Discussion
To our knowledge, this study is the first systematic review on this
topic using the GRADE approach. It included four RCTs (693 infants) and
one cohort study (371 infants) and demonstrated that permissive
hypercapnia did not significantly reduce or increase any infants’
outcomes assessed (death, IVH, BPD, NEC, PVL, and NDI) compared with the
normocapnia strategy (very low-to-low certainty of evidence). However,
the largest RCT (Thome 2015) 17 reported a higher rate
of NEC in the permissive hypercapnia group than in the normocapnia
group, which requires further investigation.
The strengths of our systematic review, compared with previous ones,
include (1) the use of the GRADE approach to evaluate the certainty of
evidence for each outcome, (2) the use of the definition of BPD at a
postmenstrual age of 36 weeks, not at 28 days after birth, and (3) the
inclusion of both RCTs and observational studies. The GRADE approach was
developed as a transparent method for grading the certainty of evidence
for systematic reviews and guidelines.12 Although
previous systematic reviews that evaluated the effect of permissive
hypercapnia on BPD assessed the risk of bias in the included studies,
they did not use the GRADE approach 12.
Unlike the previous systematic reviews that used BPD diagnosed at 28
days of age, this systematic review defined BPD as the use of oxygen or
respiratory pressure support [e.g., CPAP, high-flow nasal cannula at a
rate of >2 L/min] at 36 weeks of corrected gestational
age.21-23 Although defining BPD has been a
controversial issue in recent years, the definitions or diagnoses near
term or later (from 36 weeks to 40 weeks postmenstrual age or to 1 year
of age) are considered better than those at 28 days or a month after
birth because the former definitions predict long-term adverse
consequences better than the latter.24 The last
systematic review on this topic (Ma, 2016) 21 reported
that permissive hypercapnia did not reduce BPD (RR 0.93; 95% CI
0.83–1.03) (Ma 2016); however, the authors did not clearly describe the
definition of BPD. Based on the results of that systematic review (Ma,
2016), the outcome of BPD seemed to include both BPD diagnosed at 28
days of age and that diagnosed at a postmenstrual age of 36 weeks
together. Using the BPD definition at a postmenstrual age of 36 weeks,
we found that hypercapnia did not reduce BPD. In addition to the small
sample size, one of the other potential explanations for the negative
finding for BPD is that permissive hypercapnia used might not always
achieve low tidal volume enough to prevent BPD. However, none of the
trials included in this systematic review measured and compared the
tidal volumes of the two groups. All the included trials reported
comparable peak inspiratory pressure (PIP) measurements between the two
groups, except for one RCT (Thome 2015), which indicated that the target
PaCO2 level might be insufficient to achieve low PIP or
small tidal volume enough to prevent BPD.
This systematic review found that permissive hypercapnia did not have
significant adverse neurological effects (severe IVH and NDI),
consistent with the findings of previous systematic reviews.21,23 The increased risk of IVH due to permissive
hypercapnia was also concerning in this review. High
PaCO2 and low pH dilate cerebral blood vessels, increase
cerebral blood flow, and cause fluctuations in cerebral blood flow,
which may predispose infants to IVH.6,25, 26 Moreover, cerebral
autoregulation was attenuated in the presence of hypercapnia.
CO2 cerebral blood flow reactivity is more robust than
pressure flow 27 and there is a steep positive linear
relationship between PaCO2 and cerebral blood flow on
postnatal days 2–4.28 One potential reason for the
lack of increase in IVH with permissive hypercapnia is that the target
range of PaCO2 in the permissive hypercapnia groups
might be insufficient to increase IVH. One RCT (Mariani 1996) and one
cohort study included in this review used a target PaCO2range of less than 55 mmHg in the permissive hypercapnia group.
Moreover, in other studies, actual values of PaCO2 did
not exceed 55 mmHg despite the target PaCO2, except in
one study (Thome 2015). Even the Thome 2015 study did not achieve the
target range in the permissive hypercapnia group, and the mean
PaCO2 exceeded 55 mmHg only after day 4. Therefore, it
is possible that the actual PaCO2 values of most infants
in the permissive hypercapnia group did not reach the threshold (51–55
mmHg) that was reported to increase cerebral blood flow in previous
studies. 28-31 . Another potential explanation for the
lack of an increase in IVH is that most of the included studies
administered sodium bicarbonate to correct acidosis. The correction of
acidosis might attenuate the adverse effects of hypercapnia, although
rapid infusion of sodium bicarbonate may increase the risk of
IVH.32, 33
In this meta-analysis, the effect estimates (RR) indicated a potential
increase in NEC in infants with permissive hypercapnia, although the
difference was not statistically significant, with its 95% CI just
crossing the neutral effect estimate (RR 1.69 [95% CI:
0.98–2.91]). Furthermore, the largest RCT (Thome, 2015) reported a
significant increase in NEC in the permissive hypercapnia group. It is
important to note that the RCT with an increased NEC in the permissive
hypercapnia group (Thome 2015) used the longest intervention period (14
days after birth) and the highest target range of permissive hypercapnia
(PaCO2 of 65–75 mmHg) among all eligible studies. The
effect of lengthy permissive hypercapnia with a high
PaCO2 target range on the NEC rates requires further
investigation. An ongoing RCT aimed to enroll 160 preterm infants at
<37 gestational weeks (HYFIVE; NCT02799875). The trial
compares two different levels of target PCO2 and pH
(PCO2 60–75 mmHg and pH≧7.2 versus PCO240–55 mmHg and pH ≥ 7.25) between 7 and 14 days in terms of outcomes
such as alive ventilator-free days in 28 days, death, BPD, etc. This
trial may provide further information on the optimal
PaCO2 level and period in preterm infants.
Our systematic review has several limitations. First, the sample sizes
of the included studies did not reach the optimal information size for
all outcomes assessed (Supplemental Table D). Therefore, the negative
findings in the meta-analyses may simply be due to the insufficient
sample size. This limitation was reflected in the certainty of evidence
downgraded for imprecision. Second, there was clinical heterogeneity
among the eligible studies, in which there was a wide variation in the
range of targeted PaCO2 and period for the interventions
(permissive hypercapnia or normocapnia) (Table 1), although the
statistical heterogeneity was low (I2=0–28%).
Lastly, the included studies were relatively old, and the findings of
the studies may not be applicable to current clinical practice. In
particular, respiratory management strategies for premature babies have
been rapidly changing over the last decade, and non-invasive ventilation
and non-invasive surfactant administration avoiding mechanical
ventilation using an endotracheal tube are increasingly
used.34, 35 Therefore, infants who
are on mechanical ventilation and are eligible for permissive
hypercapnia may be sicker in the current clinical practice than those in
previous trials.