The application of techniques of endotracheal intubation and intermittent positive pressure ventilation (IPPV) for newborns with respiratory failure revolutionised neonatal intensive care. Prior to the introduction of IPPV, the mainstay of early management was supportive care, including the delivery of supplemental oxygen, maintenance of normoglycaemia and correction of metabolic acidosis. These measures had been recognised to reduce morbidity compared to controls (Usher 1963). IPPV was introduced as rescue therapy to treat apnea or correct hypoxaemia and respiratory acidosis in infants likely to die, often after bag and mask ventilation had failed. The techniques applied were initially adapted from those used in adult ventilation and met with limited success when first introduced (D-Papadopoulos 1965, Murdock 1970). The short inspiratory times used in adults to avoid impaired venous return and the fast rates to avoid asynchrony in newborns were not as effective in preterm infants with atelectatic and poorly compliant lungs (Adamson 1968). Gregory 1971 observed dramatic improvements over earlier approaches in neonates with respiratory distress syndrome (RDS) when continuous positive airway pressure (CPAP) was applied through an endotracheal tube. Ventilators were introduced in the early 1970s which used circuits with continuous gas flow and a timing device to close the expiratory valve allowing the infant to breathe spontaneously and receive intermittent mandatory ventilation (IMV). Cumarasamy 1973 reported improved survival when IMV was combined with the application of positive end expiratory pressure (PEEP), although early experiences in this era document the use of high peak inspiratory pressures (PIP) to achieve adequate oxygenation. The high PIPs which were used reflected the poor compliance of the lung and were associated with high rates of mortality and bronchopulmonary dysplasia (BPD) (Northway 1967).
Alternative strategies were sought to treat infants with HMD using lower inflating pressures. Reynolds 1971 and Herman 1973 noted that alveolar recruitment and hence oxygenation could be improved by using low rates (30 - 40 breaths per minute) and long inspiratory to expiratory (I:E) ratios. In some infants, improvements in oxygenation were seen when inspiratory times exceeded the expiratory times (inversed I:E ratios). In inverse- ratio ventilation the IT is prolonged, thereby increasing mean airway pressures and allowing the use of lower PIP. As neonatal ventilation became more widely used in nurseries in the late 1970s/early 1980s, this strategy was often adopted even though the evidence of efficacy was based on small numbers (less than ten in both studies) with only improved arterial blood gases and indices of oxygenation reported as the primary outcomes.
In assisted ventilation, the ventilator maintains oxygenation by
providing an effective mean airway pressure (MAP) exceeding atmospheric pressure
and a suitable inspired oxygen concentration. It removes carbon dioxide by
passively removing the delivered tidal volume. The tidal volume is the volume
of gas moving in and out of the lung in a respiratory cycle. The minute ventilation
is the product of tidal volume and respiratory frequency. The alveolar ventilation
(minute ventilation minus dead space ventilation) determines the amount of
carbon dioxide removed. Ventilator "cycling" refers to the change from inspiration
to expiration and may be initiated by time (a pre-determined duration of
inspiration), pressure (when a preset pressure is reached) or volume (expiration
starts after a preset tidal volume is delivered).
Early pressure limited time cycled (PLTC) ventilators produced a square
wave when pressure (on the y axis) was plotted against time (on the x axis).
MAP is equal to the integration of the area under the pressure-time curve
during a single respiratory cycle. The square wave is dependent on the pre-set
inspiratory time, gas flow rate and ventilator frequency. Reynolds 1971
used square wave analysis to hypothesise that prolonging inspiratory time
and using slower rates would improve oxygenation by increasing MAP. The longer
the IT, the longer the lungs are held distended at the set PIP. Sustained
inspiratory pressures may have their greatest incremental effect on non-functioning
lung units, thereby improving distribution of the delivered tidal volume.
With high frequency positive pressure ventilation (HFPPV; rates >60) changes
in the pressure waveform are seen with a shortening of the inspiratory plateau
such that the square wave is replaced by a sine wave. Thus any change in
IT that accompanies frequency adjustments will change pressure waveforms,
thereby altering MAP and oxygenation. Increasing MAP has been shown to improve
oxygenation in RDS (Boros 1979). In contrast to early work by Reynolds 1971, Stewart 1981
found that increasing PEEP had the greatest effect on MAP. Whilst a high
MAP may be useful in acute RDS, excessive airway pressures in the recovering
lung may impede venous return and cause overdistension.
The time required for the lungs to inflate and deflate is determined by the compliance and resistance of the respiratory system which includes the ventilator circuit, endotracheal tube and the patient's lung. The product of resistance and compliance, the time constant, is a measure of how long it takes for alveolar and proximal airway pressures to equilibrate. It provides a theoretical basis on how best to divide the respiratory cycle into inspiratory and expiratory times. The inspiratory time constant is typically short (approximately 0.05 seconds) in RDS and relatively long (0.25 seconds) in infants with normal lungs. For practical purposes, an expiratory time equivalent to three time constants must be provided to allow 95% of inspired tidal volume to be expelled (Harris 1996). Thus if the expiratory times are absolutely or relatively short (as seen in inversed I:E ratios) there is the potential for gas trapping to occur and the build up of pressure known as inadvertent PEEP (Weigl 1973). Potential complications of inadvertent PEEP include gas trapping, reduced compliance and air leak. This can lead to reduced pulmonary blood flow and central venous return, a factor implied in spontaneous intraventricular haemorrhage in preterm infants (Rennie 1987). Ahluwalia 1994 measured spontaneous inspiratory and expiratory times in newborns ventilated for RDS at a median of 0.3 (range 0.26- 0.34) and 0.46 (0.34-0.66) seconds respectively. RDS, characterised by markedly reduced compliance with very short time constants, can theoretically be managed by using either rapid rates (>60) or slow rates with long inspiratory times providing there is sufficient time for passive exhalation. With HFPPV, the expiratory time may be insufficient to allow for deflation and lung units can become overdistended and further reduce the compliance of the lung.
Meconium aspiration affects mature infants and is characterised by both parenchymal and airway disease. Inhalation of meconium or congenital pneumonias can present as non homogenous lung disease typified by adjacent areas of atelectasis and hyperinflation. Setting ventilator parameters for non homogenous lung disease with different time constants is challenging with the aim being to provide sufficient alveolar ventilation without the development of inadvertent PEEP. The measurement of compliance and resistance in these circumstances is then dependent on the frequency of ventilation. With the limitations of PLTC ventilators, it has been observed that tidal volumes decrease as inspiratory times are reduced beyond a critical point (less than the time constant of the respiratory system) and that above a certain rate (>75), dead space ventilation increases and minute ventilation is not a linear function of frequency (Boros 1984).
Recent advances in neonatal intensive care may influence the optimal inspiratory time. These include the availability of exogenous surfactant therapy (Soll 2004, Yost 2003) and the advances in ventilator technology that allow synchronisation of ventilator breaths with an infant's spontaneous breathing (Greenough 2004). Surfactant improves oxygenation by increasing functional residual capacity. By stabilising patent airways and with the gradual recruitment of atelectatic regions of the lung, surfactant improves respiratory system compliance and may alter the optimal inspiratory time (Goldsmith 1996). Attempts to achieve synchrony have included the use of muscle relaxation (Greenough 1986) and rapid rates to avoid active expiration against positive pressure inflation (Greenough 2004). Modern neonatal ventilators achieve synchronisation by assisting each spontaneous breath or providing synchronised intermittent mandatory breaths. In addition, new generation neonatal ventilators with the addition of flow sensors allow continuous respiratory function and lung volume measurements. By measuring lung volumes, tidal volumes, resistance, dynamic and static lung compliance, much of the guesswork of setting ventilator parameters has been eliminated. However, despite these advances in ventilator technology, clinicians still need to set an inspiratory time.
The many variables involved in conventional mechanical ventilation (PIP, PEEP, IT, rate, flow rates) are interdependent making it difficult to assess the effects of changing one variable (IT) whilst holding the others constant. By using stated subgroup analyses (see objectives), the aim of this review is to identify the optimal inspiratory time (or range of times) in newborn infants needing respiratory support on conventional mechanical ventilation.
Planned sub-group analyses included:
1. A subgroup of studies defining short IT as less than or equal to 0.5 seconds
2. Subgroup analysis based on the overall ventilator strategy i.e.
a. Absolute IT set at different (long and short) levels and maintained constant through the infant's treatment
b. I:E ratios set at different levels and maintained constant so that
when rate was altered the IT and expiratory time were adjusted to maintain
the I:E ratio
c. Trials where IT or I:E ratio form only part of the ventilator strategy
e.g. when absolute IT and I:E ratios were not prescribed. In these trials
an acceptable range of ITs and I:E ratios as defined by the authors would
have been used in each arm
3. Underlying pathology (RDS vs other causes)
4. Gestational age i.e. term vs preterm
5. Use of muscle relaxants vs none
6. Surfactant vs no surfactant
7. Mode of ventilation (synchronised vs non synchronised)
See: Cochrane Neonatal Research Group (CNRG) search strategy
The standard search strategy of the CNRG was used. These included MEDLINE (1966 - April 2004) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2003). The MEDLINE search terms used were newborn, neonate, infant, mechanical ventilation, positive pressure respiration and the text phrase "ventilator rate" and text words "inspiratory" or "expiratory". No language restrictions were applied. The abstracts of the Society for Pediatric Research, and the European Society for Pediatric Research were searched from 1998 - 2003.
The standard methods of the Cochrane Collaboration and the CNRG were used. The methodological quality of each trial was reviewed independently by the two authors for blinding of randomisation, blinding of intervention and outcome measurements as well as completeness of follow up.
The two authors independently assessed eligibility of retrieved studies and extracted data; the results were compared and differences resolved by discussion.
The statistical analysis used the fixed effect model. For categorical
data the relative risk (RR), risk difference (RD) and number needed to treat
(NNT) with 95% confidence intervals were calculated. Continuous data were
analysed using weighted mean difference (WMD). Where data for individual
outcomes was incomplete (i.e. did not include all randomised babies), numerators
and denominators were those presented in the published manuscript.
For the summary of the included studies see also table of included studies.
Five published trials (Spahr 1980, Heicher 1981, Greenough 1981, OCTAVE 1991, Pohlandt 1992) recruiting a total of 694 infants were identified. All trials were performed in the pre-surfactant era and when antenatal steroids were not widely used. Three (Spahr 1980, Heicher 1981 and Greenough 1989) were single centre studies whilst OCTAVE 1991 and Pohlandt 1992 involved 6 and 7 centres respectively.
One study (Nilmeier 1995) was excluded. This was a randomised controlled trial in infants with ventilator dependent HMD recruited at two weeks of age, comparing two ITs of 1.0 and 0.4 seconds over a period of seven days. Oxygenation and respiratory mechanics were measured prior to randomisation and compared after a week of the intervention. The results, however were only published in part and were descriptive in nature. Improvements in oxygenation were described as indicated by FiO2 requirement rather than our prespecified indices (AaDO2, PF ratios), and these were only presented for infants randomized to a long IT.
Study Population
The inclusion criteria varied slightly between studies. All the studies except Greenough 1989 recruited infants with acute respiratory failure. Greenough 1989 compared different ITs when weaning infants recovering from HMD. Only Pohlandt 1992 had specific gestational age criteria for inclusion, recruiting infants less than or equal to 32 weeks gestation at birth. Heicher 1981
recruited ventilated infants with a birth weight of greater than 750g. In
the study of OCTAVE all ventilated infants less than 72 hours of age were
eligible whilst Spahr 1980 recruited all ventilated newborns over a 12 month period. The age at recruitment was not stated in the studies of Heicher 1981 and Spahr 1980.
The differences in underlying respiratory pathology between the studies were
small. Most infants had HMD although some cases of pneumonia were included.
Only OCTAVE 1991 and Heicher 1981
specifically excluded infants with meconium aspiration syndrome (MAS) but
no data specific to MAS were provided by any of the included studies.
Interventions
The ventilator strategies and types of ventilator used (see table of included studies) varied with each study.
Once randomised to a long IT or short IT, all infants were ventilated
to meet therapeutic range of oxygenation and eucapnia as defined by the authors.
All studies allowed adjustments in PIP to correct hypoxia. Ventilation was
weaned by decreasing PIP. Where the IT was held constant, weaning of the
ventilator rate was achieved by lengthening the expiratory time. All studies
had a priori failure criteria (see table).
Inspiratory times as defined by the authors were as follows;
1. Concealment of allocation schedule
OCTAVE 1991 was a multi-centre trial in
which the randomisation was adequately concealed by the use of sealed opaque
envelopes held at the co-coordinating centre. Participating centres made
a telephone call to the co-ordinating centre when an infant was enrolled
and the next sealed envelope opened. Methods of concealing the allocation
schedule were not used in the studies of Heicher 1981 and Spahr 1980. Lists were constructed in the study of Pohlandt 1992
such that the numbers treated with either a long or short IT were equal after
every second infant enrolled for a particular gestation. These lists were
not concealed. The method used in randomising enrolled infants was not described
by Greenough 1989 and thus concealment of allocation was unknown.
Generation of allocation sequence -
This was not stated for OCTAVE 1991. Pohlandt 1992
used randomisation tables divided into blocks of two for each intervention
arm for each of the intended target population (under 28 weeks, 28-30 and
31-32 weeks). Spahr 1980 used a coin toss to determine the treatment allocation sequence. Heicher 1981
quasi-randomised enrolled infants using alternate selection for long and
short ITs. The generation of allocation sequence was not stated in the study
of Greenough 1989.
2. Inclusion in the analysis of all randomised participants
All participants were accounted for in the included studies. Pohlandt 1992
used an unusual recruitment and randomisation procedure. Consent was not
obtained and all preterm infants less than 32 weeks needing mechanical ventilation
were provisionally enrolled and randomised. Infants not meeting secondary
enrolment criteria (FiO2 > 0.4) were excluded and replaced by the next
preterm infant in the same gestational age category (37 of 181 initially
randomised). An additional seven infants were excluded after randomisation
because they received the alternate form of therapy during transport. Spahr 1980
excluded five (of 74) patients post randomisation either because of air leaks
(one before randomisation, two post PDA ligation), one because of sepsis
and one because of use of a muscle relaxant. The remaining three studies
had no post randomisation exclusions. OCTAVE 1991
followed a subgroup of enrolled patients (<33 weeks gestation at birth)
at a median age of 18 months. Of the 183 surviving eligible infants, 175
(96%) were seen.
3. Blinding of intervention
It was not possible to blind the caregivers in any of the studies.
4. Blinding of outcome assessments
All the primary outcome assessments were unblinded in the five included studies with one exception (Pohlandt 1992), where physicians and radiologists blinded to treatment allocation diagnosed air leak and BPD. In the OCTAVE 1991 study 98% of the long term neurodevelopmental assessments were blinded.
Five studies (Spahr 1980, Heicher 1981, Greenough 1989, OCTAVE 1991, Pohlandt 1992) enrolling 694 infants met the entry criteria and were included in the analysis.
Primary Outcomes
Comparison 01: Long versus short IT as defined by investigators (all trials)
Mortality
Mortality before hospital discharge was reported in all included studies (Table 1). OCTAVE 1991
was the only study to report mortality after hospital discharge. In this
study mortality at latest follow up was 30/126 (24%) in the long IT group
compared to 36/125 (29%) in the short IT group. In a pooled analysis, there
was a trend toward an increased rate of mortality before hospital discharge
in newborns ventilated with a long IT that reached borderline statistical
significance [typical RR 1.26 (1.00, 1.59), typical RD 0.07 (0.00, 0.13)].
Air Leak
The rates of air leak (acute lung injury) were reported in all included studies (table 2). The studies of Heicher 1981 and Pohlandt 1992
demonstrated statistically significant differences in this outcome disfavouring
the use of a long IT. There were no significant differences in the studies
of Greenough 1989, Spahr 1980. OCTAVE 1991,
the largest individual study in this meta-analysis, reported no overall difference
in the rates of air leak but when this outcome was compared within a subgroup
of infants with HMD, there was a statistically significant difference favouring
the use of a short IT (p= 0.013). In a pooled analysis, the use of a long
IT was associated with a significantly increased rate of air leak [typical
RR 1.56 (1.25, 1.94), typical RD 0.13 (0.07, 0.20), NNT 8 (5, 14)].
BPD (Chronic lung injury)
The rates of BPD in all included studies (Table 3) was defined as the
need for supplemental oxygen at 28 post natal days. None of the studies reported
on this outcome at 36 weeks post conceptual age. No individual study found
a significant difference in this outcome and in a pooled analysis, there
was no significant difference in the rates of BPD [typical RR 0.91 (0.66,
1.24), RD -0.02 (-0.08, 0.04)]. The trend towards lower rates of BPD using
a longer IT in the studies of Spahr 1980, Heicher 1981 and OCTAVE 1991 is offset by their higher rate of death.
For all primary outcomes there was no significant heterogeneity of treatment effect (I2 = 0 for all outcomes)
Secondary Outcomes
Oxygenation
Improvements in oxygenation using our pre-defined criteria (AaDO2,
OI, P/F ratios) were not reported when comparing IT greater than O.5 seconds
with shorter IT. Spahr 1980 provides data for the mean AaDO2
(SD) after 6 hours following the intervention (Table 4). At this early time
point, no statistically significant differences were noted. Analysing survivors
only, the AaDO2 was significantly lower at 24 and 48 hours in infants ventilated using an IT of 2 seconds versus 1 second.
Duration of mechanical ventilation and oxygen therapy
Data on duration of ventilation in the included studies were either
incomplete or presented in a format not permitting a pooled analysis. Pohlandt 1992 and Greenough 1989
did not publish sufficient data to allow a comparison between groups with
respect to duration of mechanical ventilation and oxygen therapy. Spahr 1980 presented data only from survivors in the first week of life and Heicher 1981 excluded more than 10% of babies from the analysis of these outcomes. OCTAVE 1991
reported no significant difference between groups with respect to median
age of extubation and median age at weaning from supplemental oxygen.
Neurological injury
No individual study reported the outcomes of IVH or PVL based on ultrasound findings. Spahr 1980 reported the incidence of IVH through examination at autopsy in those who died and using computed tomography in two survivors. Heicher 1981 described large IVH diagnosed at autopsy but rates of IVH in survivors was not reported. It was the intention of the OCTAVE 1991
group to report on rates of IVH but difficulty was found in retrieving images
from all the participating centres and this was replaced by long term neurodevelopmental
follow up. In the available data from two trials, no significant effect on
this outcome was shown (Table 6).
Patent ductus arteriosus
Symptomatic patent ductus arteriosus (PDA) requiring treatment was reported
in the studies of Spahr and Pohlandt. There was a considerable difference
in the rates of PDA, with Spahr (conducted in 1978) reporting an incidence
of 9% in all recruited infants and Pohlandt (conducted between 1983 and 1985)
reporting an incidence of 35% of all recruited infants. This probably reflects
the improvements in echocardiography in the intervening period. In a pooled
analysis of these two trials, no significant effect on this outcome was shown
(Table 6)
Developmental delay
No individual study used formal psychometric testing to assess long term
developmental status. The single study reporting long term outcome data (OCTAVE 1991)
followed up surviving infants under 33 weeks gestation to a median age of
18 months. The tools used for these assessments were not stated. The outcomes
reported were cerebral palsy (Table 7), sensory deficits (impaired hearing
or vision; Tables 8 and 9) or global developmental delay. There was an increased
rate of cerebral palsy with small numbers (12 versus 4 cases) in infants
treated with long IT but this was of borderline statistical significance
[RR 2.90 (0.97, 8.65), RD 0.09 (0.00, 0.17).
Subgroup Analyses
Comparison 02: Long (>0.5 seconds) vs Short (<0.5 seconds) IT
This subgroup analysis involved all the included studies except for Spahr 1980
and resulted in findings similar to the overall analysis. In a pooled analysis
of four trials involving 625 infants, mortality before hospital discharge
showed a trend disfavouring a long IT which did not reach statistical significance
[typical RR 1.24 (0.96, -1.60), typical RD 0.06 (-0.01, 0.13)]. A long IT
was associated with a significant increase in the number of air leaks [typical
RR 1.56 (1.24, 1.97), typical RD 0.13 (0.07,0.20), NNT 8 (5,14)]. There was
no significant difference in rates of BPD [typical RR 0.92 (0.66, 1.28)].
Analysis based on the overall ventilator strategy
a. constant IT - only Heicher 1981 maintained IT at 1.0 vs 0.5 seconds in the acute and weaning period.
b. constant I/E ratios - only Spahr 1980 and OCTAVE 1991
aimed to keep I:E ratios constant. It should be noted that the ITs in these
two studies are vastly different with the duration of inspiration set in
the "short IT" arm of Spahr 1980 equal to that set in the "long IT" arm of OCTAVE 1991.
With the vastly different ITs and ventilator rates and thus very different
absolute ratios, a subgroup analysis of these two studies was not performed
based on ventilator strategy. These two trials were combined using all enrolled
infants in Spahr 1980 and those with HMD in OCTAVE 1991 in a pooled analysis of infants with HMD (see below).
c. where both IT and I/E ratios are varied
In all studies the short IT remained unchanged. In most of the studies
adjustments of the long IT were permissible when weaning commenced. Variable
I:E ratios were seen in the long IT group when rate was either increased
or decreased. The ventilator rate ranged between 20 and 40 for Heicher 1981 and OCTAVE 1991 and 30 to 40 for Pohlandt 1992. Thus a subgroup analysis was not performed.
Comparison 03: Long versus short IT in HMD (subgroup analysis by diagnosis)
Although the primary respiratory diagnosis was HMD in most infants in the included studies, only Spahr 1980 and OCTAVE 1991 provided published data on outcomes by respiratory pathology. In a pooled analysis of patients with HMD, a significant increase in mortality before discharge [typical RR 1.54 (1.06, 2.23), typical RD 0.12 (0.02, 0.21), NNT 8 (5, 50)] and air leak [typical RR 1.73 (1.17, 2.57), typical RD 0.14 (0.04, 0.24), NNT 7 (4, 25)] was seen in the infants randomised to a long IT.
Gestational age
All the trials except for Pohlandt 1992
(infants less than or equal to 32 weeks gestation randomised) had no restrictions
on gestational age at recruitment. In this individual study there was a statistically
significant increase in air leak in the long IT group. No significant differences
were seen in rates of mortality before hospital discharge and BPD.
Comparison 04: Long versus short IT (subgroup analysis of trials allowing use of muscle relaxants)
Muscle relaxants were allowed in the trials of Heicher 1981, Pohlandt 1992 and OCTAVE 1991 but not used in Spahr 1980 and Greenough 1989. Data on the extent of use of muscle relaxants were not presented in the report by Pohlandt 1992, and were incomplete in OCTAVE 1991 (published data was sourced from only of one of the participating centres). Similar use of muscle relaxants occurred in each arm of Heicher 1981 (13 versus 14). In an analysis confined to the three trials permitting muscle relaxants usage, there was a significant increase in air leak [typical RR 1.56 (1.25, 1.94), typical RD 0.14 (0.07, 0.21), NNT 7 (5, 14)] and an increase in mortality [typical RR 1.26 (0.97, 1.62), typical RD 0.07 (-0.01, 0.14)] which reached marginal statistical significance, in infants managed with a long IT. In the trials where no muscle relaxants were used (Spahr 1980, Greenough 1989), there were no statistically significant differences in air leak or mortality.
Trials using surfactant
None of the trials used surfactant in the management of HMD.
Ventilator mode
All infants were ventilated using continuous mandatory ventilation. No
synchronised modes were used. Ventilator types differed (see table of included
studies).
The use of long vs short ITs has not been well studied in subjects with established BPD or evolving BPD. The one study excluded from this meta- analysis (Nilmeier 1995) investigated the effects of a long or short IT on subjects with BPD (more than one month of age and ventilated) and looked at pulmonary mechanics and oxygenation before and after one week of the intervention. Although a long IT improved delivered tidal volumes, no significant differences were seen in duration of ventilation or hospital stay.
The IT set by the attending clinician is a single parameter that can influence oxygenation. Other manipulations include providing sufficient PEEP, so that positive pressure delivered throughout the respiratory cycle is above the critical opening pressure of the lung, thus avoiding repeated inflation deflation cycles which are injurious to the lung. Gas flow rates are usually held constant and the effects of varying gas flow rates on oxygenation and BPD have yet to be investigated. Of all the included studies, only one (Spahr 1980) provided data on the effects of IT on oxygenation in the acute phase of HMD. Whilst the study used ITs in both arms that would be considered "long", this was a study primarily comparing two I:E ratios. The improvements in oxygenation seen in inverse ratio ventilation can be attained (using the same physiological principles of alveolar recruitment and maintenance of lung volumes) if appropriate PEEP is applied throughout the respiratory cycle. The optimum level of PEEP will vary according to the underlying pulmonary pathophysiology and is yet to be evaluated in a formal clinical trial.
The range of ITs used in the long IT groups in this systematic review was 0.66 to 2.0 seconds. In acute HMD, where the median IT is 0.3 seconds (Ahluwalia 1994), these ITs are likely to cause asynchrony and patient discomfort. If these long ITs were used in surfactant treated infants, the combination of improved compliance and greater likelihood of active expiration against a positive pressure inflation may increase the risk of air leak. Thus using a long IT in acute HMD following surfactant replacement may be an unnecessary strategy unless faced with continuing severe hypoxia. In these situations there are current alternative modes of therapy to improve oxygenation if conventional ventilation is failing, including rescue high frequency ventilation and the use of inhaled nitric oxide in mature infants. Perinatal units are now widely using ventilators that synchronise with the infant's breathing and target tidal volumes. With synchronised ventilation, square wave ventilation has been replaced by sinusoidal waves so that mean airway pressures are less influenced by the length of the IT.
This review has shown no advantage in using long IT over short IT in the treatment of acute respiratory failure (mainly HMD). Whilst there is increasing use of non invasive ventilation such as nasal continuous positive airway pressure to avoid ventilator induced lung injury in the acute management of HMD, mechanical ventilation will continue to have a role in extremely immature infants and those with HMD complicated by apnea. In institutions where surfactant is unavailable, lengthening the IT may improve oxygenation in the acute phase. However, as compliance improves, the IT should be reviewed regularly as this review demonstrates a significant risk of lung injury (airway leak) with a long IT. The use of a long IT where time constants are longer than acute HMD such as premature infants with BPD, meconium aspiration syndrome and newborns in cardiac failure may be appropriate and is yet to be investigated.
Whilst neonatal respiratory failure is not a single disease entity, relatively recent advances in technology have allowed the bedside display of real time inspiratory and expiratory tidal volumes. Clinicians therefore have the ability to adjust the IT as pulmonary mechanics change during the course of an infant's illness. These strategies will need to be evaluated in future clinical trials.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Greenough 1989 | Concealment of allocation: Can't tell - method of randomisation to either long IT (group A) or short IT (group B) not stated. Blinding of intervention: No Completeness of follow up: Yes for short-term outcomes - all participants accounted for. Blinding of outcome measurement: No
| Single centre study. All infants with RDS (n=40) and ventilated with HFPPV (>60bpm) were recruited when weaning commenced (PIP = 20cm H20 and rate =60bpm). | At recruitment all infants were ventilated using an IT of 0.5 seconds. Weaning then commenced using one of two strategies. In Group A (long IT) (n=20), the rate was reduced by increasing both the IT and ET maintaining a fixed I:E ratio at 1:1.2. Maximum IT in this group was 1 second. In group B (short IT) (n=20), the rate was weaned by keeping the IT fixed at 0.5 secs whilst increasing the expiratory time (ET). Single (Sechrist) type of ventilator. | Air leak Indices of oxygenation (paO2) Duration of weaning Rate of reintubation | Year of study = 1989. Pre-surfactant. Age at recruitment not specified. | B |
| Heicher 1981 | Concealment of allocation: No - quasi-randomised using alternate allocation for long and short ITs Blinding of intervention: No Completeness of follow up: Yes for short-term outcomes (all outcomes complete for hospital stay) Blinding of outcome measurement: No | All infants >750g and ventilated with abnormal CXR findings (n=102). Infants with gross abnormalities, chromosomal anomalies and meconium aspiration were excluded. | Long IT (n=51) compared with short IT (n=51). Long IT= 1.0 seconds; rates used 20-40bpm. Short IT=0.5 seconds; rate used 60bpm. Single ventilator (Babybird) used in both groups. Criteria for failed treatment and relaxation of allocated ventilator strategy were as follows; 1. Hypoxia - either (i)PaO2 < 50 torr with FiO2 of 1.0 and PEEP of 8 to 10cm H20 or (ii) Fi02 > 0.6 (short IT) or PIP > 30cm H20 (long IT) for 72 hours. 2. Hypercarbia - PaCO2 > 45 torr on maximum PIP and rate permitted for the group. | Mortality Air leak BPD at 30 days by Northway criteria. Combined outcome of death and IVH | Years of study = 1978 - 79. Pre-surfactant. Age at recruitment not specified. | C |
| OCTAVE 1991 | Concealment of allocation: Yes - sealed opaque, serially numbered envelopes stored at co-ordinating centre. Blinding of intervention: No Completeness of follow up: Yes for short-term outcomes - 100% follow up for in-hospital outcomes with 97% of infants born less than 33 weeks accounted for in the long term outcome assessment at 18 months. Blinding of outcome measurement: not for primary outcomes. 98% of neurodevelopmental follow up completed by physicians blinded to ventilation strategy | Newborns of any gestation ventilated for any reason (n=346). Infants with meconium aspiration excluded. Infants were enrolled before 72 hours of age. | Long IT (n=172) compared with short IT (n=174). Long IT= 1.0 seconds; starting rate=20bpm (range=20-40bpm) and I:E ratios not fixed. Short IT=0.33 seconds; rate used =60bpm and I:E ratio fixed at 1:2. Single ventilator (Sechrist IV 100B) used in both groups. Dopamine and tolazoline used at physician's discretion to treat hypotension or reduce right to left shunting. The use of muscle relaxants was permitted for recurrent air leaks and for poor gas exchange despite recruitment manouvres and optimisation of haemodynamics. Criteria for failed treatment and relaxation of allocated ventilator strategy were as follows; 1. Hypoxia - PaO2 < 50mmHg despite FiO2 >0.95 and MAP of 17cmH20. 2. Recurrent pneumothoraces | Death before discharge Air leak BPD defined as need for supplemental oxygen at 28 days A subgroup of infants less than 33 weeks gestation had long term follow up at a median age of 18 months | Years of study = 1983 - 86. Pre-surfactant. | A |
| Pohlandt 1992 | Concealment
of allocation: No - all ventilated infants provisionally randomised using
one of three randomisation tables (stratified by gestational age). If infant
subsequently excluded they were replaced by the next preterm infant in the
same gestational age category. Blinding of intervention: No Completeness of follow up: Yes for primary outcomes - 100% follow up for in-hospital outcomes Blinding of outcome measurement: Only for diagnosis of air leak and BPD | Preterm infants equal to or less than 32 weeks gestation and mechanically ventilated (n=181)were randomised if FiO2 >0.4 after 3 hours of birth (no upper age limit given). Infants later excluded if the FiO2 was < 0.4 to maintain PaO2 >50mmHg or if there were any violations of allocated ventilation protocol (exclusions post randomisation=44) | Long IT (n=63) compared with short IT (n=74). Long IT=1.0 seconds; rates of 30 to 40bpm; I:E ratio 1:1 increased to 2:1 in case of hypoxaemia. IT reduced to 0.66 seconds during weaning. Short IT=0.33 seconds; rate=60bpm. I:E ratios kept constant at 1:2; weaned by reducing PIP, PEEP and inspired oxygen. Seven different ventilators were used in this study. No failure criteria described in the report. | Mortality Extra-alveolar air leak BPD at 28 days by Northway criteria | Years of study = 1983 - 85. Parental consent not sought as ventilator frequencies of 30 -100 widely used in the participating units. Pre-surfactant. | C |
| Spahr 1980 | Concealment of allocation: No - randomised by coin toss Blinding of intervention: No Completeness of follow up: Yes for short-term outcomes Blinding of outcome measurement: No | All infants admitted in a 12 month period and ventilated for HMD (n=74). Five post randomisation exclusions (pre-existing air leaks=3, sepsis=1, use of paralysing agent=1) | Long IT (n=36) compared with short IT (n=33). Long IT=2 seconds; rate=20bpm; I:E ratio 2:1. Short IT=1 seconds; rate=20bpm; I:E ratio 1:2. Target PaO2 45 - 60mmHg and pH 7.25 to 7.35. Single ventilator (Babybird). No failure criteria described in the report. | Mortality at 28 days Air leak BPD defined as need for supplemental oxygen at one month with typical radiographic findings Pulmonary haemorrhage, IVH (all grades), PDA. | Year of study = 1978. Pre-surfactant and pre antenatal steroids. | C |
| Study | Reason for exclusion |
| Nilmeier 1995 | Randomised controlled trial of infants recruited at two weeks of age. Oxygenation and respiratory mechanics were compared after a week of intervention at two ITs (1.0 and 0.4 seconds). Published results however were incomplete (data from only one group) and descriptive in nature ( not using our prespecified indices of AaDO2 and PF ratios). |
Greenough A, Pool J, Gamsu H. Randomised controlled trial of two methods of weaning from high frequency positive pressure ventilation. Archives of Disease in Childhood 1989;64:834-8.
Heicher 1981 {published data only}
Heicher DA, Kasting DS, Harrod JR. Prospective clinical comparison of two methods for mechanical ventilation of neonates: Rapid rate and short inspiratory time versus slow rate and long inspiratory time. Journal of Pediatrics 1981;98:957-61.
OCTAVE 1991 {published data only}
Multicentre randomised controlled trial of high frequency positive pressure ventilation. Oxford Region Controlled Trial of Artificial Ventilation OCTAVE Study Group. Archives of Disease in Childhood 1991;66:770-5.
Pohlandt 1992 {published data only}
Pohlandt F, Saule H, Schroder H, Leonhardt A, Hornchen H, Wolff C et al. Decreased incidence of extra-alveolar air leakage or death prior to air leakage in high versus low rate positive pressure ventilation: results of a randomised seven-centre trial in preterm infants. European Journal of Pediatrics 1992;151:904-9.
Spahr 1980 {published data only}
Spahr RC, Klein AM, Brown DR, MacDonald HM, Holzman IR. Hyaline membrane disease - A controlled study of inspiratory to expiratory ratio in its manaagement by ventilator. American Journal of Diseases of Children 1980;134:373-6.
Nilmeier NL, Hodge GB, Dunn CE, Benitz WE, Ariagno RL. One second inspiratory time improves lung mechanics in preterm infants who are ventilator dependent post respiratory distress syndrome. Pediatric Research 1995;37:344A.
* indicates the primary reference for the study
Adamson TM, Collins LM, Dehan M, Hawker JM, Reynolds EO, Strang LB. Mechanical ventilation in newborn infants with respiratory failure. Lancet 1968;2:227-31.
Ahluwalia JS, Morley CJ, Mockridge JN. Computerised determination of spontaneous inspiratory and expiratory times in premature neonates during intermittent positive pressure ventilation. II: Results from 20 babies. Archives of Disease in Childhood Fetal Neonatal Edition 1994;71:F161-4.
Boros SJ. Variations in inspiratory:expiratory ratio and airway pressure wave form during mechanical ventilation: the significance of mean airway pressure. Journal of Pediatrics 1979;94:114-7.
Boros SJ, Bing DR, Mammel MC, Hagen E, Gordon MJ. Using conventional infant ventilators at unconventional rates. Pediatrics 1984;74:487-92.
Cumarasamy N, Nussli R, Vischer D, Dangel PH, Duc GV. Artificial ventilation in hyaline membrane disease: the use of positive end-expiratory pressure and continuous postive airway pressure. Pediatrics 1973;51:629-40.
Delivoria-Papadopoulos M, Levison H, Swyer PR. Intermittent positive pressure ventilation as a treatment in severe respiratory distress syndrome. Arch Dis Child 1965;40:474-9.
Doyle LW, Gultom E, Chuang SL, James M, Davis P, Bowman E. Changing mortality and causes of death in infants 23-27 weeks' gestational age. Journal of Paediatrics and Child Health 1999;35:255-9.
Goldsmith JP, Karotkin E (eds). Assisted Ventilation of the Newborn. 3rd edition. Philadelphia: Saunders Company, 1996.
Greenough A, Morley CJ, Pool J. Fighting the ventilator - are fast rates an effective alternative to paralysis. Early Human Development 1986;13:189-94.
Greenough A, Pool J, Greenall F, Morley C, Gamsu H. Comparison of different rates of artificial ventilation in preterm neonates with respiratory distress syndrome. Acta Paediatrica Scandinavica 1987;76:706-12.
Greenough A, Milner AD, Dimitriou G. Synchronized mechanical ventilation for respiratory support in newborn infants (Cochrane Review). In: The Cochrane Library, Issue 2, 2004. Chichester, UK: John Wiley & Sons.
Gregory GA, Kitterman JA, Phibbs RH, Tooley WH, Hamilton WK. Treatment of the idiopathic respiratory distress syndrome with continuous positive airway pressure. New England Journal of Medicine 1971;284:1333-40.
Harris TR. Assisted ventilation of the newborn. 3rd edition. Philadelphia: W.B Saunders, 1996.
Herman S, Reynolds EO. Methods of improving oxygenation in infants mechanically ventilated for severe hyaline membrane disease. Archives of Disease in Childhood 1973;48:612-17.
Murdock AI, Linsao L, Reid MM, Sutton MD, Tilak KS, Ulan OA, Swyer PR. Mechanical ventilation in the respiratory distress syndrome: a controlled trial. Archives of Disease in Childhood 1970;45:624-33.
Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline membrane disease. Bronchopulmonary dysplasia. New England Journal of Medicine 1967;276:357-68.
Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birthweights less than 1,500 gm. Journal of Pediatrics 1978;92:529-34.
Rennie J, South M, Morley C. Cerebral blood flow velocity variability in infants receiving assisted ventilation. Archives of Disease in Childhood 1987;62:1247-51.
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Soll RF, McQueen MC. Respiratory distress syndrome. In: Sinclair JC, Bracken MB, editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:325-58.
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01.01 Mortality before discharge
01.02 Air leak
01.03 BPD (supplemental oxygen at 28 days)
01.04 AaDO2 (mmHg) values after 6 hours of intervention
01.05 IVH (all grades)
01.06 Patent ductus arteriosus (PDA)
01.07 Cerebral palsy in survivors less than 33 weeks gestation at birth
01.08 Visual impairment in survivors less than 33 weeks gestation at birth
01.09 Sensorineural hearing loss in survivors less than 33 weeks gestation at birth
02 Long (greater than 0.5 seconds) vs Short IT (less than or equal to 0.5 seconds)
02.01 Mortality before discharge
02.02 Air leak
02.03 BPD (supplemental oxygenation at 28 days)
02.04 IVH (all grades)
03 Long vs Short IT in HMD (subgroup analysis by diagnosis)
03.01 Mortality before hospital discharge
03.02 Air leak
03.03 BPD (supplemental oxygen at 28 days)
04 Long vs Short IT (subgroup analysis by trials allowing use of muscle relaxation)
04.01 Mortality before discharge
04.02 Air leak
04.03 BPD (supplemental oxygen at 28 days)
04.04 IVH (all grades)
| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Long vs Short IT as defined by investigators (all trials) | ||||
| 01 Mortality before discharge | 5 | 694 | RR (fixed), 95% CI | 1.26 [1.00, 1.59] |
| 02 Air leak | 5 | 685 | RR (fixed), 95% CI | 1.56 [1.25, 1.94] |
| 03 BPD (supplemental oxygen at 28 days) | 4 | 654 | RR (fixed), 95% CI | 0.91 [0.66, 1.24] |
| 04 AaDO2 (mmHg) values after 6 hours of intervention | 1 | 69 | WMD (fixed), 95% CI | -18.60 [-93.78, 56.58] |
| 05 IVH (all grades) | 2 | 171 | RR (fixed), 95% CI | 1.11 [0.72, 1.71] |
| 06 Patent ductus arteriosus (PDA) | 2 | 206 | RR (fixed), 95% CI | 0.91 [0.58, 1.43] |
| 07 Cerebral palsy in survivors less than 33 weeks gestation at birth | 1 | 177 | RR (fixed), 95% CI | 2.90 [0.97, 8.65] |
| 08 Visual impairment in survivors less than 33 weeks gestation at birth | 1 | 177 | RR (fixed), 95% CI | 2.09 [0.83, 5.26] |
| 09 Sensorineural hearing loss in survivors less than 33 weeks gestation at birth | 1 | 177 | RR (fixed), 95% CI | 1.93 [0.60, 6.19] |
| 02 Long (greater than 0.5 seconds) vs Short IT (less than or equal to 0.5 seconds) | ||||
| 01 Mortality before discharge | 4 | 625 | RR (fixed), 95% CI | 1.24 [0.96, 1.60] |
| 02 Air leak | 4 | 616 | RR (fixed), 95% CI | 1.56 [1.24, 1.97] |
| 03 BPD (supplemental oxygenation at 28 days) | 3 | 585 | RR (fixed), 95% CI | 0.92 [0.66, 1.28] |
| 04 IVH (all grades) | 1 | 102 | RR (fixed), 95% CI | 1.08 [0.55, 2.14] |
| 03 Long vs Short IT in HMD (subgroup analysis by diagnosis) | ||||
| 01 Mortality before hospital discharge | 2 | 306 | RR (fixed), 95% CI | 1.54 [1.06, 2.23] |
| 02 Air leak | 2 | 303 | RR (fixed), 95% CI | 1.73 [1.17, 2.57] |
| 03 BPD (supplemental oxygen at 28 days) | 2 | 253 | RR (fixed), 95% CI | 0.88 [0.60, 1.30] |
| 04 Long vs Short IT (subgroup analysis by trials allowing use of muscle relaxation) | ||||
| 01 Mortality before discharge | 5 | 694 | RR (fixed), 95% CI | 1.26 [1.00, 1.59] |
| 02 Air leak | 5 | 685 | RR (fixed), 95% CI | 1.56 [1.25, 1.94] |
| 03 BPD (supplemental oxygen at 28 days) | 4 | 654 | RR (fixed), 95% CI | 0.91 [0.66, 1.24] |
| 04 IVH (all grades) | 2 | 171 | RR (fixed), 95% CI | 1.11 [0.72, 1.71] |
| This review is published as a Cochrane review in The
Cochrane Library, Issue 4, 2004 (see http://www.thecochranelibrary.com/ for information).
Cochrane reviews are regularly updated as new evidence emerges and in response
to comments and criticisms, and The Cochrane Library should be consulted
for the most recent version of the Review. |
