Dear Editor

Visveshwara's eLetter[1] emphasises that the results of the trigger trial should not be interpreted as demonstrating lack of benefit for patient triggered ventilation using other sensors or ventilators. I would concur with this statement, which was emphasised in the paper.

However, Visveshwara should not be surprised to find different outcome rates in the patients whose results he presents, as they are a different group of infants from those reported in either study. The evidence for benefit from the impedance technique is unconvincing, based as it is on a controlled study of 40 infants and a further 110 uncontrolled cases from one centre. A multicentre randomised controlled trial of sufficient power is needed to demonstrate benefit from the impedance and patient terminated ventilation techniques he describes. To date such a study has not been performed.

Yadav's eLetter[2] suggests that important risk factors have not been compared in the study. He describes two different types of risk factor, namely inherent factors in the infant (intrauterine growth retardation) and treatments applied to the infants (ventilation pressures, use of postnatal steroids and of CPAP).

In a large randomised controlled study individual patients will have varying degrees of risk for the outcomes being measured. The purpose of the study design is to allocate patients in such a way that the overall risk for each arm is the same. The larger the study, the less likely that there will be an unequal balance of risk, assuming that the randomisation process is performed correctly. We reported very similar birthweights and gestations in the two groups. The proportion of growth retarded infants was therefore allocated equally, and will not have biased the results. A study comparing two modes of ventilation cannot be conducted with the attendant clinicians blind to treatment allocation. The study protocol required all other treatments to be applied equally to infants in both arms of the study. There were written treatment protocols for each mode of ventilation. However, it is still possible that other treatments could have been applied unequally, with the possibility of bias resulting.

Interpretation of ventilator pressures is difficult, as in the trigger ventilation technique weaning was undertaken at lower peak inspiratory pressures. In Plymouth, trigger ventilated infants entered in the trial had slightly lower peak inspiratory pressures in the first 72 hours, consistent with the different weaning policy. However, as the duration of ventilation did not differ between the groups, it is reasonable to conclude that there was no systematic bias in the application of ventilation.

Information on the postnatal use of steroids was collected in the trial. There was no difference in the proportion of infants receiving postnatal steroids (25.5% vs 26.0%), nor in the postnatal age at which they were first administered (median 15 vs 17 days). There is therefore no evidence of bias resulting from their use.

The use of CPAP for weaning from ventilation has not been demonstrated to reduce chronic lung disease in randomised controlled trials. The paper Yadav cites discusses the possible benefits of a policy of early use of nasal CPAP. This is not relevant to the trigger trial, as infants recruited were by definition already being ventilated. I would also like to qualify Yadav's statement that we found an increased risk of pneumothorax in infants less than 28 weeks gestation. The difference was not statistically significant, suggesting that the observed difference may have occurred as a result of chance.

The trial therefore shows no evidence of bias, and the finding that patient triggered ventilation has no additional benefit over intermittent mandatory ventilation using the ventilators and techniques studied remains valid. The trial cannot assist clinicians in their choice of other modalities of support such as early use of CPAP or postnatal steroid use, and is applicable both to growth retarded as well as appropriately grown preterm infants.

Dr JH Baumer
on behalf of the trigger trial collaborators

References

(1) Visveshwara N. 'PTV': should it be patient triggered and patient terminated ventilation? Arch Dis Child Fetal Neonatal Ed [Rapid Response] 27 June 2000

(2) Yadav M. To trigger or not to trigger? Arch Dis Child Fetal Neonatal Ed [Rapid Response] 5 July 2000

Dear Editor

International randomised controlled trial by Dr Baumer[1] concluded that there was no benefit of patient triggered ventilation (PTV), but an added risk of increased pneumothorax in those less than 28 weeks gestation. In the same issue Beresford et al[2] concluded in a similar trial (with slightly more mature newborns 29 weeks vs 27), that PTV was feasible with no significant differences noted in medium term outcomes.

Chronic lung disease (CLD) is multifactorial in origin and in Baumer’s trial significant factors, like ventilation pressures, intrauterine growth retardation, use of post natal steroids and nasal CPAP use, have been not compared between the groups.

Intrauterine growth retardation has been shown to be an important risk factor for CLD.[3]

In a trial where primary outcome is chronic lung disease omission of the data regarding use of post natal steroid use is quite surprising. Meta-analysis of the use of dexamethasone in VLBW infants has shown significant reduction in CLD at 36 weeks post conceptional age.[4]

The use of nasal continuous positive airway pressure (nasal CPAP) that has been shown to influence the incidence of CLD, 5 fails a mention in their trial. Breseford et al did not use nasal CPAP in any of their infants, but used synchronised intermittent mandatory ventilation (SIMV) in the weaning phase.

To the clinician, who has to make the choice of using these commonly available tools to reduce death and morbidity in this vulnerable group of infants, the choice is clear or more unclear? I leave the readers to decide.

References:

1. Baumer JH. International randomised controlled trial of patient triggered ventilation in neonatal respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 2000;82:F5-F10.

2. Beresford MW, Shaw NJ, Manning D. Randomised controlled trial of patient triggered and conventional fast rate ventilation in neonatal respiratory distress syndrome. Arch Dis Child Fetal Neonatl Ed 2000;82:F14-F18.

3.Korhonen P, Tammela O, Kovisto AM, Laippala AM, Ikonen S. Frequency and risk factors in bronchopulmonary dysplasia in a cohort of very low birth weight infants. Early Hum Dev 1999;54:245-58.

4. Bhuta T, Ohlsson A. Systematic review and meta-analysis of early postnatal dexamethasone for prevention of chronic lung disease. Arch Dis Child Fetal Neonatal Ed 1998;79:F26-33.

5. Josson B, Katz-Salamon M, Faxelius G, Broberger U, Lagercrantz H. Neonatal care of very low birthweight infants in special care units and neonatal intensive care units in Stockholm. Early nasal continuous positive airway pressure versus mechanical ventilation: gains and losses. Acta Paediatr Suppl 1997;419:4-10.

Dear Editor

We were surprised at the results of the two studies published in your journal by Baumer[1] and Bersford et al[2]. Our experience with triggered ventilation over 10 years is shown in the table below:

Complications of prematurity 1991-99

	1991	1992	1993	1994	1995	1996	1997	1998	1999
<_1500 g="g" td="td">	n = 175	n = 190	n = 182	n = 184	n = 218	n = 169	n = 196	n = 203	n = 184
Retinopathy of prematurity Grade 3 or 4 (%)	2.2	5.2	6.5	4.8	5.5	7.1			3.2
Intraventricular haemorrhage Grade 3 or 4 (%)	13.1	2.5	16.4	12.3	12.8	11.8	7.6	9.3	3.2
Pneumothorax (%)	2.2	4.7	3.8	3.8	2.2	7	5	3.4	3.2
<_1250 g="g" td="td">	n = 130	n = 136	n = 133	n = 128	n = 162	n = 130	n = 154	n = 163	n = 134
Retinopathy of prematurity Grade 3 or 4 (%)	3	7.3	9	7	6.7	9.2	3.2	0.6	5.2
Intraventricular haemorrhage Grade 3 or 4 (%)	7.6	29.4	21	16.4	14.8	15.3	9.7	11.6	3.7
Pneumothorax (%)	3	4.4	5.2	4.6	3	5.3	3.5	3.6	3.7

In comparison to the outcome figures in the articles, our incidence of complications of pneumothoraces, intraventricular haemorrhage, and retinopathy of prematurity were significantly less.

As explained in our original article[3] and subsequently shown by others, pressure and flow triggered systems perform suboptimally in infants less than 1500 g. While bench testing may suggest an adequate response time, clinical practice indicates that these systems are compromised by the following:

(1) chest wall and lung compliance
(2) airway resistance
(3) leak around the endotracheal tube
(4) endotracheal tube resistance
(5) systems compliance.

The trigger delay may be aggravated by each of these factors, especially in the very low birth weight infants.

We believe that the inability of the patient to terminate the insufflation of gases at the onset of exhalation leads to increased intra thoracic pressure and even intra cranial pressure. Thus, if there is trigger delay as postulated above, the ventilator continues to force gases into the infant during the expiratory phase causing active exhalation and with consequent deleterious effects.

The system used in our unit is triggered by modified impedance technology. Peak detectors within the system detect onset of inspiration and exhalation with sensitivity and rapidly. Further, since the sensitivity depends on the rate of change of impedance, it is more sensitive when applied to very low birth weight infants or with increased rate of respiration. This may explain the marked difference in outcome, compared to the pressure triggered system, as shown by the application of the system in 1701 infants weighing less than 1500 g over 10 years. There were 1270 infants in the same group were less than 1250 g. The only problem we have encountered is that of some cardio respiratory monitors are incompatible with the triggering device. The signal processing through the monitors is crucial to the optimal performance of the respiratory analog input signal to the trigger/terminator. Prototypes of the system were used initially but since 1993 commercially available system (Sechrist SAVI) was utilized exclusively.

In large multicenter studies, derivation of consensus and consistent application of a standardized "conventional ventilation" protocol is very difficult. This may skew some of the outcome data. Perhaps the limitations of flow and pressure triggered systems need to be considered prior to abandoning triggered systems in the respiratory support of newborns. Active exhalation predisposes some of these infants to the complications cited. The incidence of ROP in our experience is less than that reported in the literature. Possibly the same mechanism described above also predisposes the infants to ROP.

Given all of the above, further studies and analysis may be prudent. Such studies of patient triggered ventilation should also incorporate the capability of patient terminated ventilation.

References

1. Baumer JH. International randomised controlled trial of patient triggered ventilation in neonatal respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 2000;82:F5-F10.

2. Beresford MW, Shaw NJ, Manning D. Randomised controlled trial of patient triggered and conventional fast rate ventilation in neonatal respiratory distress syndrome. Arch. Dis Child Fetal Neonatal Ed 2000;82:F14-F18.

3. Visveshwara N, Freeman B, Peck M, Caliwag W, Shook S, Rajani K B. Patient-triggered synchronized assisted ventilation of newborns; report of a preliminary study and three years' experience. J Perinatol 1991;XI:347-354.

Dear Editor

The interest displayed in the trigger ventilation trial by Burmester and Petros is welcome.(1) Their letter raises questions about the interpretation of the performance of the Dr�ger babylog 8000, which was used in a minority of infants in the study.

The trigger sensor device is different, and I agree with their implied statement that as each trigger ventilator performs differently results obtained using one ventilator cannot be extrapolated to another ventilator. However, both ventilators were used in PTV mode (sometimes referred to as Synchronised Intermittent Positive Pressure Ventilation, Assist Control or Synchronised Assisted Ventilation in Infants), with the ventilator set to trigger at each inspiratory effort. No infants in this study were ventilated with SIMV (Synchronised Intermittent Mandatory Ventilation) where the baby's breaths, selected during a 'time window', trigger the ventilator with the preset number of breaths per minute.

The results were reported in the way that they were for a reason. The original study design allowed a four-way randomisation between the two makes of ventilator and the two modes of ventilation. As was reported, only three centres had enough of both ventilators to allow this to occur. Other centres ventilating infants with the Dr�ger babylog had a two-way randomisation between PTV and IMV. Therefore the possibility of confounding by differences in practice between centres needed to be excluded. If the centres using the Dr�ger as well as the SLE ventilator had different outcomes from those using only one make of ventilator, this might lead to inappropriate conclusions being drawn if all infants being ventilated with one ventilator were simply compared to those being ventilated with another. A logistic regression model was therefore used to allow for possible centre effects (as well as other significant factors such as gestation).

With that caveat, I have extracted the following numbers from the database giving details of the crude observed rates of pneumothorax in the infants less than 28 weeks, separately reported for the two makes of ventilator.

	PTV mode�	IMV mode
Dr�ger without pneumothorax	19	20
Dr�ger with pneumothorax	5 (20.8%)�	4 (16.7%)
SLE without pneumothorax	154	114
SLE with pneumothorax	35 (18.5%)�	14 (10.9%)

The observed rate of pneumothorax was substantially (but not significantly, chi-squared 2.8, p>0.05 <_0.1 higher="higher" in="in" the="the" infants="infants" ventilated="ventilated" ptv="ptv" mode="mode" than="than" imv="imv" using="using" sle="sle" _2000.="_2000." although="although" numbers="numbers" are="are" small="small" observed="observed" pneumothorax="pneumothorax" rate="rate" was="was" those="those" with="with" drger="drger" babylog="babylog" _8000="_8000" ventilator.="ventilator." it="it" therefore="therefore" seems="seems" somewhat="somewhat" illogical="illogical" to="to" recommend="recommend" caution="caution" _2000="_2000" less="less" _28="_28" weeks="weeks" gestation="gestation" but="but" not="not" extend="extend" this="this" ventilating="ventilating" _8000.="_8000." given="given" that="that" none="none" of="of" these="these" differences="differences" were="were" statistically="statistically" significant="significant" no="no" clear="clear" recommendation="recommendation" can="can" be="be" given.="given." is="is" why="why" wording="wording" used="used" publication="publication" might="might" prudent="prudent" avoid.="avoid." p="p"> As regards the number of infants departing from their assigned mode of ventilation, several points should be emphasised. The study protocol permitted changing the mode of ventilation at the discretion of the attending clinicians. This was inevitably interpreted differently by each clinical team. Departure from the assigned mode of ventilation was not an intended outcome, and it is evident that this occurred more commonly in the more immature infants and those that subsequently died. High rates of departure from the assigned mode cannot therefore readily be interpreted as evidence of failure of the assigned mode. The numbers of infants of all gestations departing from the assigned mode of ventilation are shown below.

	PTV	IMV
Drager not departing	35	40
Drager departing	16 (31.4%)	15 (27.3%)
SLE not departing	303	274
SLE departing	�107 (26.1%)	�47 (14.6%)

There was therefore a higher crude rate of departure from the assigned mode of ventilation in infants ventilated with the Dr�ger babylog 8000, with a similar proportion transferred for failure to trigger.

It would be difficult to interpret the pneumothorax rates for those infants who were actually being ventilated with their assigned mode of ventilation. Some infants were switched to another mode of ventilation after sustaining their pneumothorax. Most of the pneumothoraces occurred whilst infants were receiving their assigned mode of ventilation, and this included infants being trigger ventilated using the Dr�ger ventilator.

Burmester and Petros ask whether centres contributing few patients might have higher morbidity rates, correcting for potential confounding factors by using a logistic regression model. The pneumothorax rate from centres contributing less than 20 patients was the same as the centres contributing more infants.

We have used a model to identify outcome differences in infants randomised within 3 months of the first infant being entered into the study, correcting for individual centre effects, gestation, birthweight and mode of ventilation. There was no significant difference in rates of death and chronic lung disease, abnormal cranial ultrasound scan or duration of ventilation. However, a marked and statistically significant difference was found for pneumothorax rates. The 139 infants randomised within 3 months had a pneumothorax rate of 5% versus a rate of 13% for those randomised more than 3 months into the trial (odds ratio 0.30, 95% confidence intervals 0.12 to 0.74, p=0.009). This was seen equally for both modes of ventilation.

This finding suggests that the initial educational visit by the trial co-ordinator had a beneficial effect on ventilator management that disappeared as infants continued to be enrolled.

In summary, there is no evidence from this study of any trend towards better outcomes with the Dr�ger babylog 8000 ventilator, though the small numbers enrolled make any conclusions less robust. There is evidence that suggests there may have been a short term reduction of pneumothorax rates from the educational package offered at the start of the trial.

In conclusion, there was no convincing evidence of a beneficial effect of a policy of using PTV in preterm infants with RDS with the ventilators used. Regular attention to staff education on ventilator techniques is recommended.

I would like to use this opportunity to pay tribute to the two trial co-ordinators (Sue Ellis and Tom Mill), to the trial statistician (David Wright) and to the data monitoring committee (David Field and Diana Elbourne), whose details were inadvertently omitted from the final paper, and without whom, together with the trial collaborators, the study would not have been possible.

Dr Harry Baumer, on behalf of the trial collaborators

1. Burmester M, Petros A. Triggered ventilation in neonates. [Rapid Response] Arch Dis Child Fetal Neonatal Ed 9 May 2000

Editor,

Baumer reports the results of large multi-centre study comparing the effects of patient triggered ventilation (PTV) with conventional ventilation (IMV)1. There appears to be no benefit from PTV compared to IMV in death rate, development of chronic lung disease, pneumothorax rates and cerebral ultrasound abnormality. In addition, because of an increased trend toward a higher pneumothorax rate, Baumer concludes that at present, PTV delivered with either the SLE 2000 or the Dräger babylog 8000 ventilators cannot be recommended for infants of less than 28 weeks gestation with respiratory distress syndrome (RDS).

However, we are concerned that this may be a premature conclusion given the significant difference in PTV delivered by the two main ventilators used and the potential heterogeneity of clinical practice within the different centres involved, despite agreed ventilation protocols. Dimitriou et al2 demonstrated that neonates and infants trigger a significantly lower proportion of breaths using the SLE 2000, an airway pressure triggered ventilator, compared with the Dräger babylog 8000, an airflow triggered ventilator that provides synchronised intermittent positive pressure ventilation (SIPPV). Attempts to optimise the trigger rate of the SLE 2000 ventilator by increasing pressure sensitivity often results in auto triggering as discussed by Baumer. Therefore the PTV modes of the two ventilators are substantially different. This prompts us to ask whether the findings of this multi centre study are only applicable to PTV provided by the SLE 2000? Would there have been a different outcome if all the triggered babies had received SIPPV?

It is not known how many of the 40/213 babies of less than 28 weeks gestation who had pneumothoraces were receiving SIPPV. As only 11% (52/465) of all triggered babies ever received SIPPV, we surmise that very few of the 40 were ventilated in this way. Is it fair to conclude that the Dräger babylog 8000 has a trend to pneumothorax on SIPPV?

In a separate smaller study Baumer also reports 120 patients in three centres randomly assigned to either the Dräger babylog 8000 or the SLE 2000 ventilator, and found a non-significant trend to higher pneumothorax rate, chronic lung disease and death for the former group. But we are not told how many of the babies were actually on trigger mode (PTV or SIPPV). They could all have been receiving IMV on the Dräger babylog 8000. Therefore is it possible that SIPPV is not being tested?

A further finding was a significantly higher rate (124/463) of triggered babies that departed from their assigned mode of ventilation, 45 of these failing to trigger their ventilator. Were they all on the SLE 2000 ventilator, as Dimitriou2 would predict?

Finally, we note that 10 of the 22 neonatal units each recruited less than 20 patients over the four year period, one contributing only 1 patient. Could the technique of PTV ventilation in units contributing so few numbers be different to those enrolling 60-136 neonates over the same period, despite prior visits from the trial co-ordinator? Would a logistic regression for morbidity against number of patients contributed from each unit reveal that the greatest morbidity occurred in units which contributed fewer patients, rather than those using PTV or SIPPV modes?

Given the heterogeneity of the units involved and the significant difference in ventilators used, we think that it is premature to dismiss SIPPV on the Dräger babylog 8000 in neonates less than 28 weeks gestation with RDS. We agree with Baumer that further studies are required, and extend his conclusion by saying that PTV with the SLE 2000 (n=411) rather than SIPPV from the Dräger babylog 8000 ventilator (n=52), cannot be recommended in this group.

MARGARITA BURMESTER, ANDY PETROS
Intensive Care Units, Great Ormond Street Hospital
London WC1N 3JH, UK

1. Baumer JH. International randomised controlled trial of patient triggered ventilation in neonatal respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 2000;82:F5-10.

2. Dimitriou G, Greenough A, Laubscher B, Yamaguchi N. Comparison of airway pressure triggered and airflow triggered ventilation in very immature infants. Acta Paediatrica 1998;87:1256-60.