There are currently no evidence-based oxygen saturation targets for treating children with life-threatening conditions. We reviewed evidence of SpO2 targets for oxygen therapy in children with emergency signs as per WHO Emergency Triage Assessment and Treatment guidelines. We systematically searched for physiological data and international guidelines that would inform a safe approach. Our findings suggest that in children with acute lung disease who do not require resuscitation, a threshold SpO2 for commencing oxygen of 90% will provide adequate oxygen delivery. Although there is no empirical evidence regarding oxygen saturation to target in children with emergency signs from developing countries, a SpO2 of ≥ 94% during resuscitation may help compensate for common situations of reduced oxygen delivery. In children who do not require resuscitation or are stable post resuscitation with only lung disease, a lower limit of SpO2 for commencing oxygen of 90% will provide adequate oxygen delivery and save resources.

INTRODUCTION

Previously, apart from oxygen therapy based on clinical signs, the WHO has recommended a single threshold of pulse oximetry saturation (SpO2) of <90% for giving oxygen to children with pneumonia. Although this is unchanged for stable patients with pneumonia or other respiratory infections, the recently updated WHO Emergency Triage Assessment and Treatment (ETAT) guidelines now recommend a target SpO2 of ≥94% during resuscitation for children with emergency signs [1].

WHO ETAT guidelines aim to identify children with immediately life-threatening conditions in developing countries, analogous to Advanced Paediatric Life Support Guidelines [2]. WHO emergency signs relate to severe airway, breathing, circulation or conscious state problems (see Textbox 1).

Textbox 1: WHO Emergency Triage (ETAT) clinical signs

Obstructed or absent breathing

Severe respiratory distress

Central cyanosis

Signs of shock (cold hand, capillary refill >3 seconds, rapid and weak pulse, and low or un-measurable blood pressure)

Coma

Convulsions

Signs of severe dehydration in a child with diarrhea

Oxygen therapy for hypoxemia is widely accepted and reflected in international guidelines [3–7]. Hypoxemia is identified by arterial blood oxygen saturation (SaO2) below normal ranges and is a complication of pneumonia and a risk factor for death [8–12]. Hypoxia refers to a relative deficiency of oxygen that is unable to meet needs at the tissue level [13] and is a complication of hypoxemia, or reduced oxygen delivery, or inability to use oxygen at a tissue level. Children with acute respiratory infection in developing countries are at an increased risk of hypoxemia and death due to comorbidities and late presentation. Non-respiratory causes of hypoxemia or tissue hypoxia include severe sepsis [11, 12, 14], seizures, coma and severe anemia [12]. Malnourished children are more susceptible to infections and have poorer outcomes with intercurrent disease [15, 16]. There is a high prevalence of anemia in preschool-age children in developing countries [17], and anemia commonly complicates acute infections. Combinations of lung diseases, sepsis, nutritional cardiac impairment and effect of anemia on oxygen delivery carry high risks.

This review presents the data on the SpO2 that should be targeted in sick children. We searched for international guidelines and papers on physiological data, which would provide a framework for a safe approach.

METHODS

Search methods and sources

A systematic review protocol was used. We searched MEDLINE (inception–2015), EMBASE (inception–2015), physiology/scientific journals and information in related textbook chapters for studies comparing oxygen saturation targets in children with emergency signs, using terms in Table 1. PubMed was searched using keywords only to retrieve e-pubs and items not indexed in Medline. Gray literature was searched using the British Library, WHO, The New York Academy of Science and Google Scholar. Past related reviews and reference lists of relevant articles were identified. Broad search terms were used to maximize sensitivity.

Table 1.

Medline search strategy

1. exp Airway Management/ or respiration/ or exp Airway Resistance/ or exp Airway Obstruction/ or exp Alkalosis, Respiratory/ or alkalosis/ or hyperventilation/ or exp Respiratory Therapy/ or exp Acidosis, Respiratory/ or acidosis/ or exp Respiratory System/ or exp “work of breathing”/ or exp Respiratory Tract Infections/ or exp Respiratory Tract Diseases/ or Shock, Hemorrhagic/ or exp Shock, Traumatic/ or Shock/ or Shock, Septic/ or Shock, Cardiogenic/ or exp unconsciousness/ or brain death/ or death/ or exp Hypoglycemia/ or exp Seizures/ or epilepsy/ or exp cyanosis/ or Dehydration/ or exp Anemia/ or exp Hypotension/ or exp diarrhea/ 
2. ((obstruct* adj3 (breathing or airway or respiration)) or shock or cyanosis or cyanoses or cyanotic or convulsion* or convulsive or coma or alkalosis or alkaloses or alkalotic or hyperventilate* or hyper-ventilate* or acidosis or acidoses or acidotic or (respiratory adj disease*) or unconsciousness or death* or hypoglyc?emi* or seizure* or epilep* or diarrhoea* or diarrhea* or hypotensi* or anaemi* or anemi*).tw,kf. 
3. th.fs. 
4. exp anoxia/ 
5. (anox* or hypox*).tw,kf. 
6. oxygen/bl 
7. exp oximetry/ 
8. oximetr*.tw,kf. 
9. exp Oxygen Inhalation Therapy/ 
10. ((oxygen adj3 therap*) or (oxygen adj delivery) or (oxygen adj administration) or (oxygen adj3 supplement*)).tw,kf. 
11. treatment outcome/ or exp treatment failure/ 
12. morbidity/ or mortality/ or child mortality/ or infant mortality/ or survival rate/ 
13. prognosis/ 
14. (mortalit* or morbidit* or survival or outcome* or death* or died).tw,kf. 
15. (newborn* or neonat* or infan* or pre-schooler* or preschooler* or child* or adolescen* or pediatric* or paediatric* or youth*1 or teen*).af. 
16. (1 or 2 or 3) and (4 or 5 or 6 or 7 or 8) and (9 or 10) and (11 or 12 or 13 or 14) and 15 
17. exp animals/ not human*.sh. 
18. 16 not 17 
19. limit 18 to english 
1. exp Airway Management/ or respiration/ or exp Airway Resistance/ or exp Airway Obstruction/ or exp Alkalosis, Respiratory/ or alkalosis/ or hyperventilation/ or exp Respiratory Therapy/ or exp Acidosis, Respiratory/ or acidosis/ or exp Respiratory System/ or exp “work of breathing”/ or exp Respiratory Tract Infections/ or exp Respiratory Tract Diseases/ or Shock, Hemorrhagic/ or exp Shock, Traumatic/ or Shock/ or Shock, Septic/ or Shock, Cardiogenic/ or exp unconsciousness/ or brain death/ or death/ or exp Hypoglycemia/ or exp Seizures/ or epilepsy/ or exp cyanosis/ or Dehydration/ or exp Anemia/ or exp Hypotension/ or exp diarrhea/ 
2. ((obstruct* adj3 (breathing or airway or respiration)) or shock or cyanosis or cyanoses or cyanotic or convulsion* or convulsive or coma or alkalosis or alkaloses or alkalotic or hyperventilate* or hyper-ventilate* or acidosis or acidoses or acidotic or (respiratory adj disease*) or unconsciousness or death* or hypoglyc?emi* or seizure* or epilep* or diarrhoea* or diarrhea* or hypotensi* or anaemi* or anemi*).tw,kf. 
3. th.fs. 
4. exp anoxia/ 
5. (anox* or hypox*).tw,kf. 
6. oxygen/bl 
7. exp oximetry/ 
8. oximetr*.tw,kf. 
9. exp Oxygen Inhalation Therapy/ 
10. ((oxygen adj3 therap*) or (oxygen adj delivery) or (oxygen adj administration) or (oxygen adj3 supplement*)).tw,kf. 
11. treatment outcome/ or exp treatment failure/ 
12. morbidity/ or mortality/ or child mortality/ or infant mortality/ or survival rate/ 
13. prognosis/ 
14. (mortalit* or morbidit* or survival or outcome* or death* or died).tw,kf. 
15. (newborn* or neonat* or infan* or pre-schooler* or preschooler* or child* or adolescen* or pediatric* or paediatric* or youth*1 or teen*).af. 
16. (1 or 2 or 3) and (4 or 5 or 6 or 7 or 8) and (9 or 10) and (11 or 12 or 13 or 14) and 15 
17. exp animals/ not human*.sh. 
18. 16 not 17 
19. limit 18 to english 

Similar search terms were used for other databases with adaptations as needed

Inclusion and exclusion criteria

Studies that addressed the PICOT question ‘In children presenting with emergency signs, at which oxygen saturation targets should oxygen therapy be commenced, or ceased, to prevent short and long term morbidity/mortality?’ were included for systematic review. Guidelines and physiological and mechanistic data comparing oxygen saturation targets and physiology in children with critical illness were systematically searched and summarized to form a narrative. Studies not relating to infants or children were excluded, as well as non-English-language articles.

Data synthesis

Following query of databases, titles and abstracts of retrieved studies were screened. For articles that could not be excluded based on the title and abstract, or had some possible relevance, the full text was reviewed. Studies from developing countries were preferred, but all relevant studies were included. Included studies were then assessed according to GRADE methodology, and a summary of the findings table was compiled. Physiological and mechanistic data and guidelines were compiled in a narrative synthesis with findings summarized in subject themes.

RESULTS

A total of 1824 articles were scanned from MEDLINE, EMBASE and PubMed (see Annex 1 [18]). One randomized trial and two observational studies were identified that described outcomes at different oxygen saturation targets in children, and these are described below and summarized in the GRADE summary (Table 2).

Table 2

GRADE Summary of Findings Table

Summary of findings: 
Outcomes for SpO2 targets in children with emergency signs 
Patient or population: children with emergency signs 
Setting: primary care, clinics, hospitals 
Intervention: oxygen 
Comparison: standard therapy 
Outcomes Anticipated absolute effectsa (95% CI) Relative effect (95% CI) № of participants (studies) Quality of the evidence (GRADE) Comments 
Risk with standard therapy Risk with oxygen 
Oxygen saturation target in bronchiolitis (comparing SpO2 90% vs. 94%) Assessed with: Duration of cough No difference between standard care and modified group for median time to cough resolution of 15.0 days – 615 (1 RCT) ⊕⊕⊕◯HIGHb Equivalence trial, no increased risk from using 90% vs. 94% SpO2 target, recorded adverse events did not differ significantly 
Mortality with 85% SpO2 targetAssessed with: Case fatality rates in pneumonia 101 per 1000 66 per 1000 (41 to 103) RR 0.65 (0.41 to 1.02) 961 (1 observational study) ⊕⊕◯◯LOWc  
Mortality with 90% SpO2 targetAssessed with: Case fatality rates in pneumonia 50 per 1000 32 per 1000 (26 to 39) RR 0.65 (0.52 to 0.78) 11291 (1 observational study) ⊕⊕◯◯LOWd  
GRADE Working Group grades of evidence
  •  High quality: We are very confident that the true effect lies close to that of the estimate of the effect

  •  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different

  •  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect

  •  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

 
Summary of findings: 
Outcomes for SpO2 targets in children with emergency signs 
Patient or population: children with emergency signs 
Setting: primary care, clinics, hospitals 
Intervention: oxygen 
Comparison: standard therapy 
Outcomes Anticipated absolute effectsa (95% CI) Relative effect (95% CI) № of participants (studies) Quality of the evidence (GRADE) Comments 
Risk with standard therapy Risk with oxygen 
Oxygen saturation target in bronchiolitis (comparing SpO2 90% vs. 94%) Assessed with: Duration of cough No difference between standard care and modified group for median time to cough resolution of 15.0 days – 615 (1 RCT) ⊕⊕⊕◯HIGHb Equivalence trial, no increased risk from using 90% vs. 94% SpO2 target, recorded adverse events did not differ significantly 
Mortality with 85% SpO2 targetAssessed with: Case fatality rates in pneumonia 101 per 1000 66 per 1000 (41 to 103) RR 0.65 (0.41 to 1.02) 961 (1 observational study) ⊕⊕◯◯LOWc  
Mortality with 90% SpO2 targetAssessed with: Case fatality rates in pneumonia 50 per 1000 32 per 1000 (26 to 39) RR 0.65 (0.52 to 0.78) 11291 (1 observational study) ⊕⊕◯◯LOWd  
GRADE Working Group grades of evidence
  •  High quality: We are very confident that the true effect lies close to that of the estimate of the effect

  •  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different

  •  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect

  •  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

 
a

The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

Explanations:

b

Single disease population in high-income country, infants with severe disease excluded (-2 indirectness)

c

Single disease cohort, high case fatality rate, one facility population, at high altitude (-2 indirectness)

d

Single disease cohort, high case fatality rate, at high altitude (-2 indirectness)

CI: Confidence interval; RR: Risk ratio.

Cunningham et al. [19] performed a double-blind, randomized, equivalence trial of 615 patients with bronchiolitis in the UK. Diagnosis of bronchiolitis was made according to clinical criteria (SIGN 91 bronchiolitis [20]). In total, 308 patients were randomized to receive oxygen if SpO2 was <94%, compared with 307 for SpO2 <90%, using modified oximeters. Infants admitted directly to intensive care or high dependency units or those with underlying lung or cardiac disease were excluded. Median time to resolution of cough was 15.0 days in both groups, with no difference between the two groups. Recorded adverse events were not significantly different between both groups. The authors concluded that a lower saturation target of 90% was safe and as clinically effective as 94%.

Duke et al. [9] compared a prospectively studied group of 703 children with severe pneumonia treated using a pulse oximetry protocol with a retrospective control group of 258. Diagnosis was according to criteria for severe pneumonia in Papua New Guinea, consistent with WHO classification for very severe pneumonia. In the historical control group, oxygen therapy was based on clinical signs, particularly cyanosis. Using a SpO2 lower limit of <85% for oxygen therapy in the prospective protocol, case fatality rates were reduced from 10 to 6.5%, and the mortality risk ratio was 0.65 (95% CI 0.41–1.02, two-sided Fisher’s exact test, P = 0.07). This study was done at 1600 m altitude.

Duke et al. [21] demonstrated a reduction in mortality by installing an improved oxygen system in five hospitals in Papua New Guinea. Diagnoses were made according to WHO criteria. This included the introduction of pulse oximetry-guided oxygen therapy for SpO2 <90%. Before introduction of the system, 356 of 7161 children admitted in the five hospitals for pneumonia died (case-fatality rate 4.97% [95% CI 4.5–5.5]), whereas 133 of 4130 children died in the 27 months after the introduction of the system (3·22% [2.7–3.8]). This study was done in three highland hospitals at an altitude of 1600-1800 m and in two coastal hospitals at sea level.

Physiological mechanisms

These clinical studies provide some evidence for appropriate oxygen therapy targets, but there is heterogeneity in disease etiology and setting. There were no empirical data on oxygen delivery thresholds in multi-system critically ill states; this may be different than in children with single-organ disease such as pneumonia or bronchiolitis. We summarize physiological mechanisms in the following sections, as a way of understanding an approach to provision of oxygen for children with emergency signs such as those in ETAT guidelines.

Oxygen–hemoglobin dissociation curve

The relationship between oxygen saturation and the partial pressure of oxygen in blood is not linear, illustrated by the sigmoid shape of the oxygen–hemoglobin dissociation curve (Fig. 1). Target oxygen saturations and definitions of hypoxemia are often directed toward the ‘safe’ section of the curve, corresponding to PaO2 above 60 mmHg and SaO2 greater than 90%. At pressures above PaO2 60 mmHg, oxygen saturation (SaO2) of blood does not change significantly even with large changes in oxygen partial pressure. However, below a PaO2 of 60 mmHg, small reductions in PaO2 greatly reduce SaO2 and blood oxygen content.

Fig. 1

Oxygen–hemoglobin dissociation curve.

Fig. 1

Oxygen–hemoglobin dissociation curve.

Oxygen content

Oxygen content is the sum of oxygen bound to hemoglobin (98% of all transported oxygen) and oxygen dissolved in the plasma (2%). Oxygen content is therefore highly dependent on hemoglobin saturation. It can be calculated using the following equation:  

Oxygen content=(Hb×k1×SaO2)+(k2×PaO2)

Where Hb is the hemoglobin concentration; k1 is a constant to define maximum oxygen binding capacity of hemoglobin (k1 is known as Hüfner’s constant; the milliliter of oxygen that can be bound by 1 gram of hemoglobin at standard temperature and pressure. The value for k1 varies between authors but 1.39 ml/g will be used for the purposes of this review.); SaO2 is the percent of hemoglobin saturated with oxygen; PaO2 is the partial pressure of oxygen in arterial blood; k2 is a constant to define the solubility of oxygen in the plasma (Solubility coefficient of oxygen in plasma = 0.0031).

This equation helps to illustrate the effect of various physiological abnormalities on arterial oxygen content and subsequent oxygen delivery. For example, a healthy child may have an arterial oxygen content of approximately 16.4 mL/dL (Hb 12 g/dL, 100% SaO2, PaO2 105 mmHg). In contrast, in a child with acute respiratory distress, hypoxemia and mild anemia (Hb 9 g/dL, SaO2 88%, PaO2 60 mmHg), the arterial oxygen content may be significantly lower, at approximately 10.8 mL/dL [22]. Whether this is sufficient to match metabolic demands without resulting in anaerobic metabolism, lactic acidosis and cell metabolic dysfunction depends on the adequacy of the cardiac output, regional tissue perfusion and whole body and regional tissue oxygen consumption. A cycle can be established where the increased cardiac work that is required to supply metabolic demands requires more oxygen.

Oxygen delivery

Physiological homeostasis requires that oxygen delivery meet the demands of tissue oxygen consumption. Oxygen delivery is the product of cardiac output and blood oxygen content, which as shown above depends on hemoglobin concentration and hemoglobin–oxygen saturation (SaO2). Hypoxia can be caused by inadequate transfer of oxygen across the lungs (hypoxemic hypoxia), decreased arterial oxygen content (anemic hypoxia), inadequate blood flow (ischemic hypoxia) or abnormal cellular oxygen utilization (cytotoxic hypoxia) [13]. Conditions presenting with WHO’s emergency signs may be associated with each of these pathophysiological processes.

Critical oxygen saturation levels

The oxygen tension below which cellular oxidative metabolism fails (a state called dysoxia) varies, and multiple factors, including the specific organ or tissue, cellular metabolic requirements, pH and others, determine this. There is a strong diffusion gradient from arteries to cells: within cells, the lower limit for dysoxia is a PO2 between 3-15 mmHg, depending on cell type and activity, and within mitochondria, this threshold may be as low as 1 mmHg, and even 0.1 mmHg within muscle cells[23].

Lumb [24] described a theoretical model for determining the critical venous oxygen tension that is associated with dysoxia, using venous PO2 that approximates to end-capillary PO2. In this model, physiological factors are adjusted to reflect oxygen saturation at a venous PO2 of 20 mmHg and oxygen content of 6.4 ml/dl, below which oxidative cellular metabolism fails. These calculations suggested that under conditions where the cardiac function and hemoglobin are normal, the estimated arterial oxygen content required to prevent dysoxia is 13.8 ml/dl, PaO2 36 mmHg, and this corresponds to a SaO2 of 68%. However, in uncompensated anemia, an arterial oxygen saturation (equivalent to SpO2) of at least 93% is needed to maintain cerebral metabolic demand [24]. For uncompensated cerebral ischemia, an even higher SpO2 may be necessary. Physiological compensatory mechanisms such as increased cerebral blood flow that help to maintain cerebral oxygenation and other protective factors have not been taken into consideration in these calculations. However, these examples (see Table 3) illustrate the nature of oxygen requirement in disease states with multiple comorbidities, such as might be seen in children with co-existent lung and brain disease (e.g. pneumonia and meningitis), or lung and circulatory impairment (e.g. pneumonia and sepsis), or CNS disease (such as cerebral malaria) and severe anemia.

Table 3.

Lowest arterial oxygen levels compatible with a cerebral venous PO2 of 2.7 kPa (20 mmHg) under various conditions

 Blood O2 capacity Brain O2 consumption Cerebral blood flow Cerebral venous blood
 
Art./Ven. O2 content difference Arterial blood
 
ml.dl−1 ml.min−1 ml.min1 PvO2 (mmHg) SvO2 (%) O2 Content (ml/dl)  O2 Content (ml/dl) PaO2 (mmHg) SaO2 (%) 
Normal values 20 46 620 33 63 12.6 7.4 20.0 100 98 
Uncompensated arterial hypoxemia 20 46 620 20 32 6.4 7.4 13.8 36 68 
Arterial hypoxemia with increased cerebral blood flow 20 46 1240 20 32 6.4 3.7 10.1 27 50 
Uncompensated cerebral ischemia 20 46 340 20 32 6.4 13.5 19.9 112 98 
Uncompensated anemia 12 46 620 20 32 3.8 7.4 11.2 67 93 
Combined anemia and ischemia 15 46 460 20 32 4.8 10 14.8 92 97 
 Blood O2 capacity Brain O2 consumption Cerebral blood flow Cerebral venous blood
 
Art./Ven. O2 content difference Arterial blood
 
ml.dl−1 ml.min−1 ml.min1 PvO2 (mmHg) SvO2 (%) O2 Content (ml/dl)  O2 Content (ml/dl) PaO2 (mmHg) SaO2 (%) 
Normal values 20 46 620 33 63 12.6 7.4 20.0 100 98 
Uncompensated arterial hypoxemia 20 46 620 20 32 6.4 7.4 13.8 36 68 
Arterial hypoxemia with increased cerebral blood flow 20 46 1240 20 32 6.4 3.7 10.1 27 50 
Uncompensated cerebral ischemia 20 46 340 20 32 6.4 13.5 19.9 112 98 
Uncompensated anemia 12 46 620 20 32 3.8 7.4 11.2 67 93 
Combined anemia and ischemia 15 46 460 20 32 4.8 10 14.8 92 97 

Adapted from Nunn’s Applied Physiology, 7th Edition23.

International pediatric resuscitation guidelines

Most national and international advanced pediatric resuscitation guidelines recommend delivering high concentration of oxygen in the first stages of resuscitation, for treatment of circulatory and respiratory failure, even prior to determination of oxygen saturation [3–7], summarized in Table 4.

Table 4

International guidelines describing oxygen use in resuscitation

Guideline Oxygen saturation target description 
Resuscitation Council (UK) [6‘100% oxygen should be used for initial resuscitation. After ROSC, titrate the inspired oxygen, using pulse oximetry, to achieve an oxygen saturation of 94–98%’ 
European Resuscitation Council [7‘Give oxygen at the highest concentration (i.e. 100%) during initial resuscitation…Once the child is stabilized and/or there is ROSC, titrate the fraction of inspired oxygen (FiO2) to achieve normoxemia, or at least (if arterial blood gas is not available), maintain SpO2 in the range of 94–98%.’ 
American Heart Association Guidelines [4‘It is reasonable to ventilate with 100% oxygen during CPR because there is insufficient information on the optimal inspired oxygen concentration. Once the circulation is restored, monitor systemic oxygen saturation. It may be reasonable, when the appropriate equipment is available, to titrate oxygen administration to maintain the oxyhemoglobin saturation ≥94%.’ 
Australian and New Zealand Committee on Resuscitation [5‘A high concentration of oxygen should be administered during resuscitation regardless of any preceding condition. There is insufficient evidence for choosing any concentration of oxygen during acute resuscitation. It is reasonable to use 100% oxygen initially for resuscitation. After ROSC, the concentration of inspired oxygen should be reduced to a level which yields a satisfactory level of oxygen in arterial blood measured by arterial blood gas analysis (PaO2 80-100 mmHg) or by percutaneous oximetry (SpO2 94-98%).’ 
NICE: Assessment and initial management of feverish illness in children younger than 5 years [3Oxygen should be given to children with fever who have signs of shock or oxygen saturation (SpO2) of less than 92% when breathing air. Treatment with oxygen should also be considered for children with an SpO2 of greater than 92%, as clinically indicated. 
Guideline Oxygen saturation target description 
Resuscitation Council (UK) [6‘100% oxygen should be used for initial resuscitation. After ROSC, titrate the inspired oxygen, using pulse oximetry, to achieve an oxygen saturation of 94–98%’ 
European Resuscitation Council [7‘Give oxygen at the highest concentration (i.e. 100%) during initial resuscitation…Once the child is stabilized and/or there is ROSC, titrate the fraction of inspired oxygen (FiO2) to achieve normoxemia, or at least (if arterial blood gas is not available), maintain SpO2 in the range of 94–98%.’ 
American Heart Association Guidelines [4‘It is reasonable to ventilate with 100% oxygen during CPR because there is insufficient information on the optimal inspired oxygen concentration. Once the circulation is restored, monitor systemic oxygen saturation. It may be reasonable, when the appropriate equipment is available, to titrate oxygen administration to maintain the oxyhemoglobin saturation ≥94%.’ 
Australian and New Zealand Committee on Resuscitation [5‘A high concentration of oxygen should be administered during resuscitation regardless of any preceding condition. There is insufficient evidence for choosing any concentration of oxygen during acute resuscitation. It is reasonable to use 100% oxygen initially for resuscitation. After ROSC, the concentration of inspired oxygen should be reduced to a level which yields a satisfactory level of oxygen in arterial blood measured by arterial blood gas analysis (PaO2 80-100 mmHg) or by percutaneous oximetry (SpO2 94-98%).’ 
NICE: Assessment and initial management of feverish illness in children younger than 5 years [3Oxygen should be given to children with fever who have signs of shock or oxygen saturation (SpO2) of less than 92% when breathing air. Treatment with oxygen should also be considered for children with an SpO2 of greater than 92%, as clinically indicated. 

Several guidelines recommend higher oxygen saturation targets in children who are more severely unwell. The WHO publication Oxygen Therapy for Children recommends higher targets (>94%) for severe disease states where oxygen delivery from the lungs to body tissues is impaired, or where vital organs may be susceptible to low oxygen levels [25].

DISCUSSION

There is limited evidence to determine oxygen saturation targets to reduce morbidity and mortality in children with emergency signs. Two pre–post observational studies in a developing country demonstrated benefit from oxygen therapy, for a target SpO2 of > 85 and >90% in the treatment of children with WHO-defined severe pneumonia. In a randomized controlled trial for oxygen therapy for bronchiolitis in a developed country, there was no disadvantage with a saturation target of >90% compared with 94%.

In the absence of controlled trials, principles of oxygenation are helpful in determining a safe approach by demonstrating the impact of different physiological derangements for children with emergency conditions commonly presenting in low- and middle-income countries. Maintaining SpO2 above 90% corresponds to the safe section of the oxygen–hemoglobin dissociation curve, and in the absence of co-morbid derangements in oxygen will ensure adequate cerebral oxygenation and avoid dysoxia. Lumb’s calculations also indicate there is sufficient luxury in a target SpO2 of 90%, well above critical levels associated with dysoxia.

Most international guidelines for the management of shock say to give 100% oxygen by face mask or nasal prongs, and to have a target SpO2 of 94-98%. The UK National Institute of Clinical Excellence (NICE) guideline is the only one to specify a lower SpO2 saturation limit in the setting of fever and shock, with the provision that oxygen therapy should be considered at higher SpO2 if clinically indicated (Table 4). Most of these guidelines are used in high- and middle-income countries, where oxygen therapy is more available, but where underlying comorbidities and late presentation are less common than in developing countries.

Other guidelines for oxygen therapy outside the resuscitation phase of treatment are based on etiology and focus on single-organ lung disease. In the treatment of pneumonia, for example, oxygen therapy is recommended for oxygen saturations of ≤92% by several guidelines [3, 26]. For bronchiolitis, the American Academy of Pediatrics recommends oxygen therapy if SpO2 <90% [27].

Although pulse oximetry is the most reliable, non-invasive assessment for measuring hemoglobin oxygen saturation to assess hypoxemia, it also has limitations. In anemic states, SpO2 may be in the normal range despite a reduced PaO2, making the assessment of anemia an important component of any assessment for oxygen therapy. Depending on the oximeter model and application, there is a variation in accuracy of readings [28, 29], and many oximeters are affected by movement artifact or impaired peripheral perfusion. Particularly at lower saturations, the error margin is greater [30], and this needs to be taken into account when producing guidelines.

Studies characterizing etiology and prevalence of hypoxemia in children presenting with WHO’s emergency signs are needed. More research is required to describe disease states with multiple comorbidities, as those children who present with a combination of features are most at risk of adverse cerebral oxygenation. Although randomized control studies are not possible, future implementation studies demonstrating benefit may be helpful, as part of quality improvement studies. As the provision of oximeters and availability of oxygen therapy improves, clear guidelines are needed to direct this resource in developing countries.

A target saturation of ≥ 94% will compensate for the potential of reduced oxygen delivery, which may be more common in children with WHO’s emergency signs arising from severe pneumonia, septic shock, severe anemia, CNS infection or heart failure. A target saturation of ≥ 94% during the resuscitation phase may also help to compensate for the error of the test inherent with the use of some pulse oximeters.

There are several limitations to this review. There were few studies identified, and in those included, there is heterogeneity in setting and patient selection. Whilst broad search parameters were used, it is possible that some relevant studies were not captured, and studies where the full text was not available in English were excluded. Aspects of physiologic and mechanistic data are affected in part by assumptions, calculation or theories, which are not absolute and should be interpreted in context. The quality of evidence identified in this review ranges from low to high, depending on the study, according to GRADE assessment.

Controlled trials of different oxygen targets are difficult in low-income settings, and likely to be confounded by marked population heterogeneity, co-morbidities and the many other determinants of outcomes besides the SpO2 level at which oxygen therapy is commenced. Performing randomized control trials, where oxygen is withheld for a control group or where a much lower target is given to a study group, would be unethical, as it is clear that oxygen is effective in treatment of hypoxemia and that improved oxygen systems improve quality of care in developing countries [21, 31]. Conducting studies to identify differences between smaller increments of target oxygen saturations would be difficult, as these would be confounded by heterogeneity of the populations, pulse oximeter systematic error and prohibitively large sample sizes to measure clinically relevant outcomes.

CONCLUSION

For management of stable patients with uncomplicated respiratory disease, such as severe pneumonia or bronchiolitis, a target such as SpO2 90% is appropriate and consistent with WHO and other international guidelines. The recommendation of giving oxygen to all children with WHO’s emergency signs if SpO2 <95% needs to be weighed against the increased demand that is placed on resources in developing countries where oxygen supplies may be scarce. More research is needed to support the implementation of oxygen guidelines, particularly in developing countries. Greater efforts should be put into making sufficient oxygen sources available where all seriously ill children present.

FUNDING

This systematic review was funded by the Department of Maternal, Newborn, Child and Adolescent Health, WHO, Geneva.

Acknowledgements

The authors would like to acknowledge Dr Shamim Qazi and Dr Wilson Were, Department of Maternal, Newborn, Child and Adolescent Health, WHO, for supporting this review, and Ms Poh Chua, medical librarian, Royal Children’s Hospital Melbourne, for assistance with search protocols.

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Annex 1. PRISMA flow diagram [18]

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