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Newborn-03 - Paper Draft CC
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RECOVER 2.0 Worksheet
QUESTION ID: Newborn-03
PICO Question:
In newborn dogs and cats that require resuscitation with PPV (P), how does any other concentration of inspired oxygen (I), compared with 100% oxygen (C) improve outcome (O).
Outcomes:
Histopathologic damage, PaCO2, PaO2, Hospital length of stay, Favorable neurologic outcome, Survival to Discharge
Prioritized Outcomes (1= most critical; final number = least important):
- Survival to Discharge
- Favorable Neurologic Outcome
- PaO2
- PaCO2
- Hospital Length of Stay
- Histopathologic Damage
Domain chairs: Christopher Byers - review by Manuel Boller
Evidence evaluators: Tamara Swor, Molly Racette
Conflicts of interest: Byers - Founder, CriticalCareDVM.com
Search strategy: See attached document.
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Study Design |
Reduced Quality Factors
0 = no serious, - = serious,
- - = very serious |
Positive Quality Factors
0 = none, + = one, ++ = multiple |
Dichotomous Outcome Summary |
Non-Dichotomous Outcome Summary
Brief description |
Overall Quality
High, moderate, low, |
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No of studies |
Study Type |
RoB |
Indirectness |
Imprecision |
Inconsistency |
Large Effect |
Dose-Response |
Confounder |
# Intervention with Outcome |
# Control with Outcome |
RR (95% CI) |
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Outcome: Survival to Discharge |
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4 |
CT |
- |
- |
- |
0 |
0 |
0 |
0 |
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0.82 (0.5-1.35) |
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Very low |
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Outcome: Favorable Neurologic Outcome |
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4 |
CT |
- |
- |
- |
0 |
0 |
0 |
0 |
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0.82 (0.63-1.10) |
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Very low
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2 |
ES |
- |
-- |
- |
0 |
0 |
0 |
0 |
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Very low |
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Outcome: Oxygenation (PaO2) |
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2 |
CT |
- |
- |
- |
0 |
0 |
0 |
0 |
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Very low |
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1 |
ES |
- |
- |
- |
0 |
0 |
0 |
0 |
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Very low |
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Outcome: PaCO2 |
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2 |
CT |
- |
- |
- |
0 |
0 |
0 |
0 |
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Very low |
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6 |
ES |
0 |
- |
- |
0 |
0 |
0 |
0 |
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Very low |
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Outcome: Hospital Length of Stay |
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0 |
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Outcome: Histopathologic Damage |
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1 |
CT |
0 |
-1 |
1 |
0 |
0 |
0 |
0 |
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Low |
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28 |
ES |
-1 |
-1 |
-2 |
0 |
0 |
0 |
0 |
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Very low |
PICO Question Summary
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Introduction |
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Newborn puppies and kitten have been historically resuscitated with 100% oxygen, as asphyxiation is the predominant concern [Davidson 2014]; this approach was in line with the recommendations for resuscitation of newborn infants in the early 2000’s.[ Niermeyer, 2000] However, the scientific evidence supporting the administration of 100% oxygen has not been established in dogs and cats. In addition, there is concern that delivery of high oxygen concentrations and the associated hyperoxemia may lead to oxidative injury and could lead to harm.[ Vento 2005, 1350] Conversely, inadequate oxygen supplementation and subsequent hypoxia can be harmful as well. Thus, there is a need to determine whether newborn puppies and kittens requiring resuscitation should be resuscitated with an inspiratory oxygen concentration other than 100% oxygen. This question concerns the initial administration of oxygen in newborn puppies and kitten requiring PPV immediately after birth. These animals are typically non-vigorous (i.e., low muscle tone, apneic/bradypneic, or severely bradycardic (e.g., HR < 120 bpm). The question regarding oxygen supplementation in newborns requiring chest compressions is addressed elsewhere (see NB-18). |
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Consensus on science |
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Outcome 1: Survival to discharge
For the critical outcome of survival discharge, we located 4 CTs (very low quality of evidence, downgraded for serious risk of bias, serious indirectness and imprecision).[ Saugstad 1998 1353, Ramji 1993, Ramji 2003, Bajaj 2005] No relevant observational or experimental studies were identified. Saugstad et al evaluated in the Resair-2 trial survival in asphyxiated term newborn infants that were ventilated with either room air (n=267) or 100% O2 (n=294) immediately after birth.[ Saugstad 1998 1353] If cyanosis and/or bradycardia persisted after 90 seconds of ventilation with room air, the inspired gas was changed to 100% oxygen. The mode of ventilation was bag-mask in most cases, while 25% of newborns in either group were intubated. Room air administration did not lead to a significant difference in mortality (RR=0.76, 95% CI=0.53-1.10). The remaining RCTs showed similar results. All data taken together (n=1280) demonstrated a 23% relative reduction in mortality with initial room air administration compared to 100% oxygen in term infants requiring PPV (RR=0.77, 95% CI=0.59-0.99).
Outcome 2: Favorable neurologic outcome
For the critical outcome of favorable neurologic outcome, we located the same 4 CTs (very low quality of evidence, downgraded for serious risk of bias, serious indirectness, and imprecision) as reported above.[ Saugstad 1998 1353, Ramji 1993, Ramji 2003, Bajaj 2005] These articles report neurological outcome as presence or absence of hypoxic-ischemic encephalopathy (HIE) based on a commonly used scoring system (Sarnat Stage II or III).[ Mrelashvili, 2020] While a single study including 418 asphyxiated newborns showed some benefit of room air over 100% oxygen (RR=0.66, 95% CI=0.44-0.98) [Ramji 2003], the pooled data from all studies showed no significant impact on HIE (RR=0.82, 95% CI=0.63-1.10). Importantly, there was no evidence that initial assisted ventilation with room air worsened neurological outcome.
Two ES (very low quality of evidence, downgraded for serious risk of bias, very serious indirectness and for imprecision) involving swine and rat models of newborn asphyxiation showed neither benefit nor harm of PPV with room air on neurological recovery when compared to 100% oxygen.[ 1364, Cheung; 1371, Smit]
Outcome 3: Oxygenation (PaO2)
For the important outcome of oxygenation, 3 CTs (Saugstad 1998, Vento 2001, Vento 2003) directly evaluated PaO2, SpO2 or SaO2 in intrapartum asphyxiated newborn infants resuscitated with either room air or 100% oxygen (very low quality of evidence, downgraded for serious risk of bias, serious indirectness, and imprecision). Saugstad et al found no difference in PaO2 in newborns resuscitated with room air or 100% oxygen during the first 10 minutes of life.( Saugstad 1998) These findings contrasted with Vento et al, who documented mild hyperoxemia (PaO2, 126.3 ± 21.8 mm Hg) in babies resuscitated with 100% oxygen compared to room air (PaO2, 72.2 ± 6.8 mm Hg) in the first 10 minutes after birth.(Vento 2003) Note that in this study, the PaO2 at birth in non-asphyxiated newborns was also very low (PaO2, 30.3 ± 4.5 mm Hg), and not different from asphyxiated newborns (PaO2, 27.8 ± 5.2 mm Hg in room air group; 30.0 ± 6.8 mm Hg in 100% oxygen group). A third study including 134 term newborns requiring PPV demonstrated mild hyperoxemia in infants resuscitated with 100% O2 at 5 minutes of PPV (157 ± 27 mm Hg) compared to those ventilated with room air (88 ± 9 mm Hg). (Vento 2001)
Numerous experimental studies in newborn piglets and lambs compared effects of the inspiratory oxygen concentration on PaO2 and PaCO2. The majority were excluded as these studies did not evaluate oxygenation and ventilation in newborns during transition, but in animals that were already several days old.( Goplerud 1995, Rootwelt 1996, Haase 2004, Fugelseth 2005, Stevens 2007, Cheung 2008A, Stevens 2008, Solevag 2010, Solberg 2012, Solevag 2020) Only 1 experimental study was identified that utilized a transitional newborn lamb model, in which the animals were asphyxiated by cord clamping while in-utero followed by delivery and PPV with room air or 100% oxygen (very low quality of evidence, downgraded for serious risk of bias, serious indirectness, and imprecision). (Lakshmirusimha 2011) Ventilation with 100% oxygen led to marked hyperoxemia (PaO2, 454 ± 33 mm Hg) compared to resuscitation with room air (PaO2, 68 ± 15 mm Hg) after 5 minutes of PPV.
Outcome 4: Ventilation (PaCO2)
For the important outcome of ventilation, the same human clinical trials mentioned above provided data (very low quality of evidence, downgraded for serious risk of bias, serious indirectness, and imprecision). (Saugstad 1998, Vento 2001, Vento 2003) They all showed no significant impact of the inspiratory oxygen concentration on ventilation. The same was true for an experimental study in newborn lambs. (Lakshmirusimha 2011)
Outcome 5: Hospital length of stay
There were no studies identified that evaluated the impact of oxygen concentration on hospital length of stay.
Outcome 6: Histopathologic damage
For the important outcome histologic damage, we identified 1 CT (low quality of evidence, downgraded for serious indirectness, and imprecision)[Vento 2005, 1350] and 27 experimental studies (very low quality of evidence, downgraded for serious risk of bias and serious indirectness) relevant to the PICO question.[ Haase 2005 1764, Cheung 2008B 1364, Chua 2010 1367, Feet 1997 1745, Kumar 2010 1744, Kutzsche 2001 1743, Poulsen 1993 1742, Rootwelt 1992 1735, Tyree 2006 1738, Odland 2011 1737, Borke 2004 1736, Fanos 2014 1734, Tollofsrud 2001 1762, Bockhorst 2010 1761, Stevens 2008 1760, Chapados 2010 1758, Lakshminrusimha 2011 334, Faa 2014 1757, Solberg 2007 1755, Munkeby 2005 1754, Borke 2004 1753, Haase 2004 1752, Munkeby 2004 1751, Solberg 2012 1370, Goplerud 1995 1348, Smit 2015 1371, Fokkelman 2007 1749] Note that we included studies reporting markers of tissue injury, such as indicators of oxidative injury or matrix metalloproteinase (MMP) activity as outcomes, but excluded animal models that studied reoxygenation after CPR.
Vento and colleagues reported circulating markers of oxidative injury (reduced glutathione [GSH], oxidized glutathione [GSSG], superoxide dismutase [SOD]) and myocardial (cardiac troponin T [cTNT] and renal injury (N-acetyl-glycosaminidase [NAG]) in severely asphyxiated newborns randomized to resuscitation with room air (n=17) or 100% oxygen (n=22).[ 1350] Oxidative injury and increases in NAG and cTNT concentrations were present in both groups compared to non-asphyxiated controls, but were more severe in newborns resuscitated with 100% O2.
Among the 27 experimental studies only two of them involved animals in transition [334, 1744], all other studies included animals that were at least 12 hours old and had fully (and normally) transitioned. Species represented were swine (22 studies)[ Haase 2005 1764, Cheung 2008B 1364, Feet 1997 1745, , Kutzsche 2001 1743, Poulsen 1993 1742, Rootwelt 1992 1735, Tyree 2006 1738, Odland 2011 1737, Borke 2004 1736, Fanos 2014 1734, Tollofsrud 2001 1762, Stevens 2008 1760, Chapados 2010 1758, Faa 2014 1757, Solberg 2007 1755, Munkeby 2005 1754, Borke 2004 1753, Haase 2004 1752, Munkeby 2004 1751, Solberg 2012 1370, Goplerud 1995 1348, Fokkelman 2007 1749), sheep (2 studies) [Lakshminrusimha 2011 334, Kumar 2010 1744], rabbits (1 study)[ Chua 2010 1367] and rats (2 studies)[ Smit 2015 1371, Bockhorst 2010 1761], but not dogs or cats. Most commonly, asphyxiation was induced by exposing animals to a low inspiratory oxygen concentration for a defined time or until either a hemodynamic (e.g., MAP < 20 mm Hg) or metabolic goal (e.g., BE < -20 mmol/L) was achieved. Animals were then allocated to resuscitation with room air, or 100% oxygen followed by variable lengths of observation time. Reported outcomes included oxidative, histopathologic or circulatory markers of tissue injury of brain (Chua 2010 1367, Feet 1997 1745, Kutzsche 2001 1743, Poulsen 1993 1742, Rootwelt 1992 1735, Tyree 2006 1738, Bockhorst 2010 1761, Faa 2014 1757, Munkeby 2004 1751, Solberg 2007 1755, Goplerud 1995 1348, Smit 2015 1371], heart[Haase 2005 1764, Cheung 2008B 1364, Odland 2011 1737, Borke 2004 1736, Borke 2004 1753, Fokkelman 2007 1749], lung[Kumar 2010 1744, Lakshminrusimha 2011 334, Munkeby 2005 1754, Fokkelman 2007 1749], kidney[Fokkelman 2007 1749, Cheung 2008B 1364], liver[Stevens 2008 1760, Fokkelman 2007 1749] adrenals[Chapados 2010 1758] and small intestines,[ Haase 2004 1752] or systemic markers of oxidative injury.[ Fanos 2014 1734, Tollofsrud 2001 1762, Solberg 2007 1755, Feet 1997 1745, Kumar 2010 1744, Kutzsche 2001 1743, Poulsen 1993 1742, Rootwelt 1992 1735] Taken together, the studies either showed no difference in outcome between resuscitation with 21% oxygen compared to 100% oxygen or demonstrated a benefit of resuscitation with room air. No study reported worse outcomes with room air resuscitation. |
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Treatment recommendation |
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We suggest the use of room air (21% oxygen) over 100% oxygen during early assisted ventilation of newborn dogs and cats (weak recommendation, very low quality of evidence).
We suggest the use of 100% oxygen in newborn dogs or cats in which the HR fails to increase despite 1-2 minutes of PPV (weak recommendation, expert opinion). |
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Justification of treatment recommendation |
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While there are no clinical data on the optimal selection of the inspiratory oxygen concentration in newborn dogs and cats requiring PPV, the above cited evidence suggests that room air is as effective as 100% oxygen and that oxygen might do harm. This has been a consistent finding in clinical and experimental studies and across multiple species and populations. Many studies suggest harm associated with IPPV with high inspiratory oxygen concentrations that includes evidence of increased mortality in newborn children, increased oxidative injury in newborn children and animal models, and tissue injury in various organs. Until differing evidence emerges, we suggest using room air to initiate PPV in newborn dogs and cats.
A transition to a higher inspiratory concentration of oxygen might be beneficial in some newborn dogs and cats, if clinical signs of severe hypoxemia (e.g., severe bradycardia) persist despite adequate PPV. No studies have systematically evaluated when to best switch from room air to 100% oxygen, but we propose a transition guided by HR. Heart rate is invariably decreased with perinatal asphyxiation, and an increase in HR in response to PPV is considered an indicator of resolution of hypoxemia.[ Sobotka 2014, Kibsgaard 2023]. Studies in newborn children and experimental animals suggest that the time course with which HR increases after initiation of effective PPV is variable and can be instantaneous or gradual, and accordingly can take as little as10-20 seconds or as long as several minutes.[ Yam 2010, Espinoza 2018, Kibsgaard 2023] Balancing benefit against risk, the committee therefore suggests to switch from room air to 100% oxygen if no marked increase in HR is observed after 1 minute of PPV.
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Knowledge gaps |
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There is a lack of clinical studies in animals to address the issue of supplemental oxygen administration in transitional newborn dogs and cats in general and in those requiring PPV specifically. |
Summary of studies
|
Other oxygen concentration |
100% O2 |
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Outcome: Survival to Discharge |
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4 CT
Ramji et al, 1993
-Single centre study, New Delhi, preliminary study
-Asphyxiating term newborns requiring PPV pseudorandomized
-Room air versus 100% oxygen
-Room air, n=42, dead within first week of life, n=3
Saugstad et al, 1998, Resair 2 Study
-International, controlled, multicentre study, asphyxiated newborns 1 kg or more; not blinded, quasi randomized (DOB)
-Intervention room air versus 100% oxygen
-Primary outcome: death within 1 week
-Room air: n=288; mortality 12.2%
-Time to first breath and first cry is shorter with room air.
Ramji et al, 2003
-Quasi randomized study, blinding uncertain, initial administration of room air versus 100% oxygen; newborns asphyxiated
-Room air: n=210; death 26
Bajaj et al, 2005
-Quasi randomized study (DOB), asphyxiated
-Room air: n=107, dead 17
All CTs taken together, n=1280, RR 0.7683, 95% CI 0.5944-0.993
0 OS
0 ES
|
-Oxygen, n=42, dead within first week of life, n=4
100% O2: n=321; mortality 15.0%, adjusted OR = 0.82 (95% CI, 0.5-1.35)
-100% O2: n=221, death 40; RR 0.64 (95%CI 0.4335-1.0795)
-100% O2: n=97, dead 17; RR 0.9065 (95% CI 0.4908-1.6744)
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Outcome Favorable Neurological Outcome |
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4 CT
Ramji et al, 1993
-Single centre study, New Delhi, preliminary study
-Asphyxiating term newborns requiring PPV pseudorandomized
-Room air versus 100% oxygen
-Room air, n=42, newborns with HIE, n=4
Saugstad et al, 1998, Resair 2 Study
-International, controlled, multicentre study, asphyxiated newborns 1 kg or more; not blinded, quasi randomized (DOB)
-Intervention room air versus 100% oxygen
-Room air: n=288; mortality 12.2%
-Time to first breath and first cry is shorter with room air.
-Room air, n=288, n with HIE = 47
Ramji et al, 2003
-Quasi randomized study, blinding uncertain, initial administration of room air versus 100% oxygen; newborns asphyxiated
-Room air: n=204; HIE, n=32
Bajaj et al, 2005
-Quasi randomized study (DOB), asphyxiated
-Room air: n=107, HIE, n=5
All CTs taken together, n=1280, RR 0.8189, 95% CI 0.6334-1.0586
0 OS
2 ES
Tyree, 2006
-Piglets, < 10 days old
-Controlled, block randomized,
-Intervention: FiO2 0.08 to 0.12 for 1 hrs combined with bilateral carotid occlusion, followed by reoxygenation with either 21% or 100% oxygen (n=7/group) x 1 hrs.
-Outcome: neurological function score, day 1,2,3,4 after injury
Cheung, 2008, 1364
-Piglets, 1-3 days old, hypoxic isocarbic;
-Controlled, block randomized,
-Intervention: FiO2 0.15 for 2 hrs, followed by reoxygenation with either 18%, 21% or 100% oxygen (n=7/group) x 1 hrs, then room air x 2 hrs.
-Outcome: neurological function score, day 1,2,3,4 after injury
-Room air scores: 15±2, 18±3, 18±3, 19±2
Smit, 2015, 1371
-Wistar rat pups, postnatal day 7, with brain development commensurate to newborn human
-Randomized by litter, sex, weight; blinded
-Intervention: 18% oxygen for 125 minutes, in addition to unilateral carotid ligation
-Outcome: Intactness of geotaxis as expressed in time required to rotate to 90 and 180º at postnatal day 14
-Room air: 90º: median 3.4 (IQR 2.4, 4.2) seconds; 180º: 6.6 (4.9, 10.5) seconds |
-Oxygen, n=42, newborns with HIE, n=2; RR 2.0 (95%CI 0.3869-10.3374)
-100% O2: n=321; HIE, n=55, RR = 0.9524 (95% CI, 0.6676-1.3589)
-100% O2: n=214, HIE, n= 51; RR 0.6582 (95%CI 0.4420-0.9812)
-100% O2: n=97, HIE, n=5; RR 0.9065 (95% CI 0.2207-3.0363)
-100% scores: 15±3, 19±2, 20±1, 20±0, NS
90º: median 3.8 (IQR 2.7, 7.8) ;180º: 8.0 (5.4,
9.8) seconds |
|
Oxygenation |
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3 CT
Saugstad 1998
Vento, 2001
Vento, 2003
1 ES
Lakshmirusimha 2011, 334
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Ventilation |
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3 CT
Saugstad 1998
Vento, 2001
Vento, 2003
1 ES
Lakshmirusimha 2011, 334 |
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Histopathologic damage and biomarkers of injury |
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1 CT
Vento 2005
-17 severely asphyxiated newborns with RAR, 22 with OxR.
-Outcomes: markers of oxidative injury (GSH, GSSG, SOD), myocardial injury (cTNT), kidney injury (urinary NAG)
-oxidative stress in both groups; higher cTNT in OxR; higher urinary NAG in OxR
27 ES: note that almost all animal models were neonatal hypoxia models, rather than perinatal asphyxiation models; models of neonatal CPA requiring chest compressions were excluded.
Haase, 2005
-piglets, 1-3 days old, 2 hours of hypoxia followed by reoxygenation with 21%, 50%, 100% oxygen for 1 hours, followed by room air, n=8 per group
-Outcomes: myocardial MMP activities; myocardial GSH:GSSG redox ratio, histopathological myocardial injury
-similar myocardial recovery and injury across concentrations studied
Cheung 2008
-piglets 1-3 days old, 2 hours of hypoxia, followed by 18%, 21% or 100% oxygen (1h) and room air thereafter. N=7 per group
-outcomes: plasma cTnI, myocardial GSH:GSSG, histopath heart and kidney, creatinine
-Most significant myocardial injury (histopath) in 100% group, but essentially absent in the 18% group. No difference in cTnI
Chua 2010
-premature rabbits, in infant incubator with either 100%, 40% or 21% oxygen for 15 or 60 minutes; glycerol induced IVH; euth at 24 hours; note: no respiratory depression in these rabbit pups.
-outcomes: intraventricular hemorrhage, ROS, GSH, VEGF and ANGPT-2, neuronal degeneration (TUNEL)
-IVH not different between groups; increased oxidative stress but no other effects of 100% versus other concentrations
Feet 1997
-piglets 2-5 days, hypoxemia <20 mm Hg, then room air or 100% for 30 minutes (n=9 each), followed by room air (5 h)
-Outcomes: hypoxanthine concentrations in various locations (cerebral cortex, plasma, skeletal muscle)
-Higher extracellular hypoxanthine concentrations in cerebral cortex with reox with 100%, potentially suggesting reduced energy metabolism with hyperoxic reoxygenation.
Kumar 2010
-Near term, periparturient lambs with PPV and either receiving RAR or OxR for 30 mins or OxR for 24 hours.
-Outcome: GSH, GSSG (both in blood), lung SOD, lung GP, lung LPO and MPO, pulmonary edema
-OXR associated with higher GSSG, higher LPO, higher SOD, higher GP, more edema in OXR24
Kutzsche 2001
-Piglets 2-4 days, induced hypoxemia (Fi02 0.08), followed by RAR (n=13) or OXR (n=12)for 30 minutes, followed by room air for 1.5 hours
-Outcomes:H2O2 in PMN in arterial, venous and cerebral circulation.
- H2O2 in PMN increased with hypoxia and reoxygenation, arterial and venous similar with RAR and OXR, and more in OXR group in brain.
Poulsen 1993
-Piglets 1-2 weeks old, hypoxemia x 2 hrs, reoxygenation RAR or OXR x 1 hour, n=10 per group
-Outcomes: Hypxanthine, xanthine, uric acid in plasma, CSF and vitreous humor
-Results: During hypoxemia: HX increased 4-5 fold in all fluids, X similar, UA only in plasma; Similar during reoxygenation; no difference between groups.
Rootwelt 1992
-Piglets 2-5 days old, hypoxemia with FiO2 0.08, reoxygenation with RAR (n=9) or OXR (n=11) x 20 min, followed by 21% O2
-Outcomes: Hypoxanthine (plasma and CSF), brain histopath
-No difference on brain histopath (CA1 neurons, infarcts similar); increase in hypoxanthine in all groups after injury, and reduction after reoxygenation (NS between groups in both plasma and CSF). 21% overall as effective as 100% O2
Tyree 2006
-piglets (<10 days old), controls with no carotid occlusion, exp groups hypoxia (FiO2 0.08-0.12) x 60 minutes and bilateral carotid occlusion. Release of occlusion and either RAR or OXR x 1 hour
-Outcome: Brain ROS only due to ischemia, but no difference due to oxygen conc during resusc. Generally, no worse outcomes with RAR, also physiologically.
Odland 2011
-piglets (newborn), hypoxia with 8% O2, resusc with RAR (n=13), OXR (n=16) for 30 minutes
-Outcomes: TnT; hemodynamic measurements
-Troponins higher in OXR compared to RAR; also some functional impairments in OXR compared to RAR.
Borke 2004
-Piglets 12-36 hrs of age, hypoxia with 8% oxygen until MAP 15 mm Hg, then resuscitation with RAR or OXR for 30 minutes
-Outcomes: MMP activity myocardium; antioxidant capacity myocardium (ORAC value)
-MMP higher in OXR than RAR (but increased in both compared to controls); reduction in total endogenous antioxidant capacity (ORAC)
Fanos 2014
-Newborn piglets, hypoxia with FiO2 (0.06-0.08) resuscitation with 18%, 21%, 40%, 100% oxygen and NLS resuscitation.
-Outcomes, survival; metabolomic approach to assess for free radical scavenging (from urine samples; systemic)
-Significant association between 40%/100% reoxygenation and radical scavenging
Tollofsrud 2001
-Piglets (2-5 days), hypoxia with 8% O2; followed by meconium aspiration and either RAR or OXR
-Outcome: hypoxanthine in plasma
-No difference in Hx concentrations between groups
Bockhorst 2010
-rat pups, 7 days, hypoxia with 90 min of 8% O2, followed by RAR or OXR for 120 minutes.
-Outcomes: MRI, for lesion volumes and diffusion tensor imaging (DTI) brain
-Hyperoximic treatment worsened the injury significantly in this model
Stevens 2008
-Piglets, 1-2 days old; hypoxia (FiO2 0.1-0.15) x 2 h; reoxygenation with RAR or OXR x 1 hr, then 21% O2 x 1 h (n=9 per group)
-Outcomes: liver tissue GSSG, GSH, MMP
-Higher oxidative stress and MMP elevation in liver with OXR
Chapados 2010
-Piglets, 1-2 days old; hypoxia (PaO2 20-30 mm Hg) x 2 h; reoxygenation with RAR or OXR x 1 hr, then 21% O2 x 3 h (n=14 per group, 7 as shams)
-Outcomes: Cortisol levels after ACTH stim
-The cortisol response was preserved in RAR, but not in OXR
Lakshminurismha 2011
-Lamb model of inutero asphyxiation (cord occlusion x 10 mins), followed by RAR or OXR for 30 minutes (n=6, each)
-Outcomes: dihydroethidium (DHE) in PA (measure of superoxide generation in pulmonary artery)
-higher oxidative stress and increased PA contractility with OXR; no respiratory benefits of OXR
Faa 2014
-Piglets, 1-4 days old, hypoxia induced with FiO2 0.06-0.08 until MAP < 15 mm Hg; NLS resuscitation, with 18, 21, 40 or 100% O2 until MAP > 90% of baseline.
-Outcomes: Histopathological brain injury (cortex)
-Higher apoptotic neurons in 100%O2 (59.2%) compared to lower oxygen groups.
Solberg 2007
-Piglets, 12-36 hours old, hypoxemia with 8% O2 until MAP < 15 mm Hg/BE -20 mm Hg, resusc with 21, 40, 60 or 100% O2 x 15 minutes, then 21% x 1 h, then sacrificed
-Outcomes: oxidative injury to DNA (tyrosine and guanosine) and protein (phenylalanine) in urine (systemic)
-Increased oxidation of DNA and phenylalanine in all hyperoxic groups (concentration dependent severity)
Munkeby 2005
-piglets 12-36 hours of age, hypoxemia with 8% O2 until BP <15 mmHg/BE-20; RAR or OXR x 30 min; further hyperventilation, hypoventilation or normoventilation groups (6 groups total, n=10 per group), sham
-MMPs lung tissue; oxygen radical absorbance capacity (ORAC), pulmonary histology
-Increased upregulation of MMPs, IL8 in lung and BAL with OXR; reduction in ORAC with OXR; no histological difference
Borke, 2004
-Piglets 12-36 hours; hypoxemia with 8% O2 until MAP<15/BE-20; resuscitation with RAR or OXR; further subdivided into hypo-, hyper-, or normoventlation (6 groups, n=9-10 each)
-Outcomes: cTNI, CK-MB, myoglobin (serum)
-No difference between groups regarding the measurement, no protective effect of 100% O2
Munkeby 2004
-Piglets 12-36 hours; hypoxemia with 8% O2 until MAP<15/BE-20; resuscitation with RAR or OXR; further subdivided into hypo-, hyper-, or normoventlation (6 groups, n=10 each)
-Outcomes: Glycerol leakage (microdialysis); Cerebral MMP-2 activity, quantity (WesternBlot); MMP RNA cerebral; ORAC brain, 2.5 hours after injury
-Higher MMP-2 cerebral extracellular in OXR, higher mRNA for MMP-2 and lower ORAC; increased glycrol leakage with OXR (increased brain damage)
Haase 2004
-piglets, 1-3 days old, 2 hours of hypoxia followed by reoxygenation with 21%, 50%, 100% oxygen for 1 hours, followed by room air for 6 h, n=8 per group
-Outcomes: GSSG, GSH and histopath of small intestine (necrotizing enteritis model)
-Increased oxidative stress in all post-resuscitation animals, but no significant difference between groups; some histological injury in OXR, but not statistically significant (likely beta error).
Solberg 2012
-piglets 12-36 hours, hypoxia with 8% O2 until MAP<15 mm Hg/BE -20 mm Hg; then 21, 40, or 100% oxygen for 30 min, then room air for 9 hrs.
-Outcomes: isoprostanes, isofurans, neuroprostanes, neurofurans (ROS) cerebral cortex
-Significant increases in all these ROS compounds with 100% O2, less consistent with 40% O2 compared to RAR.
Goplerud 1995
-Piglets 3-5 days, hypoxic by reduced FiO2 to MAP < 40 mm Hg for 60 minutes; then RAR or OXR x 2h. (n=5 each)
-Striatum (subcortical area): NA,K ATPase activity at the end of the study
-Na,K ATPase did return to baseline in RAR, but not OXR
Smit 2015
-rat pups 7 days old, with Rice-Vannucci model: ligation of carotid arteri (unilaterally), followed by hypoxic insult (8% O2 x 125 minutes); this is associated with 23% mortality in this study. Survivors were resuscitated with RAR or OXR for 30 minutes. Followed by room air for 5 h. Analysis at age 14 days.
-Histopath of brain showed no worse brain in jury for OXR (but also not better)
Fokkelman 2007
-Piglets 1-3 days old, FiO2 0.1-0.14 until PaO2 40-50 mm Hg and MAP 25-35 mm Hg. Reox with RAR or OXR for 2 hour, then room air for 1 h.
-Outcomes: GSSG, GSH lipid perodixation: liver, lung, left ventricle, kidney SI
-GSSG:GSH ratios higher in lung and liver after OXR, no differences for other organs. No differences in lipid peroxidation in these organs.
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Additional references:
● Bajaj N, Udani RH, Nanavati RN. Room air vs. 100 per cent oxygen for neonatal resuscitation: a controlled clinical trial. J Trop Pediatr. 2005 Aug;51(4):206-11. doi: 10.1093/tropej/fmh086. Epub 2005 May 31. PMID: 15927951.
● A. P. Davidson Neonatal resuscitation: improving the outcome. The Veterinary Clinics Of North America. Small Animal Practice 2014 Vol. 44 Issue 2 Pages 191-204. Accession Number: 24580986 DOI: 10.1016/j.cvsm.2013.11.005
● Espinoza ML, Cheung PY, Lee TF, O'Reilly M, Schmölzer GM. Heart rate changes during positive pressure ventilation after asphyxia-induced bradycardia in a porcine model of neonatal resuscitation. Arch Dis Child Fetal Neonatal Ed. 2019 Jan;104(1):F98-F101. doi: 10.1136/archdischild-2017-314637. Epub 2018 May 19. PMID: 29778994.
● Kibsgaard, A, Ersdal, H, Kvaløy, JT, Eilevstjønn, J, Rettedal, S. Newborns requiring resuscitation: Two thirds have heart rate ≥100 beats/minute in the first minute after birth. Acta Paediatr. 2023; 112: 697–705. https://doi.org/10.1111/apa.16659
● Mrelashvili A, Russ JB, Ferriero DM, Wusthoff CJ. The Sarnat score for neonatal encephalopathy: looking back and moving forward. Pediatr Res. 2020 Dec;88(6):824-825. doi: 10.1038/s41390-020-01143-5. Epub 2020 Sep 11. PMID: 32916680; PMCID: PMC7704551.
● Niermeyer S, Kattwinkel J, Van Reempts P, Nadkarni V, Phillips B, Zideman D, Azzopardi D, Berg R, Boyle D, Boyle R, Burchfield D, Carlo W, Chameides L, Denson S, Fallat M, Gerardi M, Gunn A, Hazinski MF, Keenan W, Knaebel S, Milner A, Perlman J, Saugstad OD, Schleien C, Solimano A, Speer M, Toce S, Wiswell T, Zaritsky A. International Guidelines for Neonatal Resuscitation: An excerpt from the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: International Consensus on Science. Contributors and Reviewers for the Neonatal Resuscitation Guidelines. Pediatrics. 2000 Sep;106(3):E29. doi: 10.1542/peds.106.3.e29. PMID: 10969113.
● Ramji S, Ahuja S, Thirupuram S, Rootwelt T, Rooth G, Saugstad OD. Resuscitation of asphyxic newborn infants with room air or 100% oxygen. Pediatr Res. 1993 Dec;34(6):809-12. doi: 10.1203/00006450-199312000-00023. PMID: 8108199.
● Ramji S, Rasaily R, Mishra PK, Narang A, Jayam S, Kapoor AN, Kambo I, Mathur A, Saxena BN. Resuscitation of asphyxiated newborns with room air or 100% oxygen at birth: a multicentric clinical trial. Indian Pediatr. 2003 Jun;40(6):510-7. PMID: 12824660.
● Saugstad OD, Rootwelt T, Aalen O. Resuscitation of asphyxiated newborn infants with room air or oxygen: an international controlled trial: the Resair 2 study. Pediatrics. 1998 Jul;102(1):e1. doi: 10.1542/peds.102.1.e1. PMID: 9651453.
● Sobotka KS, Morley C, Ong T, Polglase GR, Aridas JD, Miller SL, Schmölzer GM, Klingenberg C, Moss TJ, Jenkin G, Hooper SB. Circulatory responses to asphyxia differ if the asphyxia occurs in utero or ex utero in near-term lambs. PLoS One. 2014 Nov 13;9(11):e112264. doi: 10.1371/journal.pone.0112264. PMID: 25393411; PMCID: PMC4230987.
● Vento M, Asensi M, Sastre J, García-Sala F, Viña J. Six years of experience with the use of room air for the resuscitation of asphyxiated newly born term infants. Biol Neonate. 2001;79(3-4):261-7. doi: 10.1159/000047103. PMID: 11275663.
● Vento M, Asensi M, Sastre J, Lloret A, García-Sala F, Viña J. Oxidative stress in asphyxiated term infants resuscitated with 100% oxygen. J Pediatr. 2003 Mar;142(3):240-6. doi: 10.1067/mpd.2003.91. Erratum in: J Pediatr. 2003 Jun;142(6):616. PMID: 12640369.
● Yam CH, Dawson JA, Schmölzer GM, Morley CJ, Davis PG. Heart rate changes during resuscitation of newly born infants <30 weeks gestation: an observational study. Arch Dis Child Fetal Neonatal Ed. 2011 Mar;96(2):F102-7. doi: 10.1136/adc.2009.180950. Epub 2010 Dec 1. PMID: 21126997.
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