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Evolution of tidal volume requirement during the first 3 weeks of life in infants <800 g ventilated with Volume Guarantee
  1. M Keszler,
  2. S Nassabeh-Montazami,
  3. K Abubakar
  1. Department of Pediatrics, Division of Neonatology, Georgetown University, Washington DC, USA
  1. Professor M Keszler, Department of Pediatrics, Division of Neonatology, Georgetown University Hospital, 3800 Reservoir Rd NW, Washington DC 20007, USA; keszlerm{at}


Background: Volume-targeted ventilation is used in neonates to reduce volutrauma and inadvertent hyperventilation. Little is known about appropriate tidal volume (VT) settings in extremely low birthweight (ELBW) infants who remain intubated for extended periods.

Hypothesis: The VT required to maintain adequate partial pressure of carbon dioxide (Pco2) levels changes as the underlying disease evolves in infants ventilated for prolonged periods.

Objective: To obtain normative data for VT associated with normocapnia in ELBW infants ventilated with Volume Guarantee over the first 3 weeks of life.

Design/Methods: Set and measured VT, peak pressure, respiratory rate and blood gas values were extracted from the records of babies <800 g born January 2003 to August 2005 and ventilated with Volume Guarantee. Data were collected at the time of each blood gas measurement during days 1–2, 5–7 and 14–21. Only the VT corresponding to Pco2 values within a defined normal range were included. Descriptive statistics were used to define the patient cohort. Mean VT and Pco2 for each patient during each epoch was calculated, and these values were analysed by repeated-measures analysis of variance.

Results: Twenty-six infants, mean (SD) birth weight 615 (104) g, were included. A total of 828 paired blood gas and VT sets were analysed: days 1–2 = 251; days 5–7 = 185; days 14–17 = 216; days 18–21 = 176. Pco2 values (mean (SD)) rose from 44.0 (5.4) mm Hg on days 1–2 to 46.3 (5.2) mm Hg on days 5–7 and remained stable during days 14–17 and 18–21 (53.9 (6.8) and 53.9 (6.2) mm Hg, respectively). Mean exhaled VT rose from 5.15 (0.62) ml/kg on day 1 to 5.24 (0.71) ml/kg on days 5–7, 5.63 (1.0) ml/kg on days 14–17, and 6.07 (1.4) ml/kg on days 18–21 (p<0.05).

Conclusions: Despite permissive hypercapnia, VT requirement rises with advancing postnatal age in ELBW infants. The increase is greatest during the third week of life, which is probably due to distension of the upper airways (acquired tracheomegaly) and increasing heterogeneity of lung inflation (increased alveolar dead space).

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With a shift to non-invasive ventilation of larger preterm infants, clinicians most often now face the challenge of ventilating extremely low birthweight (ELBW) infants with limited information about the optimal settings that would best serve this vulnerable population. Despite increasing acceptance of volume-targeted ventilation, there are limited data to guide the clinician in selecting optimal settings in this unique group of infants. In addition, the impact of the proportionally larger fixed dead space of the flow sensor in these extremely small infants may require some degree of tidal volume (VT) compensation. Selection of an optimal target VT is critical in ensuring the success of all volume-targeted modes of mechanical ventilation.1 An excessive VT setting will lead to inadvertent hyperventilation, increase dependence on mechanical ventilation, and could cause volutrauma. A target VT that is too low may increase the work of breathing, energy expenditure and oxygen consumption, increase the risk of atelectasis, and potentially lead to more lung injury, rather than less.2

What is already known on this topic

  • Volume Guarantee ventilation maintains relatively stable tidal volume (VT) and reduces the incidence of hypocapnia in preterm infants.

  • A VT of 4–5 ml/kg is generally associated with normocapnia in larger preterm infants during the first few days of life.

What this study adds

  • Even infants weighing 400–800 g, in whom the fixed instrumental dead-space of the flow sensor is more significant, are able to maintain normocapnia with an initial VT of 5 ml/kg when ventilated with Volume Guarantee combined with assisted control or pressure support ventilation.

  • Despite progressive permissive hypercapnia, the VT required to achieve those Pco2 values rose significantly to >6 ml/kg by the end of the third week.

  • These are the first normative data that establish the evolution of VT needed for adequate gas exchange over the first 3 weeks of life in infants at the extremes of low birth weight.

The Volume Guarantee (VG) option available on the Dräger Babylog 8000+ ventilator (Dräger, Lübeck, Germany) is the most widely used and most extensively studied type of volume-targeted ventilation. In VG, inspiratory pressure is regulated in response to changing lung compliance and patient effort using exhaled VT measurements.3 Earlier studies of VG generally included relatively large infants, often in the recovery phase of the acute respiratory disease47; normative data are lacking for the smallest preterm infants who now constitute an increasing proportion of ventilated infants and often remain ventilator-dependent for extended periods of time. There is no consensus as to the optimal means of weaning from mechanical ventilation with VG. Many clinicians believe that the VT settings should be progressively lowered during weaning, but our clinical experience suggests otherwise.

On the basis of empirical observations of progressively increasing VT needed to maintain adequate partial pressure of carbon dioxide (Pco2) with advancing postnatal age, we hypothesised that changes in anatomical and alveolar dead space caused by evolution of the underlying disease lead to alterations in the appropriate VT settings in ELBW infants with prolonged ventilator dependence. The objective of this study was to establish the evolution over time of VT associated with normocapnia/mild permissive hypercapnia in ELBW infants ventilated with VG during the first 3 weeks of life.


Study design

This was a retrospective analysis of data collected in the course of normal patient care. The study was approved by the Georgetown University Institutional Review Board, which granted a waiver of informed consent requirements.


All ELBW infants with a birth weight <800 g admitted to Georgetown University Hospital between January 2003 and August 2005 were eligible for the study if they received mechanical ventilation with VG during the first 3 weeks of life. Infants with chromosomal anomalies, pulmonary hypoplasia or other anomalies of the lungs/upper airway and those with documented sepsis were excluded.

Ventilators and ventilation strategies

During the study, the Dräger Babylog 8000+ was used exclusively in patients receiving conventional mechanical ventilation. VG was the standard mode of ventilation, combined with either assist control (AC) or pressure support ventilation (PSV), with the latter used far more often. The initial target VT during the first few days of life was 4–6 ml/kg, the exact value being left to the judgement of the clinical team. Subsequent adjustments to target VT settings were based on blood gas values and on clinical observation of the work of breathing, tachypnoea or other signs of distress. Standard practice was to set the peak inspiratory pressure 3–5 cm above the prevailing working pressure. The target Paco2 was not dictated by a specific unit policy. The general consensus in our neonatal intensive care unit (NICU) is that, during the first days of life, we aim to keep Paco2 in the range 35–50 mm Hg, as long as the pH remains >7.20. Subsequently, we allow increasing degrees of permissive hypercapnia with Paco2 45–65 mm Hg, as long as the pH remains >7.20.

Data acquisition and statistical analysis

Infants meeting inclusion criteria were identified from our clinical database. The patient’s medical record was then retrieved, and basic demographic data were extracted and entered into the study database. At the time of each blood gas measurement, the respiratory rate, fraction of inspired oxygen, target and measured VT, ventilator settings, respiratory rate, arterial or capillary pH and Pco2 were documented during the first 48 h of life, days 5–7 and 14–21. Minute ventilation was calculated by multiplying the recorded VT and respiratory rate.

Descriptive statistics were used to define the patient population and baseline respiratory variables. The relationship between postnatal age and Pco2, minute ventilation and VT at normocapnia was evaluated by analysis of variance for repeated measures. Because the number of paired VT and blood gas observations for individual patients varied, the mean VT/kg and Pco2 for each infant for each of the study periods was calculated, and these mean values were then used for the analysis of variance. For the purposes of this study, normocapnia was defined as Pco2 of 35–55 mm Hg during the fist week and 40–65 mm Hg during the third week. Because our intent was to determine the VT that is associated with normocapnia, VT associated with Pco2 values outside of these ranges were excluded from the final analysis. Birth weight was used to calculate VT/kg on days 1–7, and actual weight was used for days 14–21. During the latter two periods, many infants no longer had arterial blood gas values available. Mean capillary and arterial Pco2 values did not differ from each other and were thus combined for analysis. Statistical significance was accepted at p<0.05.


A total of 79 infants with birth weight <800 g were admitted to our NICU during the study period. Forty-nine did not meet the eligibility criteria: 21 were extubated before the third week of life, 12 were switched to other modes of ventilation (usually high-frequency ventilation), nine were transported to us at >2 days of age, and seven died during the first days of life. Four records were unavailable, leaving 26 eligible infants. Twenty-one percent (160/757) of CO2 values were outside the defined “normocapnic” range during days 1–7 and 12% (67/541) during days 14–21, and were therefore excluded. A total of 828 paired normocapnic blood gas and VT sets were analysed: days 1–2 = 251; days 5–7 = 185; days 14–21 = 392. Because the last period was longer than the others and contained the largest number of paired measurements, we subsequently further subdivided this period into days 14–17 (n = 216) and days 18–21 (n = 176). All infants had been intubated with a size 2.5 endotracheal tube at birth, making it very unlikely that, given the babies’ size, any endotracheal tube leak could be present at least during the first week. Fifteen of the 26 infants (58%) were male. Their mean (SD) birth weight was 615 (104) g (range 400–790) and mean (SD) gestational age was 25.5 (1.4) weeks (range 24–29). Twelve infants were white, 10 were African–American, and four were of other racial origin. Table 1 shows the baseline ventilator variables during the first 48 h.

Table 1 Respiratory variables during the first 48 h

Consistent with the generally accepted practice of mild permissive hypercapnia, Pco2 progressively increased from 44.0 (5.40) mm Hg on days 1–2 to 53.90 (6.2) mm Hg by the end of the third week (p<0.01). Measured VT rose from 5.15 (0.62) ml/kg on days 1–2 to 6.07 (1.4) ml/kg on days 18–21 (p<0.01) (table 2). The minute ventilation rose in parallel with the VT from 287 (46) ml/kg/min on days 1–2 to 337 (67) ml/kg/min by days 18–21 (p<0.01) (table 2).

Table 2 Progression of respiratory variables during the first 3 weeks of life

The standard deviation of both Pco2 and VT progressively increased as well, indicating that there is substantial individual variability in the rate and degree of increase; in other words, the group of infants was becoming more heterogeneous. Furthermore, it can be seen in table 2 that there was an increasing difference between the set and measured VT with advancing postnatal age and a modest increase in the difference between the pressure limit and actual working pressures, indicating that some infants were spontaneously generating larger VT than those set by the NICU staff. When the data were reanalysed without excluding the “out-of-range” values, the mean Pco2 and VT differed only slightly from the data presented in table 2 and the differences remained highly significant.


Volume-targeted ventilation is a promising modality of mechanical ventilation because of its documented ability to achieve more stable VT, reduce the proportion of excessively large VT values, and reduce the incidence of hypocapnia.57 The potential to reduce the risk of chronic lung disease has been clearly demonstrated by Lista et al,8 who showed that proinflammatory cytokine concentrations in bronchoalveolar lavage could be reduced and duration of mechanical ventilation shortened with the use of VG ventilation. Although other types of volume-targeted ventilation have not been studied as extensively as VG, most modern ventilators have some form of volume-targeted mode available. The need for normative data to guide VT settings thus potentially applies to all neonatal ventilators.

Limited information is available to guide the clinician’s choice of VT setting in volume-targeted modes, especially in ELBW infants, who often remain ventilator-dependent for many weeks. Although there is general consensus that a VT of 4–5 ml/kg (measured at the airway opening) is an appropriate starting point for VG, there has not been a systematic attempt to determine whether these values remain optimal as the underlying pulmonary condition evolves. Clinicians have relied on empirical adjustments in response to blood gas measurements, but these adjustments are not based on published data. Weaning infants from mechanical ventilation has always been an inexact science with no consensus regarding optimal strategies even when the standard pressure-limited modes are used. In general, weaning is accomplished by lowering inspiratory pressure and allowing the infant’s own effort to gradually take over the work of breathing. Implicit in the strategy is the understanding that, with improved lung compliance and spontaneous respiratory effort, the infant is able to maintain adequate VT and minute ventilation as the inspiratory pressure is reduced. With volume-targeted ventilation, VT becomes the primary control variable. Some clinicians mistakenly believe that, similar to lowering pressure with pressure-limited ventilation, target VT should be progressively lowered in volume-targeted modes. However, that reasoning is not physiologically sound, because the normal physiological VT does not decrease; rather, the ventilator pressure needed to achieve that VT decreases as lung compliance improves and the infant generates more spontaneous inspiratory pressure.

Our data confirm this premise and indicate that the physiological VT needed to maintain mild permissive hypercapnia gradually increases over the first 3 weeks of life in ELBW infants. There are probably at least two mechanisms that contribute to the increasing VT requirement. With positive pressure ventilation, the immature trachea and bronchi are exposed to cyclic stretch as many as 86 000 times/day, resulting in progressive dilatation of the trachea and bronchi (acquired tracheomegaly), which leads to increased anatomical dead space by as much as 90%.9 With evolution of chronic lung disease, the lung inflation becomes more heterogeneous and the lungs often become somewhat hyperinflated, resulting in increased alveolar (or physiological) dead space. There may also be a gradual increase in CO2 production as the infant matures, generates more spontaneous activity, and receives increased enteral nutrition. The relative contribution of these factors is unknown, but, in combination, they appear to result in increasing VT and minute ventilation requirement with advancing postnatal age. Because we only examined data for the first 3 weeks, we cannot comment on whether there is further increase in these values beyond the period of the study.

We noted increasing heterogeneity of the Paco2 and VT values with increasing postnatal age, along with some divergence between set and observed VT and working pressure and peak inspiratory pressure limit. This observation indicates that many infants were spontaneously generating larger VT than those set by the NICU staff. This progressive discrepancy between set and observed VT may reflect attempts at reducing VT by the clinical team in an effort to wean the infant from mechanical ventilation, and suggests that, in some instances, the set VT was below the infant’s physiological need. This phenomenon is a common occurrence that we have noted in clinical practice in our NICU and elsewhere.

The effectiveness of volume-targeted ventilation largely depends on the selection of an appropriate target VT. Empirically, a value of 4–5 ml/kg has become the standard target VT, based on early clinical studies of VG.47 However, these studies included much larger infants, and some used synchronised intermittent mandatory ventilation (SIMV) rather than AC or PSV. It has been shown that the VT needed to achieve an equivalent minute ventilation is larger with low-rate SIMV than with AC, a mode in which every spontaneous breath is supported.10 Therefore, target VT values need to be specific to the basic underlying mode. We have shown previously that VG was more effective when combined with AC than with SIMV at a rate of 30 breaths/min.11 The present data were generated in infants on VG combined with AC or PSV modes, and therefore these results may not be directly applicable to low-rate SIMV + VG. Eighty-nine percent of the paired values were obtained while the infant was on PSV and 11% on AC. Both modes support every spontaneous breath, with the only difference being that PSV is flow-cycled rather than time-cycled, and therefore we believe it appropriate to combine the findings. Because the number of values obtained on AC was quite small, meaningful statistical comparison between PSV and AC was not feasible.

Retrospective data from Dawson and Davies12 support the validity of initiating ventilation with a target VT of ∼4 ml/kg (range 2.9–5.1) in larger preterm infants (mean weight 955 (306) g) ventilated with SIMV +VG with a relatively rapid set rate of 57.3 (9.8) breaths/min. They reported acceptable Pco2 levels during the first 48 h of life (defined as 25 mm Hg>Paco2<65 mm Hg) 96% of the time. We defined a narrower target range of 35–55 mm Hg, which explains the larger proportion of out-of-range values in our patients. There was no correlation between VT and Paco2, nor between calculated minute ventilation and Paco2, possibly because they did not take into account the effect of instrumental dead space. In addition, because with SIMV there may be spontaneous breathing between mechanical breaths, the total minute ventilation may have been higher than the values calculated from the set respiratory rate and VT.

The importance of choosing an appropriate VT is illustrated by a pair of studies by Lista et al.8 These investigators initially showed the benefits of VG combined with AC when a VT of 5 ml/kg was used. They then compared AC + VG for a VT of 3 ml/kg with AC + VG for a VT of 5 ml/kg in a similar group of preterm infants with respiratory distress syndrome. They found an increase in proinflammatory cytokines in the bronchoalveolar lavage fluid with the smaller VT,13 probably as a result of atelectasis resulting from insufficient distending airway pressure.2 In addition, an inappropriately low VT target has been shown to shift the work of breathing almost entirely to the infant.6 Although this was tolerated in the short-term study, prolonged periods of breathing through narrow endotracheal tubes with an inadequate target VT are likely to increase the work of breathing, energy expenditure and oxygen consumption, thus interfering with adequate growth.

There are several limitations of this study. The VT data were collected retrospectively from nursing and respiratory flow sheets and not downloaded in real time from the ventilator output port. Therefore, the recorded VT is only a point estimate of the measured VT at the time of the blood gas measurement. This is because, in actively breathing infants, the actual VT fluctuates somewhat from breath to breath. However, because the notation obviously took place without knowledge that the data would be used for a study like this, there is no reason to believe that a systematic bias was introduced. The same is true for the respiratory rate and therefore the calculated minute ventilation. Secondly, it is not possible to be sure that, especially during the later periods when tracheal/laryngeal dilatation may have occurred, some leak around the endotracheal tube did not develop. However, because VG uses the exhaled VT, the leak would cause the measured VT to be underestimated, rather than overestimated, and therefore we do not believe that this would have been a major problem. The development of a significant leak would be expected to result in some degree of dead space washout as well, which in turn would probably reduce the Pco2 levels and allow VT settings to be reduced.14 Neither of these phenomena was in evidence, strongly suggesting that a leak around the endotracheal tube was not a material issue. Furthermore, because we are well aware that VG does not work reliably in the presence of a large leak, it is our practice to actively look for a leak around the endotracheal tube and reintubate with a larger size tube when such a leak is present. Finally, VG displays and uses exhaled VT to regulate the working pressure. Because any leak around the tube is always less during expiration than inspiration, the exhaled VT more accurately reflects the true VT. Therefore, if some degree of leak was present in a few infants, the net effect, if any, would have been to underestimate the increase in VT requirement over time that is demonstrated by our observations.


We believe that this study provides useful information to guide clinicians tasked with managing volume-targeted ventilation of ELBW infants, who often require mechanical ventilation for prolonged periods. Although the data were generated using VG, the findings should be applicable to other forms of volume-targeted ventilation, with caveats regarding differences in specific ventilator performance and way of measuring VT. Further studies are needed to prospectively evaluate different approaches to weaning from volume-targeted ventilation modes. Such studies should prospectively compare clearly defined alternative weaning strategies, assessing such variables as the work of breathing and weight gain, in addition to time to extubation.



  • Competing interests: MK is a consultant to Draeger Medical. No research funds were received for this study and the company has had no input into the study design, data analysis or contents of the paper.

  • Ethics approval: Obtained.