Send letter to journal:
Re: Response to Duke et al

Dear Editor

We read with interest the article by Duke et al[1] regarding hypoxaemia in acute respiratory and non-respiratory illnesses in infants and children in developing countries published recently in the ADC.[1] The authors have rightly pointed out the limited availability of published data on the incidence, significance or clinical signs predicting hypoxaemia in infants less than three months of age. With similar concerns we had conducted a study in infants less than two months, a part of which was published in the Archives[2] . We found that tachypnoea, defined as RR>60/min, predicted hypoxia with 80% sensitivity and 68% specificity[2]. In that study we had also examined six functional and behavioural responses as predictors of hypoxemia (Table 1). Five of these six variables had a very good sensitivity to detect hypoxaemia.

Table 1: Sensitivity and positive predictive value of six behavioural and observation variables to detect hypoxaemia in a cohort of 200 infants < 2 months attending Pediatric Emergency.

*Definitions : Abnormal Spontaneous Activity : Reduced or less than normal activity, or not playful, or not active. Abnormal cry: whimpering, or sobbing, or weak, or moaning or not crying at al. Poor or paradoxical consolability : Irritable, or cries off and on, or continued cry for longer period. Poor or decreased responsiveness 0r consciousness level: less alert than usual, or opens eyes off and on, or wakes up with difficulty, or obtunded, or does not wake up, or coma. Abnormal colour: Not usual pink, or pale, or ashen-pale, or cyanotic. Increased respiratory efforts: fast breathing, or laboured breathing.

A very high prevalence of hypoxaemia in the population studied by Duke et al1 is rather intriguing. Out of total 257 sick neonates and children 52%, were hypoxaemic. Among children with Acute Lower Respiratory Infection (ALRI) 73% and those with non-ALRI - 32% were hypoxaemic. In an ongoing study we have measured oxygen saturation (by Nellcore® oximeter) in a prospective cohort of 683 children 2-59 months brought to Pediatric Emergency Department (ED) with any respiratory symptom. Oxygen saturation using a fingertip sensor in these children at the time of arrival to ED ranged from 78% - 99%. The overall prevalence of hypoxaemia defined as SpO2 <90% was 4.5% (Table 2). Additional 5.1% children had borderline hypoxaemia, i.e. a SpO2 value of 90%. This is similar to a prevalence of 5.9% hypoxaemia (defined as SpO2 <90%) in Gambian children, 2-33 months of age, reported by Usen et al[3]. Even in our previous study of 200 infants less than two months, only 38.5% of the sick infants attending ED were hypoxaemic[2].

Table 2 : Prevalence of hypoxaemia (SpO₂ < 90%, or SpO₂ < 90%) in 683 children, 2-59 months of age, presenting with a respiratory illness in Pediatric Emergency, PGIMER, Oct. 2001- Feb. 2002.

*Includes: Acute tonsillo-pharyngitis- 12, Foreign body aspiration –19, Pertussis like illness-7, Pulmonary tuberculosis-7, Empyema-7, Pleural effusion-4, Infectious mononucleosis-2, Diphtheria-2, Pneumothorax and Lung cyst- 1 each.

A systematic review of studies on prevalence and predictors of hypoxemia in children by Lozano et al[4] found that the prevalence of hypoxia was dependent upon a number of factors including the setting of the study. The prevalence ranged from 6-9% in outdoor setting to 31-43% in emergency departments to a maximum of 47% in hospitalized children. Yet, in our study, which represents the situation near sea level (Chandigarh being a plain topographically) and the setting of an emergency department, the prevalence of hypoxaemia is much lower than that reported at heights. In light of our data and published literature. We believe that either the definition of hypoxemia used by Duke et al[1] is too liberal or the children with respiratory symptoms living at high altitude decompensate more frequently to develop hypoxia. More information is needed in this respect to formulate guidelines for general use. The cumulative data clearly suggest that hypoxaemia is more frequent in children living at high altitude. Interestingly most studies including that of Duke et al on this subject in children 2 to 59 months have been from high altitudes. It is most likely that geographic location, 1600m above sea level is responsible for the high frequency of `hypoxaemia' in their patient population. This, however, may not necessarily reflect the need for oxygen therapy. If definition of hypoxemia suggested by Duke et al[1] were to be applied as a guideline to oxygen therapy almost half of their patients would need oxygen therapy. We need to answer as to whether oxygen therapy makes any difference to outcome of patients labeled as hypoxaemic using cut-off limits proposed by Duke et al1. It may also be worthwhile to conduct studies with a large sample size at see-level (plains) and in various settings before reaching a conclusion about SpO2 cut-off for hypoxia at heights.

SUNIT SINGHI
Professor of Pediatrics

BHAVNEET BHARTI
Assistant Professor
Department of Pediatrics, Advanced Pediatrics Centre,
Postgraduate Institute of Medical Education & Research,
Chandigarh-160 012,INDIA

References

(1) Duke T, Blaschke AJ, Sialis S, Bonkowsky JL. Hypoxaemia in acute respiratory and non-respiratory illnesses in neonates and children in a developing country. Arch Dis Child 2002;86:108-112.

(2) Rajesh VT, Singhi S, Kataria S. Tachypnoea is a good predictor of hypoxia in acutely ill children. Arch Dis Child 2000;82:46-49.

(3) Usen S, Weber M, Mullholland K et al. Clinical predictors of hypoxaemia in Gambian children with acute lower respiratory infection: prospective cohort study Brit Med J 1999;318:86-91.

(4) Lozano JM. Epidemiology of hypoxaemia in children with acute lower respiratory infection. Int J Tuberc Lung Dis 2001;5:496-504.

Send letter to journal:
Re: Hypoxaemia in children: "abnormal" values may be misleading

Dear Editor

Duke et al. are to be commended for their interesting report aimed to determine normal oxygen saturation values in healthy infants and children and to assess the performance of clinical signs for predicting hypoxaemia in sick neonates and children with and without acute lower respiratory infections (ALRI).[1]

Acute lower respiratory infections (ALRI) account for a substantial burden of disease in children and adults, being pneumonia the leading cause of deaths in under five children, particularly in developing countries. Tachypnoea and chest retraction have been shown to be the most useful clinical signs for determining the presence of pneumonia and thus they are widely used in the diagnosis and management of this condition in children.[2] The World Health Organization pneumonia case-detection and management programme [3] which relies on these simple signs, seems to be justified by the existing body of evidence.

Varying degrees of hypoxaemia may be present in children with pneumonia. However, surprisingly few studies have been performed to assess normal values of haemoglobin oxygen saturation (SpO₂) through the use of transcutaneous pulse oximetry, at both sea level and high altitude. Singhi’s response to Duke et al. rightly emphasizes that altitude of studies reported must be taken into account in the interpretation of their results.[4] There are some reports on SpO₂ values at mid- and high altitude settings in healthy and sick children.[5-8] We previously reported normal values of SpO₂ in 1264 healthy children and adolescents living at 4100 m.[9]

The main conclusions of these studies performed at different altitudes are: first, values considered abnormal at sea level are very frequently found at high altitude in healthy children; second, normal values vary for different altitudes; third, recommended SpO₂ cut-offs for giving supplementary oxygen to sick children at sea level are clearly not applicable to high altitude settings, as according to these recommendations oxygen should be administered for values below 92%.[2] There is the need to perform more studies for determining which cut-off values for supplementary oxygen are related to better outcomes in sick children living at high altitude. Moreover, our study at 4100 m revealed that SpO₂ values may be different according to different ethnic groups and history of exposure to high altitude. Higher SpO₂ values in Quechua children suggest a better degree of adaptation to high altitude in native populations with a longer time to exposure to high altitude. This latter finding has obvious practical implications, as high altitude-native children, with higher baseline oxygen saturation levels than newcomers or resident non-native children, may need oxygen at higher cut-off SpO₂ values when they are sick.

Singhi is justifiably concerned on the cost of giving oxygen to children who may not need it. Oxygen may be unacceptably expensive for health services in developing countries, particularly at primary level, where most sick children seek health care. However, hypoxaemia may be a serious, life-threatening problem in sick children, particularly at high altitude, and thus we need to extend the study of Duke et al. for different altitudes, in healthy and sick infants and children, to determine normal values of SpO₂ and to identify highly predictive clinical signs of hypoxaemia. The potential aggravating role of co-existing prevalent childhood diseases other than ALRI, namely diarrhoea, malnutrition, malaria and HIV/AIDS, is also an area that warrants more attention. These data will allow providing both good quality and cost-effective health care to sick children with and without ALRI.

Millions of children and adults live at high altitude. Developing a medicine based on scientific evidence that can be applicable to this setting is a major public health challenge for all of us working in those parts of the world.

References

(1) Duke T, Frank D, Mgone J. Hypoxaemia in children with severe pneumonia in Papua New Guinea. Int J Tuberc Lung Dis 2000;5:511–19.

(2) British Thoracic Society of Standards of Care Committee. BTS Guidelines for the management of community acquired pneumonia in childhood. Thorax 2002;57:i1-i24.

(3) World Health Organization. Acute respiratory infections in children: case management in small hospitals in developing countries. Geneva: World Health Organization, 1994.

(4) Singhi S, Bharti B. Response to Duke et al [electronic response to Duke T et al, Hypoxaemia in acute respiratory and non-respiratory illnesses in neonates and children in a developing country]. archdischild.com 2002 http://adc.bmjjournals.com/cgi/eletters/archdischild;86/2/108#307

(5) Reuland DS, Steinhoff MC, Gilman RH, Olivares EG, Jabra A, Finkelstein D. Prevalence and prediction of hypoxemia in children with respiratory infections in the Peruvian Andes. J Pediatr 1991;119:900-6.

(6) Nicholas R, Yaron M, Reeves J. Oxygen saturation in children living at moderate altitude. J Am Board Fam Pract 1993;6:452-56.

(7) Lozano JM, Steinhoff M, Ruiz JG, Meza ML, Martinez N, Dussan B. Clinical predictors of acute radiological pneumonia and hypoxaemia at high altitude. Arch Dis Child 1994;71:323-27.

(8) Gamponia MJ, Babaali H, Yugar F, Gilman RH. Reference values for for pulse oximetry at high altitude. Arch Dis Child 1998;78:461-65.

(9) Huicho L, Pawson IG, León-Velarde F, Rivera-Ch M, Pacheco A, Muro M, Silva J. Oxygen saturation and heart rate in healthy school children and adolescents living at high altitude. Am J Hum Biol 2001;13:761-70.

Send letter to journal:
Re: Hypoxaemia in developing countries

Dear Editor

Drs Huicho, Singi and Bharti make the important points that definitions of hypoxaemia should be based on altitude-specific normal values and that further research at sea level and higher altitudes is needed. An altitude-specific definition of hypoxaemia (being an arbitrary value of SpO₂ more than 2 [1] or 3 standard deviations below the normal population mean) may be different from the threshold SpO₂ for giving oxygen. Other considerations for giving oxygen are at what level of SpO₂ (at different altitudes) oxygen is beneficial, local resource availability, and, in an individual child, confounding factors including the duration of exposure to altitude, age, or co-existent disease such as brain injury, severe anaemia, pulmonary hypertension and cardiac failure.

We studied Papua New Guinean neonates and children living at an altitude of 1600m to determine normal range of oxygen saturation.[2] Hypoxaemia in our study was a SpO₂ less than 2SD below the mean. In practice our threshold for giving oxygen to sick children (SpO₂<85%: more than 3SD below the mean) was lower than this because of limited oxygen availability. However there is evidence that this is safe and effective.[3] We stated that without further evaluation this should not be applied to hospitals at substantially lower altitudes than 1600m or in areas where oxygen availability is greater.

In comparing the prevalence of hypoxaemia between studies in different health facilities referral and selection biases are likely. Hypoxaemia will be more common in emergency departments of referral hospitals than at primary care settings, and more common still among children requiring hospital admission.[4] The prevalence of hypoxaemia in hospitalized children will depend on thresholds for admission and case- mix. The 491 children in our study constituted about 20% of all the children admitted during the course of the study. A specialist paediatrician, whose practice was to oversee the care of sicker children, enrolled many of the patients, so this was a further source of selection bias. The much lower overall prevalence of hypoxaemia seen by Drs Singhi and Bharti in their emergency department population is therefore understandable. Of note the prevalence of hypoxaemia among sick neonates admitted to Goroka Hospital (43%) was similar to the prevalence among young infants (<2 months of age) attending the emergency department in Chandigarh (38.5%).[5]

It is interesting to consider the effects of altitude on hypoxaemia in children with pneumonia. Some populations living at higher altitudes have a greater tendency to pulmonary hypertension; this susceptibility may be genetically determined [6] and supports Dr Huicho’s statement that ethnic differences in SpO₂ at the same altitude are important. At altitude in response to hypoxaemia, pulmonary blood flow is shunted to the lung apices associated with an exaggerated vasoconstriction in the basal lung.[7] This may have an adverse effect on ventilation perfusion matching in the supine position. In addition cardiac expression of natriuetic peptides increases in parallel with pulmonary artery pressure.[8] These and other pathophysiological changes may account for the greater severity and prolonged duration of hypoxaemia seen at higher altitudes.[3,9,10] It may be useful to evaluate the simple intervention of nursing children with pneumonia and hypoxaemia at high altitude in an inclined head-up position, rather than supine, to determine if this reduces the severity of hypoxaemia.

There is a need for more evidence about the prevalence of hypoxaemia at sea level and different altitudes; which children benefit from oxygen; for how long oxygen should be given and the best ways to deliver oxygen in remote settings. Controlled trials of oxygen in mild hypoxaemia may not be justified for ethical reasons, but other evidence will be informative. Before the introduction of pulse oximetry in Goroka we used the World Health Organization guidelines for giving oxygen (cyanosis, inability to feed or severe respiratory distress). With the introduction of pulse oximetry we set a threshold for giving oxygen at SpO₂ 85%. The severe pneumonia case-fatality rate fell from 10% (26 / 258) pre-pulse oximetry to 5.8% (65 / 1116) 2 years later.[3,10] In highland PNG children cyanosis was only detected in 44% of those with an SpO₂ 70-84%.[3] Although there will be confounders in the before-and-after analysis of outcome, we conclude that clinical signs must miss a significant proportion of children who would otherwise benefit from supplemental oxygen, and adherence to a protocol for the administration of oxygen based on a threshold SpO₂ of 85% (more than 3 SD below the mean for normal children in Goroka) resulted in improved outcomes, and was within available resources.

The costs of oxygen and logistics of transporting cylinders are major problems in many developing countries; Dr Huicho is right that these are important public health challenges. They call for innovative research and development into how best to supply oxygen to children who need it. The role of oxygen concentrators need to be further explored;[11] the combination of concentrators with pulse oximetry would be appropriate technology for many hospitals in developing countries. Increasing the availability of any drug that is crucial to the management of more than 20% of children hospitalized worldwide should be a very high priority; oxygen is one such drug.

Dr Trevor Duke
Centre for International Child Health
University Department of Paediatrics
Royal Children’s Hospital
Parkville, 3052
Victoria
Australia

References

(1) Reuland DS, Steinhoff MC, Gilman RH, Bara M, Olivares EG, Jabra A et al. Prevalence and prediction of hypoxemia in children with respiratory infections in the Peruvian Andes. J Pediatr 1991;119:900-6.

(2) Duke T, Blaschke AJ, Sialis S, Bonkowsky JL. Hypoxaemia in acute respiratory and non-respiratory illness in neonates and children in a developing country. Arch Dis Child 2002;86:108-12.

(3) Duke T, Frank D, Mgone J. Hypoxaemia in children with severe pneumonia in Papua New Guinea. Int J Tuberc Lung Dis 2000;5:511-9.

(4) Lozano JM. Epidemiology of hypoxaemia in children with acute lower respiratory infection. Int J Tuberc Lung Dis 2001;5:496-504.

(5) Rajesh VT, Singhi S, Kataria S. Tachypnoae is a good predictor of hypoxia in acutely il infants under 2 months.Arch Dis Child 2000;82:46-9.

(6) Aldashev AA, Sarybaev AS, Sydykov AS, Kalmyrzaev BB, Kim EV, Mamanova LB et al. Characterisation of high-altitude pulmonary hypertension in the Kyrgyz: association with angiotensin-converting enzyme genotype. Am J Resp Crit Care Med 2002;166:1396-402.

(7) Hanaoka M, Tanaka M, Ge RL, Droma Y, Ito A, Miyahara T et al. Hypoxia-induced pulmonary blood redistribution in subjects with a history of high-altitude pulmonary oedema. Circulation 2000;101:1418-22.

(8) Nakanishi K, Tajima F, Itoh H, Nakata Y, Osada H, Hama N et al. Changes in atrial natriuretic peptide and brain natriuretic peptide associated with hypobaric hypoxia-induced pulmonary hypertension in rats. Virchows Arch 2001;439:808-17.

(9) Shann F, MacGregor D, Richens J, Coakley J. Cardiac failure in children with pneumonia in Papua New Guinea. Pediatr Infect Dis J 1998;17:1141-3.

(10) Duke T, Poka H, Frank D, Michael A, Mgone J, Wal T. Chloramphenicol versus benzylpenicillin and gentamicin for the treatment of severe pneumonia in children in Papua New Guinea: a randomised trial. Lancet 2002;359:474-80.