographic and ventilatory requirements of these infants at the time of lavage are shown in Table 1, and details of the lavage procedure appear in Table 2. The initial patients in the case series were lavaged with a smaller total volume than that found to be efficacious in the piglet model of MAS. This allowed the Investigators to gain confidence and experience with the technique. Note that the last three infants in the series had lavage using volumes of at least 25 mL/kg, with the last two of these having lavage before 24 hours of age (i.e. sufficiently early to halt or slow progression of the disease). At the time of lavage, all infants in this series were receiving high frequency ventilation, and most were being treated with nitric oxide and inotropes. Despite relatively high mean airway pressures, all infants had marked impairment of gas exchange, with mean AaDO2 of 540 mm Hg. Two of the infants had received bolus surfactant therapy (with minimal effect) prior to arrival at RCH. Cases 5 and 6 were referred to RCH for consideration of extracorporeal membrane oxygenation; in both cases lavage therapy was associated with improvement in oxygenation such that ECMO was not required. Table 1 Demographic and ventilation indices in 7 lavaged infants Case Age at Hrs postMode of PAW AaDO2* no. lavage (hrs) admission ventilation (cm H 2O) (mm Hg) 1 2 3 4 5 6 7 24 15 26 18 57, 83 23 13 19 11 19 8 14, 40 2 3 HFOV HFJV HFOV HFOV HFOV HFOV HFOV 21 17 19 25 14, 13.5 18 20 554 442 586 601 630, 579 490 506 OI† † 23 23 37 20 37, 21 28 13 Adjunctive therapies NO dopamine, NO dopamine, NO adrenaline, NO ‡ adrenaline, NO dobutamine, NO ‡ nil Mean 25 11 19 544 25 * AaDO2 = alveolar-arterial oxygen difference (see section 3.3.1) † OI (oxygenation index) = PAW x FiO2 x 100 / PaO2 ‡ Also had received bolus surfactant therapy prior to transfer HFO(J)V = high frequency oscillatory (jet) ventilation Table 2 Details of each episode of lavage Case no. 1 2 3 4 5a 5b 6 7 Lavage sequence 3 x 3 mL/kg 3 x 5 mL/kg 3 x 5 mL/kg 3 then 10 mL/kg 2 x 10 mL/kg 2 x 15 mL/kg 2 x 12.5 mL/kg 2 x 15 mL/kg Total lavage SurvantaTM volume concentration 9 mL/kg 15 mL/kg 15 mL/kg 13 mL/kg 20 mL/kg 30 mL/kg 25 mL/kg 30 mL/kg 5 mg/mL 2.5 mg/mL 2.5 mg/mL 2.5 mg/mL 5 mg/mL 5 mg/mL 4.4 mg/mL 5 mg/mL Fluid recovery* 33% 38% 37% 37% 30% 43% 32% 64% Return fluid characteristics blood, meconium blood, meconium blood, meconium blood, meconium particulate meconium particulate meconium blood, meconium blood, meconium * Expressed as percentage of the volume instilled In all cases in this series, therapeutic lung lavage removed considerable quantities of meconium from the lung. The return fluid was usually haemorrhagic, in keeping with the experience of others lessMAS trial protocol Version 2, December 2003 6 [13], and our previous finding that infants with MAS consistently have haemorrhagic pulmonary oedema, with blood-stained lung fluid [18], and high concentration of plasma protein in the alveolar space [16]. There was no evidence that the blood-staining of the fluid was caused by lavage procedure itself. Small volume diagnostic bronchoalveolar lavage samples taken immediately prior to lavage in cases 6 and 7 both showed significant blood-staining, indicating that there was preexisting haemorrhagic oedema. Further, in case 7, in whom the return fluid was very haemorrhagic, the infant was weaned to room air within 9 hours of the lavage procedure. This would not be expected if lavage had caused a new pulmonary haemorrhage. 2.5.2 Safety data from the RCH cases During large volume therapeutic lung lavage, the lung is transiently filled with aqueous fluid, and gas exchange is significantly impaired. This manifests primarily as reduced oxygen desaturation, which resolves once the retained lung fluid has been cleared from the airspaces. The lavage technique adopted for the lessMAS trial aims to minimise the duration and severity of physiological disturbance during lavage. Our preliminary experience is that, whilst desaturation during instillation of each lavage aliquot may be pronounced, but is usually short-lived, particularly if strategies to clear lavage fluid from the lung and re-recruit lung volume are employed. Figure 1 shows the typical cardiorespiratory changes that occur during lavage, and as well as data on the duration of desaturation for each lavage episode. Note that SaO 2 was above 80% within 12 minutes in all cases. Figure 2 shows that large volume lavage (at least 20 mL/kg) had no adverse effect on any important physiological parameter in the hours after lavage. Figure 1 Physiological changes during lavage in Case 7 Duration of desaturation with each lavage episode 7.50 Figure 2 Physiological changes in reponse to lavage Lavage volume ≥ 20 mL/kg ≥ 7.40 pCO 2 (mm Hg) Case no. 1 2 3 4 5a 5b 6 7 Heart rate (HR), mean blood pressure (BP) and preductal arterial oxygen saturation (SpO2) before, during and after 2 x 15 mL/kg lavage. Instillation of each aliquot is indicated by the black arrows. SaO2 < 80% Recovery time* (mins) (mins) 0 0 5 3 2 1 12 5 1 10 pH pH 50 45 7.45 pCO2 40 35 7.35 7.30 30 25 -2 5 145 18 10 Base excess 7.25 -2 -1 0 1 2 3 4 Time (hrs post-lavage) 5 -1 0 1 2 3 4 Time (hrs post-lavage) 5 2.0 0.0 -2.0 Base excess AaDO2 (mm Hg) 700 600 500 AaDO 2 35 5 -4.0 400 *Time to return to baseline SaO2 -6.0 -8.0 -2 300 200 -1 0 1 2 3 4 Time (hrs post-lavage) 5 -2 -1 0 1 2 3 4 Time (hrs post-lavage) 5 Timing of lavage indicated by the black arrow 2.5.3 Potential efficacy In examining the potential efficacy of lung lavage in the RCH cases, respiratory outcomes in the lavaged infants were compared with a group of non-lavaged historical controls with severe MAS, all treated with high frequency ventilation. Figure 3 shows oxygenation data for non-lavaged controls, all lavaged infants, and those infants undergoing a lavage that would be considered potentially efficacious (lavage volume at least 25 mL/kg, age < 24 hrs). Note that AaDO2 at the outset is similar in the 3 groups, and improved more rapidly in infants receiving an optimal lavage. These infants showed a non-significant trend to reduced days of intubation and respiratory support (Table 3). lessMAS trial protocol Version 2, December 2003 7 Figure 3 Oxygenation after lavage compared with historical controls not receiving lavage 700 No lavage (n = 24) 600 All lavaged infants Lavage ≥ 25 mL/kg at ≥ less than 24 hrs of age Duration of Duration of respiratory intubation (days) support (days) Duration of RCH admission (days) Table 3 Respiratory outcomes after lavage compared with historical controls not receiving lavage AaDO2 (mm Hg) 500 400 300 200 100 0 No lavage group All lavaged infants Lavage ≥ 25 mL/kg at less than 24 hrs 6.6 6.1 3.1 7.1 7.4 3.1 13 9.2 4.1 * 0 10 20 30 40 50 60 70 80 Time (hrs post-admission) * AaDO2 values lower than no lavage group, p < 0.05 2.6 STUDY POPULATION 2.6.1 Disease severity MAS is an extremely variable disease, related in part to variation in the amount of meconium inhaled, and the wide spectrum of physiological disturbance caused thereby. Experience of lavage therapy in MAS has been both in infants with mild-moderate oxygenation disturbance (mean oxygenation index (OI) at the time of lavage in the Surfaxin trial was ~13) [13], and in infants with severe lung disease (mean OI in the RCH case series was 25, and all infants were receiving high frequency ventilation). Positive effects after lavage were seen in both groups, and lavage was well tolerated even in infants with severe disease. The lessMAS trial will enrol infants with severe MAS, as this group stands to gain the most from a therapeutic lavage procedure. Infants will be eligible if they are ventilated with a mean airway pressure (PAW) of at least 12 cm H O, and an alveolar2 arterial oxygen difference (AaDO2) of at least 450 mm Hg on two separate blood gases at least 30 minutes apart. This AaDO2 corresponds to a pO 2 of 70 mm Hg when in an FiO 2 of 0.8. These PAW and AaDO2 criteria are designed to achieve early selection of infants who have the most severe MAS. We estimate, from ANZNN data and RCH figures, that about 40-50% of all ventilated infants with MAS will be eligible using these criteria. 2.6.2 Timing of lavage The progressive nature of the pathophysiology in MAS would suggest that the earlier that lavage is performed, the more likely it is to benefit the infant. The mean age at randomisation in the published human trials of lavage has been 3 hrs [12], and 14 hrs [13]. Mean age at lavage in the RCH cases was 25 hours, reflecting the patterns of referral to our institution. Whilst positive effects have been seen in several infants lavaged well beyond 24 hours, there seems little doubt that in order to maximise the impact, lavage should be performed as early as possible. With this in mind, the lessMAS trial will enrol infants less than 24 hrs of age, with an emphasis on early recruitment of a mechanically-ventilated infant once the diagnosis is established and entry criteria fulfilled and the infant's condition stabilised. lessMAS trial protocol Version 2, December 2003 8 3. 3.1 TRIAL OBJECTIVE lessMAS TRIAL PROTOCOL To evaluate in a randomised controlled trial the efficacy of lung lavage with dilute surfactant in ventilated infants with MAS. The primary outcome measure will be duration of respiratory support (including nasal CPAP); secondary outcomes will be duration of intubation, oxygen therapy, and hospitalisation. 3.2 STUDY POPULATION The study population will consist of term infants with MAS ventilated at one of the participating study centres, who fulfill the entry criteria detailed below. All ventilated infants with MAS cared for in participating centres will be screened for potential eligibility by the Site Study Investigator. 3.3 3.3.1 Entry criteria 1. A diagnosis of meconium aspiration syndrome based on the following criteria: i) Evidence of passage of meconium at, or prior to, delivery and ii) Early onset of respiratory distress (within 2 hours of birth) and iii) either a) A chest X-ray compatible with the diagnosis of MAS or b) Meconium aspirated from below the cords at any time (either at delivery or during routine endotracheal tube suction) 2. Greater than 36/40 gestation, birth weight at least 2.0 kg, and age less than 24 hours 3. Intubated and receiving mechanical ventilatory support of any type with PAW at least 12 cm H2O 4. Sequential blood gases at least 30 minutes apart demonstrating an AaDO2 of at least 450 mm Hg.* Once eligibility is established, an AaDO2 < 450 prior to randomisation does not exclude the infant from inclusion in the study, providing the FiO 2 is a t least 0.5 5. Agreement of the Treating Physician in charge of the infant’s care 6. Signed parental consent. Enrolled infants would normally be expected to have an in-dwelling arterial line in place. 3.3.2 Exclusion criteria 1. Any infant where withdrawal of active treatment is being considered, based on the presence of a major congenital anomaly or severe hypoxic-ischaemic encephalopathy. Lesser degrees of encephalopathy, where full active treatment is being pursued, do not preclude enrolment in the study. Enrolment in the ICE trial† also does not preclude enrolment in the lessMAS trial (and vice versa), but it is not expected that many patients would fulfill entry criteria for both studies. 2. Known or suspected structural cardiac disease. 3. Cardiorespiratory instability deemed by the Treating Physician to preclude enrolment in a trial. RECRUITMENT 3.4 CONSENT Informed parental consent will be obtained prior to randomisation. A plain language document outlining the rationale for the study will be given to the parent(s) (see lessMAS Parent Information Sheet RCH), and a specifically-designed consent form will be used for parental signature (see lessMAS Consent Form RCH). For outborn infants, the trial information document will be given to parents at the time of transfer of their infant, if possible. The design and complexity of the consent forms at each study centre will be determined primarily by the local Human Ethics Committee or its equivalent, and may vary from institution to institution. * AaDO2 = (713 x FiO2) – (pCO2 / 0.8) – (paO2). At a pCO2 of 40 mm Hg, AaDO2 is >/= 450 mm Hg where: FiO2 is 0.8 and pO2 is < 70 mm Hg; FiO2 is 0.9 and pO2 is < 140 mm Hg, FiO2 is 1.0 and pO2 is < 210 mm Hg. † ICE trial: Infant Cooling Evaluation Trial, Dr. S. Jacobs, Chief Investigator lessMAS trial protocol Version 2, December 2003 9 3.5 RANDOMISATION Enrolled infants will be randomised into "Lung Lavage" and "No Lavage" groups using random numbers in sequentially numbered opaque sealed envelopes, with an allocation ratio of 1:1. The envelopes will be supplied to each Study Centre by the Centre for Clinical Epidemiology and Biostatistics at RCH. The randomisation will be in randomly permuted blocks of 2, 4 or 6, stratified by study centre. 3.6 MASKING Given the nature of the lung lavage procedure (in particular the number of assistants required when lavage is performed), it will not be possible to conceal the group assignment from the Clinical Team. However, where possible, the objective assessment of outcome measures will be performed by personnel unaware of the group assignment. Given that the primary outcome measure (duration of respiratory support) is one which is directly controlled by the Clinical Team, strict criteria for extubation, use of nasal CPAP, and discontinuation of nasal CPAP have been set. In this way, the potential for bias related to lack of concealment will be minimised. The team performing developmental assessment at 2 years will be blinded to the original randomisation group. 3.7 (see Appendix A for a more detailed lavage protocol) Given the experimental nature of therapeutic lung lavage, it is the expectation of the Chief Investigators that participating centres would only offer lavage therapy within the context of the lessMAS trial. 3.7.1 Setting In this study therapeutic lung lavage will only be performed in a neonatal intensive care setting, with available monitoring equipment utilised as appropriate. Lavage should be performed with the infant on an open cot, under a servo-controlled radiant heater. 3.7.2 Stabilisation of the infant prior to lavage Infants enrolled in the study will receive therapeutic lung lavage as soon as practicable after randomisation, but only after all necessary measures have been performed to optimise the infant's condition. Lavage must not be performed in an infant in an unstable physiological state; all efforts should be made to correct physiological disturbances prior to lavage. Lavage should not be undertaken in an infant with a pre-ductal SaO 2 < 85%, a mean arterial blood pressure < 35 mm Hg or an arterial pH < 7.20. 3.7.3 Sedation and muscle relaxation during therapeutic lung lavage Infants will require heavy sedation (narcotic ± benzodiazepine*) and preferably muscle-relaxation prior to lavage therapy. This is not considered by the Study Investigators to be a departure from normal practice in managing ventilated infants with severe MAS. If an infant randomised to lavage is not being managed with muscle relaxants, administration of a short-acting paralytic agent (such as vecuronium or atracurium) prior to the lavage is recommended, preceded by top-up doses of sedation and analgesia, if necessary. Inadequate sedation and/or muscle relaxation during lavage may result in coughing/gagging, as has been noted by others [13]. 3.7.4 Preparation for lavage (see Appendix A for complete checklist) • Perform prelavage chest X-ray (maximum 2 hrs prior to lavage). • Correctly position and adequately secure the endotracheal tube • Perform pre-lavage arterial blood gas analysis (maximum 30 mins prior to lavage) • Ensure adequate physiological monitoring is in place (ECG, SaO 2 ± transcutaneous pO 2/pCO2) * INTERVENTION – THERAPEUTIC LUNG LAVAGE morphine as 50-100 µg/kg boluses or an infusion of 20-40 µg/kg/hr; midazolam as an infusion of 0.5-2.0 µg/kg/min; diazepam as 0.2 mg/kg boluses lessMAS trial protocol Version 2, December 2003 10 • • • • Preoxygenate in FiO 2 1.0 for at least 5 mins prior to lavage Prepare a hand ventilation circuit, preferably with a manometer. Prepare the suctioning equipment, and connect to wall suction at -150 mm Hg Prewarm ampoules of saline to 37 ºC in a water bath 3.7.5 Lavage equipment and lavage fluid preparation (see Appendix A for complete details) • Prepare 60 mL syringes, drawing-up needles and dispensing catheters on a sterile surface. • Calculate the amount of lavage fluid based on administration of two aliquots of 15 mL/kg, with a surfactant concentration of 5 mg/mL. Total fluid volume is thus 30 mL/kg, including 6 mL/kg of full-strength SurvantaTM . The manufacturers of SurvantaTM , Abbott Australasia, have agreed to provide surfactant free of charge for the trial. When preparing lavage fluid, vials of SurvantaTM will be obtained from ward stock, and this stock later replenished by Abbott at no cost. Ideally each aliquot should be dispensed from a single 60 mL Luer lock syringe. Where body mass is > 4 kg, extra fluid for each aliquot will be drawn up in a supplementary syringe with its own dispensing catheter (see Lavage Fluid Preparation Table, Appendix A). • Draw up required volume of SurvantaTM into each of the 60 mL syringes (± supplementary syringe), avoiding bubbles as much as possible. • Immediately prior to lavage, draw up the requisite amount of warmed saline into each syringe, to make an aliquot volume of 15 mL/kg. This will then be a 1 in 5 dilution of SurvantaTM , with a phospholipid concentration of 5 mg/mL.* • Attach the pre-cut dispensing catheter to each syringe. 3.7.6 Lavage method (see Appendix A for complete details) Personnel required In addition to the Study Investigator, at least 3, and preferably 4 assistants will be needed to ensure the lavage procedure is conducted rapidly, effectively and safely. Lavage sequence - 1st aliquot • Position the infant with the head midline and slightly elevated, and the chest right side down. • Instillation phase (~ 20 secs) Disconnect the ventilator circuit, and pass the dispensing catheter down the ETT to its full depth. Instill the 1st 15 mL/kg aliquot into the lung. • Dwell phase (~ 10 secs) Reconnect to positive pressure ventilation in the supine position, and deliver several positive pressure breaths. • Suction phase (30-40 secs) Disconnect the ventilator circuit, and insert a premeasured suction catheter into the lower trachea, and aspirate as much return fluid as possible using standard suction pressure (-150 mm Hg). Maximise fluid recovery by gentle chest compression and rolling of the torso. • Oxygenation will deteriorate during suctioning, and the Study Investigator must judge when to reconnect to positive pressure ventilation, based on the SaO 2 readings, and how complete the recovery of lavage fluid has been. Maximising the recovery of return fluid is critical to the success of the lavage, and should take precedence unless SaO 2 is falling below 50%. • When suctioning is complete, reconnect ventilation circuit, and apply positive pressure breaths with long inspiratory and expiratory times, to re-recruit lung volume and recover oxygenation. • Manoeuvres to encourage recovery of oxygenation include: a. Using higher peak pressure and longer inspiratory time b. Increasing PEEP * Product information for Survanta details risks of ordinary use of Survanta in hyaline membrane disease, including transient episodes of bradycardia and decreased oxygen saturation during administration, as well as the potential for rapid changes in lung compliance after administration. A possible increase in the risk of sepsis has been identified in some studies. These risks should be borne in mind when using Survanta in the lessMAS trial lessMAS trial protocol Version 2, December 2003 11 c. Applying cricoid pressure if there is a leak around the ETT d. Reconnecting to HFOV and performing recruitment manoeuvres e. Performing further suctioning Lavage sequence – 2nd aliquot Instill the 2nd lavage aliquot once SaO 2 has recovered to near baseline readings. This would normally be expected to be within 5 mins of the 1st aliquot. The 2nd aliquot should not be instilled if SaO 2 remains below 80%; in this case further measures to encourage recovery of oxygenation should be undertaken, as outlined directly above. Procedure for the 2nd aliquot is identical to the 1st except that: • The infant should be placed left side down during the instillation phase • Suctioning may need to be more prolonged, and multiple suction episodes may be required before finally reconnecting to mechanical ventilation. Overall fluid recovery from both lavage aliquots should be between 30 and 70% of the instilled volume (it was 63% in the piglet studies). The fluid will show meconium staining to a varying degree, and may show considerable blood staining. This is not related to mucosal trauma from the lavage procedure; instead it is a reflection of the haemorrhagic pulmonary oedema that is regular feature of MAS [18]. 3.7.7 Post-lavage management Once physiological parameters have recovered to near baseline readings, the pre-lavage ventilation mode should be reinstituted, but with ventilator settings that in the clearance of retained lavage fluid. For conventional ventilation these would be: • Peak pressure 2-5 cm H2O higher than previously • PEEP of at least 6 cm H2O • Inspiratory time of at least 0.4 secs, with respiratory rate 60/min For high frequency oscillation these would be: • PAW 2-4 cm H2O higher than previously • Higher amplitude only if transcutaneous or arterial pCO2 dictates Higher ventilator settings may be required for up to 30 mins; thereafter ventilator settings can often be weaned quite rapidly. FiO 2 should remain at 1.0 until SaO 2 is satisfactory, and thereafter be reduced as appropriate. 3.7.8 Post-lavage investigations • An arterial blood gas analysis should be performed at 1 hr post-lavage, or earlier if clinically indicated. Arterial blood analyses should also be performed 2 and 4 hours after lavage. • The recording of physiological parameters on the Treatment Data Form should continue for 4 hrs post-lavage. • A post-lavage chest X-ray should be performed within 4 hours of the procedure. Ideally this Xray would be done at around 1 hour post-lavage, at which time it will assist in optimisation of ventilator settings and exclusion of air leak. 3.8 NO LAVAGE Infants randomised to the No Lavage group will receive all neonatal intensive care treatments deemed appropriate by the Clinical Team, other than therapeutic lung lavage. This may include bolus surfactant therapy, although it must be recognized that normal doses of exogenous surfactant have not been shown to improve respiratory outcome in MAS, other than to reduce the use of ECMO [19]. There is no provision in the lessMAS trial for crossover from the No Lavage group to the Lung Lavage group. lessMAS trial protocol Version 2, December 2003 12 3.9 POST-INTERVENTION MANAGEMENT Other than the period around the time of therapeutic lung lavage, and the criteria concerning extubation and nasal CPAP set out below, this trial protocol deliberately makes no recommendations about the specific nature of neonatal intensive care in either study group. Enrolment in the lessMAS trial should in no way interfere with the provision of any and all therapies deemed appropriate by the Clinical Team, including high frequency ventilation, nitric oxide therapy and extracorporeal membrane oxygenation. Blood gas analyses would be expected to be performed at least 4-6 hourly until the infant is in the recovery phase, thereafter 6-12 hrly until assisted ventilation is discontinued. 3.9.1 Criteria for extubation and use of nasal CPAP Given that the main outcome measure of the study (duration of respiratory support) is under the influence of the Clinical Team, it is necessary to include criteria to ensure that the timing of transition from assisted ventilation is not inadvertently influenced by knowledge of the assignment group. These criteria apply to all infants included in the study, regardless of their randomisation group. Criteria for extubation (proceed to extubation once all applicable criteria are met) 1. FiO 2 50% reduction in duration of respiratory support in the "optimal lavage group"), and on the preliminary experience of others (ventilation days reduced by 58% [12], and 36% [13]). To detect a 30% reduction in duration of respiratory support with a power of 0.8 and an alpha of 0.05 will require 33 infants to be enrolled in each group [20]. The total number of infants randomised in the study will therefore be 66. 3.13 TRIAL PLAN Stage 1 January – December 2003. Neonatal intensive care units within Melbourne will be invited to participate in the study, with each episode of lavage being supervised by one of the Chief Investigators. A training course for Site Study Investigators will be conducted at the Royal Children's Hospital. Stage 2 January 2004 – July 2006. Neonatal intensive care units around Australia and New Zealand will be invited to participate, and a further training course will be conducted at the Royal Children's Hospital. Depending on recruitment, selected international centres will also be invited to join the study in Stage 2. 3.14 FEASIBILITY It is estimated that each year approximately 60 Australasian infants per year will fulfill criteria for enrolment in this study. Over a 4 year period, it will be necessary to enrol around 30% of these infants to complete the study. Selected international centres will be invited to join the study depending on Australasian recruitment. 3.15 SAFETY AND ADVERSE EVENTS A Data Monitoring and Safety Committee (DMSC) has been established for the lessMAS trial, consisting of two independent Neonatologists (Dr. Peter Davis, Royal Women's Hospital, Melbourne, and Dr. Andrew Watkins, Mercy Hospital for Women), and a Pharmacologist (Dr. Noel Cranswick, Royal Children's Hospital, Melbourne). All adverse events will be reported to the DMSC, as well as to the local Ethics Committee, using the Adverse Event Form. The data pertaining to the adverse event will be considered by the DMSC, and any recommendations arising from their deliberations will be passed to the Chief Investigators, the Site Study Investigator, and the local Ethics Committee. 3.16 INTERIM ANALYSIS Two interim analyses will be performed by the DMSC. The first analysis, after enrolment of 10 infants, will re-evaluate the safety of lavage (in particular, any Adverse Events reported with lavage), and the potential efficacy of the technique. Only if, in the opinion of the DMSC, the data reaffirm that lung lavage appears safe and potentially efficacious, would further patient recruitment continue. A further interim analysis will be performed at the half way stage of the trial, i.e. when a total of 33 infants have been randomised. 3.17 FUNDING The lessMAS trial is supported by project grants from the Murdoch Childrens Research Institute and the Australian NH&MRC. Abbott Australasia has agreed to provide the surfactant for the trial free of charge. lessMAS trial protocol Version 2, December 2003 15 4. REFERENCES 1. Kamlin O, Dargaville PA, for the Australian and New Zealand Neonatal Network. The epidemiology of meconium aspiration syndrome. Presented at the Annual Scientific Conference of the Perinatal Society of Australia and New Zealand, Christchurch, March 2002. 2. Wiswell TE, Bent RC. Meconium staining and the meconium aspiration syndrome. Unresolved issues. Pediatr Clin North Am (1993); 40: 955-81. 3. Paranka MS, Walsh WF, Stancombe BB. Surfactant lavage in a piglet model of MAS. Pediatr Res (1992); 31: 625-8. 4. Ohama Y, Itakura Y, Koyama N et al. Effect of surfactant lavage in a rabbit model of meconium aspiration syndrome. Acta Paediatrica Japonica (1994); 36: 236-8. 5. Cochrane CG, Revak SD, Merritt TA et al. Bronchoalveolar lavage with KL4-surfactant in models of meconium aspiration syndrome. Pediatr Res (1998); 44: 705-15. 6. Ohama Y, Ogawa Y. Treatment of meconium aspiration syndrome with surfactant lavage in an experimental rabbit model. Pediatr Pulmonol (1999); 28: 18-23. 7. Dargaville PA, Mills JF, Headley BM, Chan Y, Coleman L, Loughnan PM, Morley CJ. Therapeutic lung lavage in the piglet model of meconium aspiration syndrome. Am J Respir Crit Care Med (2003); 168: 456-463. 8. Burke-Strickland M, Edwards NB. Meconium aspiration in the newborn. Minn Med (1973); 56: 1031-5. 9. Ibara S, Ikenoue T, Murata Y, et al. Management of meconium aspiration syndrome by tracheobronchial lavage and replacement of Surfactant-TA. Acta Paediatrica Japonica (1995); 37: 64-7. 10. Mosca F, Colnaghi M, Castoldi F. Lung lavage with a saline volume similar to functional residual capacity followed by surfactant administration in newborns with severe meconium aspiration syndrome. Int Care Med (1996); 22: 1412-3. 11. Ogawa Y. Bronchial lavage with surfactant solution for the treatment of meconium aspiration syndrome. In: Hot Topics in Neonatology (1997) Conference Book; pp 259-64. 12. Lam BC, Yueng CY: Surfactant lavage for meconium aspiration syndrome: a pilot study. Pediatrics (1999); 103: 1014-8. 13. Wiswell TE et al. A multicenter, randomized, controlled trial comparing Surfaxin (Lucinactant) lavage with standard care for treatment of meconium aspiration syndrome. Pediatrics (2002); 109: 1081-7. 14. Dargaville PA, Mills JF, Loughnan PM, Campbell NT, McDougall PN. Large volume therapeutic pulmonary lavage in meconium aspiration syndrome. Abstract presented at the Annual Scientific Conference of the Royal Australasian College of Physicians, Brisbane, May 2002. 15. Moses D, Holm BA, Spitale P et al. Inhibition of pulmonary surfactant function by meconium. Am J Obstet Gynecol (1991); 164: 477-81. 16. Dargaville PA, South M, McDougall PN. Surfactant and surfactant inhibitors in meconium aspiration syndrome. J Pediatr (2001); 138: 113-5. 17. Fuchimukai T, Fujiwara T, Takahashi A, Enhorning G. Artificial pulmonary surfactant inhibited by proteins. J Appl Physiol (1987); 62: 429-37. 18. Dargaville PA, South M, McDougall PN. Comparison of two methods of diagnostic lung lavage in ventilated infants with lung disease. Am J Respir Crit Care Med (1999); 160: 771-7. 19. Soll RF, Dargaville P. Surfactant for meconium aspiration syndrome in full term infants (Cochrane Review). In: The Cochrane Library, Issue 3, 2000. 20. Wolfe R, Carlin JB. Sample-size calculation for a log-transformed outcome measure. Control Clin Trials 1999; 20: 547-54. lessMAS trial protocol Version 2, December 2003 16 Appendix A Detailed protocol for large volume therapeutic lung lavage SETTING In this study therapeutic lung lavage will only be performed in a neonatal intensive care setting, with available monitoring equipment utilised as appropriate. Lavage should be performed with the infant on an open cot, under a servo-controlled radiant heater. STABILISATION OF THE INFANT PRIOR TO LAVAGE Infants enrolled in the study will receive therapeutic lung lavage as soon as practicable after randomisation, but only after all necessary measures have been performed to optimise the infant’s condition. Lavage must not be performed in an infant in an unstable physiological state. Pre-ductal should be SaO 2 at least 90%, mean arterial blood pressure at least 40 mm Hg, and arterial pH at least 7.25 prior to lavage. Lavage should not be undertaken in an infant with a pre-ductal SaO 2 < 85%, a mean arterial blood pressure < 35 mm Hg or an arterial pH < 7.20. All efforts should be made to correct these physiological disturbances prior to lavage. Correction of hypoxaemia checklist • ETT size and position – change ETT if large leak • Inadequate mean airway pressure for the degree of lung disease – adjust as appropriate • Inadequate expiratory time – keep rate at least 60/min on conventional ventilation; on HFOV consider lowering frequency to 6-8 Hz • Pulmonary hypertension – correct acidosis and normalise CO2, bolster systemic blood pressure, normalise temperature, Hb, Ca++, Mg++ and glucose, then consider nitric oxide therapy • Air leak – perform chest X-ray, drain pneumothorax if present • Seizures – treat if detected Correction of hypotension checklist • Intravascular volume depletion - administer volume (particularly where central venous pressure low) • Poor myocardial contractility, poor peripheral vasomotor tone - initiate or increase inotrope therapy • Impairment of central venous return – rule out pneumothorax and ventilator-induced overdistension • Acidosis – correct as appropriate SEDATION AND MUSCLE RELAXATION DURING THERAPEUTIC LUNG LAVAGE Infants will require heavy sedation (narcotic ± benzodiazepine) and preferably muscle-relaxation prior to lavage therapy. This is not considered by the Study Investigators to be a departure from normal practice in managing ventilated infants with severe MAS. If an infant randomised to lavage is not being managed with muscle relaxants, administration of a short-acting paralytic agent (such as vecuronium or atracurium) prior to the lavage is recommended, preceded by top-up doses of sedation and analgesia, if necessary. Inadequate sedation and/or muscle relaxation during lavage may result in coughing/gagging, as has been noted by others [13]. Using a regime of heavy sedation and muscle relaxation, the lessMAS investigators have not encountered these problems in the human infants lavaged to date. PREPARATION FOR LAVAGE 1) Optimise the physiological condition of the infant, as above 2) Perform a pre-lavage chest X-ray (maximum 2 hrs prior to lavage) 3) Ensure the endotracheal tube tip is at or above the mid-trachea (on pre-lavage CXR), and measure and record the distance from the ETT connector to the tube tip. 4) Ensure that the ETT is securely taped in position. Considerable traction may be inadvertently applied to the ETT during the lavage. 5) Perform pre-lavage arterial blood gas analysis (maximum 30 mins prior to lavage), and calibrate transcutaneous monitors (pO 2 and pCO2) 6) Position and secure pre- ± post-ductal SaO 2 monitor, and ensure waveform is adequate lessMAS trial protocol Version 2, December 2003 17 7) Top up sedation and administer muscle relaxant. Adjust ventilator settings as necessary thereafter (settings may need to be increased after institution of muscle-relaxation). 8) Preoxygenate in FiO 2 1.0 for at least 5 mins prior to the commencement of lavage 9) Prepare a hand ventilation circuit, preferably with a manometer. It is recommended to use hand ventilation during the lavage procedure to re-recruit lung volume; an alternative is to place the infant on conventional ventilation and adjust settings to achieve lung volume recruitment. Nitric oxide should also be delivered through the bagging circuit if this is being administered to the infant. 10) Prepare the suctioning equipment and the lavage fluid, as described below 11) Prewarm ampoules of saline to 37 ºC in a water bath Suction equipment Adjust suction pressure to –150 to –200 mm Hg, and place a large mucus trap (Davol Inc, Cranston, USA) in the suction circuit to collect return fluid. Ensure that the cannister of the mucus trap remains in an upright position during the procedure. Use the largest bore standard suction catheter that the ETT will allow. Generally this will be a size 8 FG catheter for a 3.5 mm ETT, and a size 6 or preferably 7 FG catheter for a size 3.0 ETT. Lavage equipment (prepared sterile on a procedure trolley) • 2-4 vials of SurvantaTM . The manufacturers of SurvantaTM , Abbott Australasia, have agreed to provide surfactant free of charge for the trial. When preparing lavage fluid, vials of SurvantaTM will be obtained from ward stock, and this stock later replenished by Abbott at no cost. • 2 x 60 mL Luer lock syringes • (1 x 20 or 60 mL supplementary syringe) • 2 (3*) x 19 gauge needles for drawing up SurvantaTM • 2 (3*) x drawing up needles for drawing up saline • 2 (3*) x dispensing catheters with a Luer lock connection, for instillation of lavage fluid down ETT. These must fit easily down the ETT, and should be cut to length (maintaining sterility) so that when fully advanced through the ETT connector, the catheter tip sits just beyond the end of the ETT. Dispensing catheters should preferably packed straight, rather than coiled. * extra one needed if supplementary syringe Lavage fluid preparation Volume calculation: Calculate the amount of lavage fluid based on administration of two aliquots of 15 mL/kg. This calculation should be based on birth weight, or the best estimate thereof. Ideally each aliquot should be dispensed from a single 60 mL Luer lock syringe. For babies more than 4 kg, a supplementary syringe will be needed, as the volume of each aliquot will be greater than 60 mL. Half of the volume in the supplementary syringe will be instilled with the 1st aliquot, and the other half with the 2nd aliquot. The lavage fluid preparation table (see next page) assists with calculating the precise amounts of SurvantaTM and warmed saline to be drawn up in each syringe. Examples 2.5 kg baby: 3.5 kg baby: 4.5 kg baby: Draw up 7.5 mL Survanta and 30 mL saline into each of two 60 mL syringes Draw up 10.5 mL Survanta and 42 mL saline into each of two 60 mL syringes Draw up 12 mL Survanta and 48 mL saline into each of two 60 mL syringes, and in a supplementary syringe draw up 3 mL Survanta and 12 mL saline. Half the volume of the supplementary syringe will be instilled with the 1st aliquot, and the other half with the 2nd. Fluid preparation method: • Prepare the syringes, drawing up needles and dispensing catheters, as described above. • Draw up the Survanta into each of the syringes, avoiding bubbles as much as possible. • Immediately prior to lavage, draw up the requisite amount of warmed saline into each syringe. lessMAS trial protocol Version 2, December 2003 18 • • • Draw up a further 2 mL of air into each syringe, to clear the dead volume of the dispensing catheter when the fluid is instilled down the ETT. Mix the lavage fluid by gentle rotation from side to side. Do not shake! Attach the pre-cut dispensing catheter to each syringe. LAVAGE FLUID PREPARATION TABLE Amounts for each 60 mL syringe (one per aliquot) Weight (kg) Amount of Survanta (= 3 mL/kg) Amount of warmed saline (= 12 mL/kg) Total volume in each 60 mL syringe (= 15 mL/kg) Amounts for supplementary syringe Amount of Survanta Amount of warmed saline Total volume in supplementary syringe 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 4.0 4.1 4.2 4.3 4.4 4.5 6.0 6.3 6.6 6.9 7.2 7.5 7.8 8.1 8.4 8.7 9.0 9.3 9.6 9.9 10.2 10.5 10.8 11.1 11.4 11.7 12.0 12.0 12.0 12.0 12.0 12.0 24.0 25.2 26.4 27.6 28.8 30.0 31.2 32.4 33.6 34.8 36.0 37.2 38.4 39.6 40.8 42.0 43.2 44.4 45.6 46.8 48.0 48.0 48.0 48.0 48.0 48.0 30.0 31.5 33.0 34.5 36.0 37.5 39.0 40.5 42.0 43.5 45.0 46.5 48.0 49.5 51.0 52.5 54.0 55.5 57.0 58.5 60.0 60.0 60.0 60.0 60.0 60.0 ------------------------------------------0.6 1.2 1.8 2.4 3.0 ------------------------------------------2.4 4.8 7.2 9.6 12.0 ------------------------------------------3.0 6.0 9.0 12.0 15.0 LAVAGE METHOD Personnel required Study investigator – will direct the lavage procedure, instill the lavage aliquots, manipulate the chest during the dwell time, initiate the suction and perform further chest compression and positioning during the suctioning phase. Only persons that have received instruction in the technique of lavage should perform this task. Assistant 1 – will control the position of the head, and support the endotracheal tube at all times Assistant 2 – will perform the suction, and ensure the mucus trap remains in the upright position Assistant 3 – will administer the manual ventilation (and/or control the ventilator settings), and connect and disconnect the ventilator circuit during the lavage cycle Assistant 4 – will document the physiological changes during lavage and the timing of the lavage cycles, call out the relevant physiological indices from the cardiorespiratory monitor, and act as scout for any extra bits of equipment required. If four assistants are not available, the tasks of assistants 1 and 2 can be combined. The lessMAS investigators consider that, in the interests of safety, therapeutic lung lavage should be performed with the assistance of a minimum of 3 people in addition to the study investigator. lessMAS trial protocol Version 2, December 2003 19 Lavage sequence – 1st aliquot Preliminary • Move procedure trolley close to the bedside • Gather assistants in position, and make sure they are conversant with their roles • Ensure baseline physiological data have been recorded • Position the infant with head in the midline, and the head and neck slightly elevated off the cot • Institute hand ventilation if on HFOV • Adopt a chest position with R side down Instillation phase – recommended duration 20 secs, maximum 30 secs • Disconnect the ventilator circuit, pass the dispensing catheter fully into the endotracheal tube, and administer the 1st aliquot over about 20 seconds. Use half the volume from the supplementary syringe if required. • The whole process of instillation of each aliquot should not take more than 30 secs. • During the latter stages of instillation, it is quite common for some lavage fluid to efflux up the ETT. Do not be deterred by this – continue until all lavage fluid has been instilled. Dwell phase – recommended duration 10 secs, maximum 20 secs • Reconnect the ventilator circuit, and position the chest midline. • Apply positive pressure ventilation for 3-4 breaths using long inspiratory and expiratory times, with a peak pressure of around 30 cm H O. During each expiration, the study investigator should 2 perform bilateral chest compression and vibratory massage to mobilise and admix meconium in the fluid-filled lung Suctioning phase – recommended duration 30 secs, maximum 40 secs • Disconnect ventilator circuit, and advance premeasured suction catheter to beyond the ETT tip. It is vital that the suction catheter is in the correct position – if it is caught at the ETT tip or within the ETT, the recovery of lavage fluid may be seriously impaired. • Immediately apply suction, and collect return fluid in the mucus trap • During the suction phase, the study investigator should administer vibratory chest compressions, and roll the chest from side to side to optimise recovery of return fluid. • During suctioning, SaO 2 will fall considerably. The study investigator must judge when to reconnect to positive pressure ventilation, based on the SaO 2 readings, and how complete the recovery of lavage fluid has been. Maximising the recovery of return fluid is critical to the success of the lavage, and should take precedence unless SaO 2 is falling below 50%. Recovery phase Reconnect ventilation circuit, and apply positive pressure breaths with long inspiratory and expiratory times, as before. Pressures of 35 cm H O or higher may transiently be required to 2 recruit lung volume. • Watch for gradual recovery of SaO 2 to pre-lavage values over the next few minutes. • If recovery is slow, consider doing the following: a. Using higher peak pressure and longer inspiratory time b. Increasing PEEP c. Applying cricoid pressure if there is a leak around the ETT d. Reconnecting to HFOV and performing recruitment manoeuvres e. Performing further suctioning Expected fluid recovery from the first lavage aliquot should be somewhere between 20 and 50% of the instilled volume. (In the piglet model of MAS it was 46%, but has been noted to be generally less than this in human infants). Lavage sequence - 2nd aliquot The 2nd aliquot of lavage fluid should be instilled without delay once SaO 2 has recovered to near baseline readings. The procedure for the 2nd aliquot should be exactly as for the 1st, with the following exceptions. • The chest should be placed L side down during the instillation phase • Recovery of lavage fluid must be complete as possible during the suctioning phase – chest compression and positioning should be relatively vigorous lessMAS trial protocol Version 2, December 2003 20 • Once SaO 2 has recovered, a further brief episode of ETT suctioning should be performed as described above, with the return fluid also collected in the mucus trap. Expected fluid recovery from the 2nd lavage aliquot should be somewhere between 50 and 90% of the instilled volume. (In the piglet model of MAS it was 79%, but may be slightly less in human infants). Overall fluid recovery from both lavage aliquots should be between 30 and 70% of the instilled volume (it was 63% in the piglet studies). The fluid will show meconium staining to a varying degree, and may show considerable blood staining. This is not related to mucosal trauma from the lavage procedure; instead it is a reflection of the haemorrhagic pulmonary oedema that is regular feature of MAS [18]. POST-LAVAGE MANAGEMENT Once physiological parameters have recovered to near baseline readings, the pre-lavage ventilation mode should be reinstituted, but with ventilator settings which aid in the clearance of retained lavage fluid. For conventional ventilation these are: • Peak pressure 2-5 cm H2O higher than previously • PEEP of at least 6 cm H2O • Inspiratory time of at least 0.4 secs, with respiratory rate 60/min For high frequency oscillation these are: • PAW 2-4 cm H2O higher than previously • Higher amplitude only if transcutaneous or arterial pCO2 dictates Higher ventilator settings may be required for up to 30 mins; thereafter ventilator settings can often be weaned quite rapidly. FiO 2 should remain at 1.0 until SaO 2 is satisfactory, and thereafter be reduced as appropriate. POST-LAVAGE INVESTIGATIONS • • • An arterial blood gas analysis should be performed at 1 hr post-lavage, or earlier if clinically indicated. Arterial blood analyses should also be performed 2 and 4 hours after lavage. The recording of physiological parameters on the Treatment Data Form should continue for 4 hrs post-lavage. A post-lavage chest X-ray should be performed within 4 hours of the procedure. Ideally this X-ray would be done at around 1 hour post-lavage, at which time it will assist in optimisation of ventilator settings and exclusion of air leak. lessMAS trial protocol Version 2, December 2003 21