Oxygen therapy in the newborn infant Statement
by the fetus and newborn
This statement
committee*
of the
Canadian Paediatric Society
replaces the original tient seems to depend on the degree of
In
a
few infants with
early neonatal
published in the Sept. 21, 1968 retinal immaturity, the Pao2 and the respiratory symptoms the concentration issue of the Journal (page 564). It is duration of exposure to an increased of oxygen needed may decrease from intended to take account of the ad¬ Pao2. Retinal vascular changes in im- 50% or more at 1 to 2 hours to 30% one,
in knowledge since then and the revised standards for oxygen ad¬
vances
ministration.
Increasing the concentration of inspired oxygen is one of the commonest and most important therapeutic meas¬ ures in the management of newborn infants with cardiorespiratory disor¬ ders. Too little oxygen is associated with increased neonatal mortality1 and an increased incidence of long-term neurologic morbidity.2 An excessive concentration of oxygen carries with it the risk of pulmonary oxygen toxicity8 in infants of any maturity and of retrolental fibroplasia (RLF), or retino¬ pathy of prematurity, in premature infants.4 Thus, oxygen therapy for new¬ born infants must be closely monitored and adjusted to meet the physiological needs of the patient. Complications Retrolental fibroplasia RLF
occurs
in premature infants
mature infants have been observed
or
aortic Po2 just over 100 mm Hg,7 and the time required to cause irreversible change is believed probably to be hours rather than minutes.
commonly the requirement for high concentrations of inspired oxygen is clinically underestimated in the first few hours of life, with the undesirable sequelae of acidosis, hypothermia, and eventually cyanosis of the body and apnea. In contrast to newborn infants with respiratory disorders, those with congenital heart disease and large ana¬ tomic shunts do not necessarily re¬ quire supplemental oxygen, and the use of high concentrations may be harm¬ ful. Because of the leftward position of the fetal oxyhemoglobin dissociation curve, cyanosis in newborn infants be¬ comes apparent at a lower Pao2 than in adults. For example, at pH 7.30 fetal hemoglobin is 75% saturated at a Pao2 of 36 mm Hg, whereas adult hemoglobin is 75% saturated at a Pao2 of 46 mm Hg. The clinical recognition of cyanosis is influenced not only by the percentage of unsaturated hemo¬ globin but also by the hematocrit, skin blood flow and lighting conditions. For these reasons clinical estimation of hy¬ poxemia is difficult and central cya¬ nosis in a baby usually means a Pao2 well below 40 mm Hg. Clinical recog¬ nition of hyperoxemia in a newborn infant is impossible. Since there is little change in skin colour with hemoglobin saturations over 80% (Pao2 40 mm Hg at pH 7.30), increases in Pao2 into the range known to cause retinal vasocon¬ striction can only be identified by di¬ rectly measuring the Pao2.
with
an
Pulmonary oxygen toxicity Prolonged breathing of an ambient
oxygen concentration above 60% is associated with a sequence of patho¬ logie changes in the lungs that lead eventually to widespread fibrosis.8 The effect is time- and dose-related, but in the absence of assisted ventilation the exudative lesions of pulmonary oxygen toxicity reach their peak after 2 to 3 days of breathing a high concentration of oxygen. The fibrotic lesions in sur¬ vivors may last for years. Positive pres¬ sure ventilation with high concentra¬ tions of inspired oxygen in newborn infants is associated with a higher in¬ cidence of severe pulmonary oxygen toxicity or so-called bronchopulmonary
dysplasia.9
as
sequela of obliterative vasoconstriction in immaturely vascularized areas of the retina. It can cause mild visual impairment or total blindness. The ini¬ tial vasoconstriction is believed in most instances to be due to unphysiologically high oxygen tension in the arterial blood (Pao2) of the retina, although there are rare reports of RLF in in¬ fants who did not receive supplemental oxygen.5'6 The pathologie changes fol¬ lowing the hyperoxemia-induced vaso¬ constriction are dilatation and tortuosity of the retinal vessels, neovascularization by thin-walled anastomosing vessels, retinal hemorrhage from the neovascular sites and sometimes mas¬ sive vitreous hemorrhage. The hemor¬ rhages gradually become fibrotic, lead¬ ing to distortion and detachment of a
Indications In spite of the risks of oxygen ther¬ apy for newborn infants, high concen¬ trations of inspired oxygen (50 to
100%)
often required to keep the physiologic level and thus prevent tissue hypoxia. This is because the hypoxemia observed in neonatal respiratory disorders is mainly due to the shunting of blood from the venous to the arterial side of the circulation,10 either early in the disease through an anatomic shunt (ductus arteriosus or foramen ovale) or later by perfusion of atelectatic areas of lung. Moreover, because of the lability of circulatory adjustments in sick newborn infants, there may be wide fluctuations in Po2 in the descending aorta, either in rela¬ tion to small changes in ambient oxy¬ the retina. The end stage of severe dis¬ gen concentration ("flip-flop pheno¬ ease is a retrolental mass of fibroblastic menon") or over short periods. The tissue. explanation of these fluctuations is The Pao2 below which the eyes are based, in part, on the fact that oxygen safe has not been defined; rather, the causes pulmonary arteries to dilate (de¬ occurrence of RLF in a particular pacreasing the pulmonary vascular resist¬ ance) and the ductus arteriosus to constrict vascular changes that are like¬ *Drs. P.R. Swyer (chairman), R.W. Boston, A. C. Pare, E.P. Rees, S. Segal and ly to alter the amount of blood shunted Murdock, J.C. Sinclair. Reprint requests to: Secretariat, Canadian Paedi¬ atric Society, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, PQ J1H SN4
750 CMA JOURNAL/OCTOBER 18,
Pao2 at
are a
from the venous to the arterial side of the circulation and as a result affect the Po2 below the ductus.
1975/VOL. 113
less at 8 to 12 hours. Much
more
Initial assessment Because both the incidence of
res¬
piratory distress syndrome and the risk of retinal damage increase with de¬ creasing maturity, the infants most likely to require oxygen at high con¬ centrations and for long periods are also those most susceptible to the risks of oxygen toxicity. Thus, the initial
assessment of any newborn infant who may benefit from added oxygen should include not only the diagnostic pos¬ sibilities but also the maturity of the infant, the probable need for concen¬ trations of inspired oxygen above 35 to 40%, and the personnel and equip¬ ment available to monitor ambient and arterial oxygen concentrations and make appropriate adjustments. The im-
mediate question in the hospital without an intensive care nursery is whether the baby should be transferred to such a unit; in the intensive care nursery the question is whether the Pao2 should be measured (usually by sampling from an indwelling arterial catheter). Not every infant with mild transient respiratory symptoms requires arterial sampling. A useful rule is that if during the first 3 hours of life the infant needs to breathe an oxygen concentration of 35% or more to overcome cyanosis or is anticipated to require this concentration at any later age, arterial sampling should be undertaken. The occurrence of asphyxia at birth would also favour early transfer of a premature infant to an intensive care nursery. Transfer is recommended for the following groups: all infants weighing less than 1500 g or born after less than 32 weeks' gestation, and all infants of any weight or maturity needing to breathe an oxygen concentration greater than 35 % for more than 3 hours. Although an inspired oxygen concentration of 35 % is not necessarily safe in a very premature infant, it is an acceptable concentration to give under observation to sick infants for the first 2 or 3 hours of life; early signs of respiratory abnormality may be clearly subsiding at the end of that time. Monitoring When added oxygen is given to any infant it is essential to measure frequently and accurately the inspired concentration to ensure that the prescribed concentration is being given and to assess the response of the patient to a particular concentration of inspired oxygen. Paramagnetic oxygen analysers are simple to operate but have an important source of error; if the bungs on the water absorber are not tightly fitted, room air can dilute the incubator gas sample sucked into the apparatus and give a falsely low reading. If one of the newer oxygen electrodes or fuel cell monitors is used, the calibration must be carefully checked regularly (one or two times per nursing shift or more frequently if humidity is found to cause drift in readings). Despite the increased accuracy of oxygen concentration provided by air-oxygen blenders, the need for oxygen measurement remains. The rate of flow of oxygen into an incubator is a totally unreliable guide to the incubator concentration, and oxygen regulating devices on some incubators do not obviate the requirement for direct measurement of the oxygen concentration of inspired gas. Oxygen given through a hood, mask or endo-
tracheal tube must be humidified and warmed. The ultimate aim of oxygen therapy is to ensure an adequate supply of oxygen to the body tissues. The attainment of this goal is influenced by the oxygen-carrying capacity of the blood, the state of the circulation, the ability of the hemoglobin to take up and to release oxygen, and the Paol. Thus, adjustment of the ambient oxygen concentration to achieve a physiologic Pao2 is just one, but nevertheless an important, component of oxygen therapy. Ideal sampling sites for measuring the Pao2 are right radial or temoral arteries (i.e., above the ductus arteriosus) but sampling from an indwelling umbilical artery catheter is easier and is satisfactory in most instances, so the umbilical artery is generally the site of choice. Current opinion is that in treating neonatal respiratory disorders the ambient oxygen concentration should be adjusted to maintain the Po2 in the descending aorta between 40 and 80 mm Hg, with the lower value favoured if inspired concentrations of oxygen above 60% are required. Because of the difficulties and risks associated with the insertion and maintenance of an arterial catheter11 the value of capillary blood sampling to guide oxygen therapy has been assessed repeatedly.1215 Results of these studies show clearly that during the first hours of life, and at any age when the peripheral circulation is impaired because of shock, the P02 of capillary blood does not accurately reflect the Po2 of arterial blood and should not be used. However, under clinically stable conditions, properly collected capillary blood can be useful in recognizing hypoxemia. Blood collected by heel stab may be "arterialized" by warming the heel to 420C for 5 minutes or by using a vasodilating cream. A free-flowing sample is then collected anaerobically and iced until measurements are made. Under these circumstances the correlation between the arterial and the capillary P02 is reasonably good when the aortic Po2 is less than 60 mm Hg (aortic Po2 approximately 5 mm higher than capillary P02); but when the capillary Po2 is above 50 to 55 mm Hg, the aortic Po2 can be above 100 mm Hg, with risk of retinal injury in susceptible infants. Thus, while capillary blood measurements are of value in guiding oxygen therapy, their severe Jimitations in shock and in the recognition of dangerous hyperoxemia must be clearly recognized. If an infant of any maturity has cyanosis of the body there should be no hesitation about giving enough oxygen to overcome the cyanosis if that is possible. However, in cyanotic prema-
ture infants there is greater urgency in obtaining arterial oxygen measurements to guide oxygen therapy, and appropriate management usually requires the early placement of an arterial catheter. If such an infant is not in a neonatal intensive care unit immediate transfer should be arranged. If facilities for blood gas monitoring are not available and if transfer to an intensive care unit is impracticable, then the concentration of inspired oxygen should be increased enough to overcome body cyanosis but must be decreased at regular intervals (every 2 to 3 hours) until duskiness is again apparent, then increased 5 to 10% for the next 2 to 3 hours. This is at best a crude means of monitoring oxygen need when no laboratory facilities are available.
Apnea Apneic spells in premature infants unresponsive to simple cutaneous stimulation should be treated promptly with artificial ventilation, usually with a self-inflating bag and mask. If 100% oxygen rather than ambient incubator oxygen is used to resuscitate a very premature infant the risk of RLF is much increased. The periodic breathing observed in premature infants is not in itself an indication for increasing the concentration of inspired oxygen. Eye examination All premature infants born after less than 36 weeks' gestation or weighing less than 2000 g who have been nursed in an oxygen-enriched environment during the neonatal period should have an eye examination by an ophthalmologist experienced in recognizing RLF before discharge from the nursery and again at 3 months if that age has not already been reached. The onset of proliferative lesions in the retina has been noted as late as 3 months after birth (A. Patz, S. Segal: personal communication). If the fundi are not well visualized or if any abnormality is detected, appropriate follow-up examination should be arranged. References 1.AVERY ME, OPPENHEIMER EH: Recent increase in mortality from hyaline membrane disease. J Pedjair 57: 553, 1960 2. MCDONALD AD: Cerebral palsy in children of very low birth weight. Arch Dis Child 38: 579, 1963 3. ANDERSON WR, STRICKLAND MB: Pulmonary complications of oxygen therapy in the neonate. Arch Pathol 91: 506, 1971 4. PATZ A: The role of oxygen in retrolental fibroplasia. Pediatrics 19: 504, 1957 5. BRUCKNER HL: "Retrolental fibroplasia": associated with intrauterine anoxia. Arch Ophthalmol 80: 504, 1968 6. TIZARD JPM: Modern management of oxygen therapy in the newborn. Proc R Soc Med 64: 17, 1971 7. ARANDA JV, SAHEB N, STERN L, et al: Arterial oxygen tension and retinal vasoconstriction in newborn infants. Am J Dis Child 122: 189, 1971
continued on page 763
CMA JOURNAL/OCTOBER 18, 1975/VOL. 113 751
ther studies on the patient reported by Goodman and colleagues, calculated from the rate of excretion of total hydroxyproline (Hyp) that 2 to 2.5 g of collagen was degraded per day. With this calculation the patient reported by Powell and colleagues6 degraded 6.0 g/d and our patient degraded 0.86 g/d. While it is clear that Hyp must arise from collagen (or elastin in lesser degree) the assumption that all the Hyp must pass through a dipeptide of the form X-Hyp is not necessarily valid. Some could pass through a Hyp-X dipeptide form, which is split by prolinase (which was present in normal amounts in one patient.6) Hence, it is likely that calculations based on the excretion of total Hyp would err on the low side. Almost all of the proline (Pro) is introduced into the protocollagen in one or other of the triplets Gly (glycine)-Pro-X, Gly-X-Pro or Gly-ProPro. The hydroxylation of Pro to Hyp occurs specifically on the third residue in Gly-X-Pro or Gly-Pro-Pro, converting these triplets to Gly-X-Hyp or Gly-Pro-Hyp. Hence, in the fully hydroxylated collagen the Pro occurs almost exclusively as Gly-Pro. In a scan of Gly-Pro residues in a. chains of collagen this doublet occurred 25 times in a total of 235 amino acids. On the other hand, Pro in other proteins shows no tendency to be coupled to Gly in this manner; with the possible exception of the heavy chain of immunoglobulins, in which one quarter of the Pro occurs as Gly-Pro, and in human Clq (a subcomponent of the first component of complement), which has a repeating sequence of Gly-X-Y, in which X is often Pro and Y is often Hyp.12"3 Hence, most of the Gly-Pro dipeptide excreted by these patientis must arise from collagen degradation and the amount of this collagen can be calculated as 235 amino acid residues per 25 Gly-Pro moles. Buist and colleagues1' reported that prolidase liberated 4960 .mol of glycine per 24 hours from the urine of their patient, presumably from 4960 .imol of Gly-Pro. This was equivalent to 46700 p.mol of collagen amino acid residues. The mean molecular weight of a collagen amino acid residue is 100 (109 minus ½ H10). Hence, 4.67 g of collagen was degraded (or twice the amount indicated by Hyp excretion). Accurate figures for Gly-Pro excretion are not available for the patient of Powell and colleagues.6 In our patient 1280 ,.Lmol of Gly-Pro was excreted per day, which is equal to 1.2 g collagen. This estimation was based on quantitation of the Gly-Pro peak in the amino acid chromatogram of the urine ultrafiltrate. It compares with the fig-
ure of 0.89 g of collagen calculated from the total Hyp excretion. All the patients reported were afflicted to some degree with respiratory infections. In view of the collagen-like ammo acid sequences in Clq, one may speculate that there may be an immunologic deficit related to this factor. In conclusion, the collagen-related defects in hereditary prolidase deficiency can be explained by the inhibitory effects on normal recycling of collagen. The extent of this collagen deficit is best estimated by the rate of excretion of the Gly-Pro dipeptide. References 1. JACKSON SH, HEININGER JA: A reassessment of the collagen reutilization theory by an isotope ratio method. Clin Chim Acta 46: 153, 1973 2. Idem: A study of collagen reutilization using an iSOg labeling technique. Clin Chim Acta 51: 163, 1974 3. Idem: Proline recycling during collagen metabolism as determined by concurrent 180. and .H. Blochim Biophys Acta 381: 359, 1975 4. TaN CATE AR: Morphological studies of fibrocytes in connective tissue undergoing rapid remodelling..! Anat 112: 401, 1972 5. GOODMAN SI, SoLoMoNs CC, MuscssaNiimN F, et al: A syndrome resembling lathyrism associated with iminodipeptiduria. Am I Med 45: 152, 1968 6. POWELL GF, RAsco MA, MANIscALcO RM: Prolidase deficiency in man with iminodipeptiduria. Metabolism 23: 505, 1974 7. JOHNsTONB RAW, POVALL TJ, BATY JD, et al: Determination of dipeptides in urine. Clmn Chim Acta 52: 137, 1974 8. JACKSON SH, SAIDHARWALLA IB, Esais GC: Two systems of amino acid chromatography suitable for mass screening. Clin Biochem 2: 163, 1968 9. Sins YE, EFRON ML, MECHANIC GL: Rapid short-column chromatography of amino acids. A method for blood and urine specimens in diagnosis and treatment of metabolic disease. Anal Biochem 20: 299, 1967 10. Sasrris AE: Methods of Enzymology, vol IT, New York, Acad Pr, 1955, p 100-105 11. BUIST NRM, STRANDHOLM JJ, .ELLINGER JR, et ci: Further studies on a patient with iminodipeptiduria. A probable case of prolidase deficiency. Metabolism 21: 1113, 1972 12 REm KEM: A collagen-like amino acid sequence in a polypeptide chain of human Clq (a subcomponent of the first component of complement). Biochem 1 141: 189, 1974 13. LowE DM, REID KBM: Studies on the structure and activity of rabbit Clq (a subcomponent of the first component of complement).. Biochem .! 143: 265, 1974
OXYGEN THERAPY continued from page 751 8. BANEIJEE CK, GIaLINO DJ, WIooLaswoaTH JS: Pulmonary fibroplasia in newborn babies treated with oxygen and artificial ventilation. Arch Dis Child 47: 509, 1972 9. NORTEWAY WH, ROsAN RC, PORTER DY: Pulmonary disease following respirator therapy of hyaline-membrane disease. N Engl I Med 276: 357, 1967 10. NELSON NM, PROD'HOM LS, CHERRY RB, et ci: Pulmonary function in the newborn infant. II. Perfusion.estimation by analysis of the arterial-alveolar carbon dioxide difference. Pediatrics 30: 975, 1962 11. Krrrnnwe JA, Pinsas RH, TOOLEY WH: Catheterization of umbilical vessels in newborn infants. Pedlatr Clin North Am 17: 895, 1970 12. GANDY G, GRANN L, CUNNINGHAM N, et al: The validity of pH and Pco2 measurements in capillary samples in sick and healthy newborn infants PedIatrics 34: 192, 1964 13. KOcH G, WENDEL H: Comparison of pH, carbon dioxide tension, standard bicarbonate and oxygen tension in capillary blood and in arterial blood during the neonatal period. Acta Paediatr Scand 56: 10, 1967 14. GLASGOW JET, FLYNN DM, Swma PR: A comparison of descending aortic and "arterialized" capillary blood in the sick newborn. Can Med Assoc 1 106: 660, 1972 15. HUNT CE: Capillary blood sampling in the infant: usefulness and limitations of two methods of sampling, compared with arterial blood. PedIatrics 51: 501, 1973
'Slow-K
tablets are the only satisfactory method of giving potassium by mouth"2 Brief Prescribing information
indications - All circumstances in which potassium supplementation is necessary, and particularly during prolonged or intensive diuretic therapy. Patients at special risk are those with advanced hepatic cirrhosis or renal disease, patients with considerable edema (particularly if urinary output is large), patients on a salt-restricted diet and patients receiving digitalis (a lack of potassium sensitizes the myocardium to the toxic effects of digitalis). The range of indications for SLOW-K may be summarized as follows: As a supplement to diuretics Hypochioremic alkalosis Cushing's Syndrome Steroid therapy Liver cirrhosis Diseases characterized by persistent vomiting or diarrhea
Digitalis therapy Steatorrhea Chronic diarrhea Regional ileitis Ileostomy Neoplasms or obstructions referable to the gastrointestinal tract Ulcerative colitis
Dosage - The dosage is determined according to the needs of the individual patient. When administered as a potassium supplement during diuretic therapy, a dose ratio of one SLOW-K tablet with each diuretic tablet will usually suffice, but may be increased as necessary. In general, a dosage range between 2-6 SLOW-K tablets (approximately 16-48 mEq K +) daily, or on alternate days, will provide adequate supplementary potassium in most cases. Preferably, administer after meals. Warning - A probable association exists between the use of coated tablets containing potassium salts, with or without thiazide diuretics, and the incidence of serious small bowel ulceration. Such preparations should be used only when adequate dietary supplementation is not practical, and should be discontinued if abdominal pain, distention, nausea, vomiting or gastro-intestinal bleeding occurs. Side Effect - To date, only three cases of small bowel ulceration, one of which is of doubtful origin, have been reported. Cautions - Administer cautiously to patients in advanced renal failure to avoid possible hyperkalemia. Slow-K should be used with caution in diseases associated with heart block since increased serum potassium may increase the degree of block. Contraindications - Renal impairment with oliguria or azotemia, untreated Addison's Disease, myotonia congenita, hyperadrenalism associated with adrenogen ital syndrome, acute dehydration, heat cramps and hyperkalemia of any etiology; conditions associated with stat is of the GI tract. Supplied - Tablets (pale orange, sugar coated), each containing 600 mg. of potassium chloride in a slow-release, inert wax core; bottles of 100, 1,000 and 5,000.
References 1. Leading Article, Brit. Med. J., 1,1 91, 1967 (April 22). 2. ODriscoll, B.J.: Potassium Chloride with Diuretics, Br. Med. J., Vol. 11, pg. 348,1966.
CIBA
DoRvAL, QUEBEC H9S1B1
c-4073
CMA JOURNAL/OCTOBER 18, 1975/VOL. 113 763
by the fetus and newborn
This statement
committee*
of the
Canadian Paediatric Society
replaces the original tient seems to depend on the degree of
In
a
few infants with
early neonatal
published in the Sept. 21, 1968 retinal immaturity, the Pao2 and the respiratory symptoms the concentration issue of the Journal (page 564). It is duration of exposure to an increased of oxygen needed may decrease from intended to take account of the ad¬ Pao2. Retinal vascular changes in im- 50% or more at 1 to 2 hours to 30% one,
in knowledge since then and the revised standards for oxygen ad¬
vances
ministration.
Increasing the concentration of inspired oxygen is one of the commonest and most important therapeutic meas¬ ures in the management of newborn infants with cardiorespiratory disor¬ ders. Too little oxygen is associated with increased neonatal mortality1 and an increased incidence of long-term neurologic morbidity.2 An excessive concentration of oxygen carries with it the risk of pulmonary oxygen toxicity8 in infants of any maturity and of retrolental fibroplasia (RLF), or retino¬ pathy of prematurity, in premature infants.4 Thus, oxygen therapy for new¬ born infants must be closely monitored and adjusted to meet the physiological needs of the patient. Complications Retrolental fibroplasia RLF
occurs
in premature infants
mature infants have been observed
or
aortic Po2 just over 100 mm Hg,7 and the time required to cause irreversible change is believed probably to be hours rather than minutes.
commonly the requirement for high concentrations of inspired oxygen is clinically underestimated in the first few hours of life, with the undesirable sequelae of acidosis, hypothermia, and eventually cyanosis of the body and apnea. In contrast to newborn infants with respiratory disorders, those with congenital heart disease and large ana¬ tomic shunts do not necessarily re¬ quire supplemental oxygen, and the use of high concentrations may be harm¬ ful. Because of the leftward position of the fetal oxyhemoglobin dissociation curve, cyanosis in newborn infants be¬ comes apparent at a lower Pao2 than in adults. For example, at pH 7.30 fetal hemoglobin is 75% saturated at a Pao2 of 36 mm Hg, whereas adult hemoglobin is 75% saturated at a Pao2 of 46 mm Hg. The clinical recognition of cyanosis is influenced not only by the percentage of unsaturated hemo¬ globin but also by the hematocrit, skin blood flow and lighting conditions. For these reasons clinical estimation of hy¬ poxemia is difficult and central cya¬ nosis in a baby usually means a Pao2 well below 40 mm Hg. Clinical recog¬ nition of hyperoxemia in a newborn infant is impossible. Since there is little change in skin colour with hemoglobin saturations over 80% (Pao2 40 mm Hg at pH 7.30), increases in Pao2 into the range known to cause retinal vasocon¬ striction can only be identified by di¬ rectly measuring the Pao2.
with
an
Pulmonary oxygen toxicity Prolonged breathing of an ambient
oxygen concentration above 60% is associated with a sequence of patho¬ logie changes in the lungs that lead eventually to widespread fibrosis.8 The effect is time- and dose-related, but in the absence of assisted ventilation the exudative lesions of pulmonary oxygen toxicity reach their peak after 2 to 3 days of breathing a high concentration of oxygen. The fibrotic lesions in sur¬ vivors may last for years. Positive pres¬ sure ventilation with high concentra¬ tions of inspired oxygen in newborn infants is associated with a higher in¬ cidence of severe pulmonary oxygen toxicity or so-called bronchopulmonary
dysplasia.9
as
sequela of obliterative vasoconstriction in immaturely vascularized areas of the retina. It can cause mild visual impairment or total blindness. The ini¬ tial vasoconstriction is believed in most instances to be due to unphysiologically high oxygen tension in the arterial blood (Pao2) of the retina, although there are rare reports of RLF in in¬ fants who did not receive supplemental oxygen.5'6 The pathologie changes fol¬ lowing the hyperoxemia-induced vaso¬ constriction are dilatation and tortuosity of the retinal vessels, neovascularization by thin-walled anastomosing vessels, retinal hemorrhage from the neovascular sites and sometimes mas¬ sive vitreous hemorrhage. The hemor¬ rhages gradually become fibrotic, lead¬ ing to distortion and detachment of a
Indications In spite of the risks of oxygen ther¬ apy for newborn infants, high concen¬ trations of inspired oxygen (50 to
100%)
often required to keep the physiologic level and thus prevent tissue hypoxia. This is because the hypoxemia observed in neonatal respiratory disorders is mainly due to the shunting of blood from the venous to the arterial side of the circulation,10 either early in the disease through an anatomic shunt (ductus arteriosus or foramen ovale) or later by perfusion of atelectatic areas of lung. Moreover, because of the lability of circulatory adjustments in sick newborn infants, there may be wide fluctuations in Po2 in the descending aorta, either in rela¬ tion to small changes in ambient oxy¬ the retina. The end stage of severe dis¬ gen concentration ("flip-flop pheno¬ ease is a retrolental mass of fibroblastic menon") or over short periods. The tissue. explanation of these fluctuations is The Pao2 below which the eyes are based, in part, on the fact that oxygen safe has not been defined; rather, the causes pulmonary arteries to dilate (de¬ occurrence of RLF in a particular pacreasing the pulmonary vascular resist¬ ance) and the ductus arteriosus to constrict vascular changes that are like¬ *Drs. P.R. Swyer (chairman), R.W. Boston, A. C. Pare, E.P. Rees, S. Segal and ly to alter the amount of blood shunted Murdock, J.C. Sinclair. Reprint requests to: Secretariat, Canadian Paedi¬ atric Society, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, PQ J1H SN4
750 CMA JOURNAL/OCTOBER 18,
Pao2 at
are a
from the venous to the arterial side of the circulation and as a result affect the Po2 below the ductus.
1975/VOL. 113
less at 8 to 12 hours. Much
more
Initial assessment Because both the incidence of
res¬
piratory distress syndrome and the risk of retinal damage increase with de¬ creasing maturity, the infants most likely to require oxygen at high con¬ centrations and for long periods are also those most susceptible to the risks of oxygen toxicity. Thus, the initial
assessment of any newborn infant who may benefit from added oxygen should include not only the diagnostic pos¬ sibilities but also the maturity of the infant, the probable need for concen¬ trations of inspired oxygen above 35 to 40%, and the personnel and equip¬ ment available to monitor ambient and arterial oxygen concentrations and make appropriate adjustments. The im-
mediate question in the hospital without an intensive care nursery is whether the baby should be transferred to such a unit; in the intensive care nursery the question is whether the Pao2 should be measured (usually by sampling from an indwelling arterial catheter). Not every infant with mild transient respiratory symptoms requires arterial sampling. A useful rule is that if during the first 3 hours of life the infant needs to breathe an oxygen concentration of 35% or more to overcome cyanosis or is anticipated to require this concentration at any later age, arterial sampling should be undertaken. The occurrence of asphyxia at birth would also favour early transfer of a premature infant to an intensive care nursery. Transfer is recommended for the following groups: all infants weighing less than 1500 g or born after less than 32 weeks' gestation, and all infants of any weight or maturity needing to breathe an oxygen concentration greater than 35 % for more than 3 hours. Although an inspired oxygen concentration of 35 % is not necessarily safe in a very premature infant, it is an acceptable concentration to give under observation to sick infants for the first 2 or 3 hours of life; early signs of respiratory abnormality may be clearly subsiding at the end of that time. Monitoring When added oxygen is given to any infant it is essential to measure frequently and accurately the inspired concentration to ensure that the prescribed concentration is being given and to assess the response of the patient to a particular concentration of inspired oxygen. Paramagnetic oxygen analysers are simple to operate but have an important source of error; if the bungs on the water absorber are not tightly fitted, room air can dilute the incubator gas sample sucked into the apparatus and give a falsely low reading. If one of the newer oxygen electrodes or fuel cell monitors is used, the calibration must be carefully checked regularly (one or two times per nursing shift or more frequently if humidity is found to cause drift in readings). Despite the increased accuracy of oxygen concentration provided by air-oxygen blenders, the need for oxygen measurement remains. The rate of flow of oxygen into an incubator is a totally unreliable guide to the incubator concentration, and oxygen regulating devices on some incubators do not obviate the requirement for direct measurement of the oxygen concentration of inspired gas. Oxygen given through a hood, mask or endo-
tracheal tube must be humidified and warmed. The ultimate aim of oxygen therapy is to ensure an adequate supply of oxygen to the body tissues. The attainment of this goal is influenced by the oxygen-carrying capacity of the blood, the state of the circulation, the ability of the hemoglobin to take up and to release oxygen, and the Paol. Thus, adjustment of the ambient oxygen concentration to achieve a physiologic Pao2 is just one, but nevertheless an important, component of oxygen therapy. Ideal sampling sites for measuring the Pao2 are right radial or temoral arteries (i.e., above the ductus arteriosus) but sampling from an indwelling umbilical artery catheter is easier and is satisfactory in most instances, so the umbilical artery is generally the site of choice. Current opinion is that in treating neonatal respiratory disorders the ambient oxygen concentration should be adjusted to maintain the Po2 in the descending aorta between 40 and 80 mm Hg, with the lower value favoured if inspired concentrations of oxygen above 60% are required. Because of the difficulties and risks associated with the insertion and maintenance of an arterial catheter11 the value of capillary blood sampling to guide oxygen therapy has been assessed repeatedly.1215 Results of these studies show clearly that during the first hours of life, and at any age when the peripheral circulation is impaired because of shock, the P02 of capillary blood does not accurately reflect the Po2 of arterial blood and should not be used. However, under clinically stable conditions, properly collected capillary blood can be useful in recognizing hypoxemia. Blood collected by heel stab may be "arterialized" by warming the heel to 420C for 5 minutes or by using a vasodilating cream. A free-flowing sample is then collected anaerobically and iced until measurements are made. Under these circumstances the correlation between the arterial and the capillary P02 is reasonably good when the aortic Po2 is less than 60 mm Hg (aortic Po2 approximately 5 mm higher than capillary P02); but when the capillary Po2 is above 50 to 55 mm Hg, the aortic Po2 can be above 100 mm Hg, with risk of retinal injury in susceptible infants. Thus, while capillary blood measurements are of value in guiding oxygen therapy, their severe Jimitations in shock and in the recognition of dangerous hyperoxemia must be clearly recognized. If an infant of any maturity has cyanosis of the body there should be no hesitation about giving enough oxygen to overcome the cyanosis if that is possible. However, in cyanotic prema-
ture infants there is greater urgency in obtaining arterial oxygen measurements to guide oxygen therapy, and appropriate management usually requires the early placement of an arterial catheter. If such an infant is not in a neonatal intensive care unit immediate transfer should be arranged. If facilities for blood gas monitoring are not available and if transfer to an intensive care unit is impracticable, then the concentration of inspired oxygen should be increased enough to overcome body cyanosis but must be decreased at regular intervals (every 2 to 3 hours) until duskiness is again apparent, then increased 5 to 10% for the next 2 to 3 hours. This is at best a crude means of monitoring oxygen need when no laboratory facilities are available.
Apnea Apneic spells in premature infants unresponsive to simple cutaneous stimulation should be treated promptly with artificial ventilation, usually with a self-inflating bag and mask. If 100% oxygen rather than ambient incubator oxygen is used to resuscitate a very premature infant the risk of RLF is much increased. The periodic breathing observed in premature infants is not in itself an indication for increasing the concentration of inspired oxygen. Eye examination All premature infants born after less than 36 weeks' gestation or weighing less than 2000 g who have been nursed in an oxygen-enriched environment during the neonatal period should have an eye examination by an ophthalmologist experienced in recognizing RLF before discharge from the nursery and again at 3 months if that age has not already been reached. The onset of proliferative lesions in the retina has been noted as late as 3 months after birth (A. Patz, S. Segal: personal communication). If the fundi are not well visualized or if any abnormality is detected, appropriate follow-up examination should be arranged. References 1.AVERY ME, OPPENHEIMER EH: Recent increase in mortality from hyaline membrane disease. J Pedjair 57: 553, 1960 2. MCDONALD AD: Cerebral palsy in children of very low birth weight. Arch Dis Child 38: 579, 1963 3. ANDERSON WR, STRICKLAND MB: Pulmonary complications of oxygen therapy in the neonate. Arch Pathol 91: 506, 1971 4. PATZ A: The role of oxygen in retrolental fibroplasia. Pediatrics 19: 504, 1957 5. BRUCKNER HL: "Retrolental fibroplasia": associated with intrauterine anoxia. Arch Ophthalmol 80: 504, 1968 6. TIZARD JPM: Modern management of oxygen therapy in the newborn. Proc R Soc Med 64: 17, 1971 7. ARANDA JV, SAHEB N, STERN L, et al: Arterial oxygen tension and retinal vasoconstriction in newborn infants. Am J Dis Child 122: 189, 1971
continued on page 763
CMA JOURNAL/OCTOBER 18, 1975/VOL. 113 751
ther studies on the patient reported by Goodman and colleagues, calculated from the rate of excretion of total hydroxyproline (Hyp) that 2 to 2.5 g of collagen was degraded per day. With this calculation the patient reported by Powell and colleagues6 degraded 6.0 g/d and our patient degraded 0.86 g/d. While it is clear that Hyp must arise from collagen (or elastin in lesser degree) the assumption that all the Hyp must pass through a dipeptide of the form X-Hyp is not necessarily valid. Some could pass through a Hyp-X dipeptide form, which is split by prolinase (which was present in normal amounts in one patient.6) Hence, it is likely that calculations based on the excretion of total Hyp would err on the low side. Almost all of the proline (Pro) is introduced into the protocollagen in one or other of the triplets Gly (glycine)-Pro-X, Gly-X-Pro or Gly-ProPro. The hydroxylation of Pro to Hyp occurs specifically on the third residue in Gly-X-Pro or Gly-Pro-Pro, converting these triplets to Gly-X-Hyp or Gly-Pro-Hyp. Hence, in the fully hydroxylated collagen the Pro occurs almost exclusively as Gly-Pro. In a scan of Gly-Pro residues in a. chains of collagen this doublet occurred 25 times in a total of 235 amino acids. On the other hand, Pro in other proteins shows no tendency to be coupled to Gly in this manner; with the possible exception of the heavy chain of immunoglobulins, in which one quarter of the Pro occurs as Gly-Pro, and in human Clq (a subcomponent of the first component of complement), which has a repeating sequence of Gly-X-Y, in which X is often Pro and Y is often Hyp.12"3 Hence, most of the Gly-Pro dipeptide excreted by these patientis must arise from collagen degradation and the amount of this collagen can be calculated as 235 amino acid residues per 25 Gly-Pro moles. Buist and colleagues1' reported that prolidase liberated 4960 .mol of glycine per 24 hours from the urine of their patient, presumably from 4960 .imol of Gly-Pro. This was equivalent to 46700 p.mol of collagen amino acid residues. The mean molecular weight of a collagen amino acid residue is 100 (109 minus ½ H10). Hence, 4.67 g of collagen was degraded (or twice the amount indicated by Hyp excretion). Accurate figures for Gly-Pro excretion are not available for the patient of Powell and colleagues.6 In our patient 1280 ,.Lmol of Gly-Pro was excreted per day, which is equal to 1.2 g collagen. This estimation was based on quantitation of the Gly-Pro peak in the amino acid chromatogram of the urine ultrafiltrate. It compares with the fig-
ure of 0.89 g of collagen calculated from the total Hyp excretion. All the patients reported were afflicted to some degree with respiratory infections. In view of the collagen-like ammo acid sequences in Clq, one may speculate that there may be an immunologic deficit related to this factor. In conclusion, the collagen-related defects in hereditary prolidase deficiency can be explained by the inhibitory effects on normal recycling of collagen. The extent of this collagen deficit is best estimated by the rate of excretion of the Gly-Pro dipeptide. References 1. JACKSON SH, HEININGER JA: A reassessment of the collagen reutilization theory by an isotope ratio method. Clin Chim Acta 46: 153, 1973 2. Idem: A study of collagen reutilization using an iSOg labeling technique. Clin Chim Acta 51: 163, 1974 3. Idem: Proline recycling during collagen metabolism as determined by concurrent 180. and .H. Blochim Biophys Acta 381: 359, 1975 4. TaN CATE AR: Morphological studies of fibrocytes in connective tissue undergoing rapid remodelling..! Anat 112: 401, 1972 5. GOODMAN SI, SoLoMoNs CC, MuscssaNiimN F, et al: A syndrome resembling lathyrism associated with iminodipeptiduria. Am I Med 45: 152, 1968 6. POWELL GF, RAsco MA, MANIscALcO RM: Prolidase deficiency in man with iminodipeptiduria. Metabolism 23: 505, 1974 7. JOHNsTONB RAW, POVALL TJ, BATY JD, et al: Determination of dipeptides in urine. Clmn Chim Acta 52: 137, 1974 8. JACKSON SH, SAIDHARWALLA IB, Esais GC: Two systems of amino acid chromatography suitable for mass screening. Clin Biochem 2: 163, 1968 9. Sins YE, EFRON ML, MECHANIC GL: Rapid short-column chromatography of amino acids. A method for blood and urine specimens in diagnosis and treatment of metabolic disease. Anal Biochem 20: 299, 1967 10. Sasrris AE: Methods of Enzymology, vol IT, New York, Acad Pr, 1955, p 100-105 11. BUIST NRM, STRANDHOLM JJ, .ELLINGER JR, et ci: Further studies on a patient with iminodipeptiduria. A probable case of prolidase deficiency. Metabolism 21: 1113, 1972 12 REm KEM: A collagen-like amino acid sequence in a polypeptide chain of human Clq (a subcomponent of the first component of complement). Biochem 1 141: 189, 1974 13. LowE DM, REID KBM: Studies on the structure and activity of rabbit Clq (a subcomponent of the first component of complement).. Biochem .! 143: 265, 1974
OXYGEN THERAPY continued from page 751 8. BANEIJEE CK, GIaLINO DJ, WIooLaswoaTH JS: Pulmonary fibroplasia in newborn babies treated with oxygen and artificial ventilation. Arch Dis Child 47: 509, 1972 9. NORTEWAY WH, ROsAN RC, PORTER DY: Pulmonary disease following respirator therapy of hyaline-membrane disease. N Engl I Med 276: 357, 1967 10. NELSON NM, PROD'HOM LS, CHERRY RB, et ci: Pulmonary function in the newborn infant. II. Perfusion.estimation by analysis of the arterial-alveolar carbon dioxide difference. Pediatrics 30: 975, 1962 11. Krrrnnwe JA, Pinsas RH, TOOLEY WH: Catheterization of umbilical vessels in newborn infants. Pedlatr Clin North Am 17: 895, 1970 12. GANDY G, GRANN L, CUNNINGHAM N, et al: The validity of pH and Pco2 measurements in capillary samples in sick and healthy newborn infants PedIatrics 34: 192, 1964 13. KOcH G, WENDEL H: Comparison of pH, carbon dioxide tension, standard bicarbonate and oxygen tension in capillary blood and in arterial blood during the neonatal period. Acta Paediatr Scand 56: 10, 1967 14. GLASGOW JET, FLYNN DM, Swma PR: A comparison of descending aortic and "arterialized" capillary blood in the sick newborn. Can Med Assoc 1 106: 660, 1972 15. HUNT CE: Capillary blood sampling in the infant: usefulness and limitations of two methods of sampling, compared with arterial blood. PedIatrics 51: 501, 1973
'Slow-K
tablets are the only satisfactory method of giving potassium by mouth"2 Brief Prescribing information
indications - All circumstances in which potassium supplementation is necessary, and particularly during prolonged or intensive diuretic therapy. Patients at special risk are those with advanced hepatic cirrhosis or renal disease, patients with considerable edema (particularly if urinary output is large), patients on a salt-restricted diet and patients receiving digitalis (a lack of potassium sensitizes the myocardium to the toxic effects of digitalis). The range of indications for SLOW-K may be summarized as follows: As a supplement to diuretics Hypochioremic alkalosis Cushing's Syndrome Steroid therapy Liver cirrhosis Diseases characterized by persistent vomiting or diarrhea
Digitalis therapy Steatorrhea Chronic diarrhea Regional ileitis Ileostomy Neoplasms or obstructions referable to the gastrointestinal tract Ulcerative colitis
Dosage - The dosage is determined according to the needs of the individual patient. When administered as a potassium supplement during diuretic therapy, a dose ratio of one SLOW-K tablet with each diuretic tablet will usually suffice, but may be increased as necessary. In general, a dosage range between 2-6 SLOW-K tablets (approximately 16-48 mEq K +) daily, or on alternate days, will provide adequate supplementary potassium in most cases. Preferably, administer after meals. Warning - A probable association exists between the use of coated tablets containing potassium salts, with or without thiazide diuretics, and the incidence of serious small bowel ulceration. Such preparations should be used only when adequate dietary supplementation is not practical, and should be discontinued if abdominal pain, distention, nausea, vomiting or gastro-intestinal bleeding occurs. Side Effect - To date, only three cases of small bowel ulceration, one of which is of doubtful origin, have been reported. Cautions - Administer cautiously to patients in advanced renal failure to avoid possible hyperkalemia. Slow-K should be used with caution in diseases associated with heart block since increased serum potassium may increase the degree of block. Contraindications - Renal impairment with oliguria or azotemia, untreated Addison's Disease, myotonia congenita, hyperadrenalism associated with adrenogen ital syndrome, acute dehydration, heat cramps and hyperkalemia of any etiology; conditions associated with stat is of the GI tract. Supplied - Tablets (pale orange, sugar coated), each containing 600 mg. of potassium chloride in a slow-release, inert wax core; bottles of 100, 1,000 and 5,000.
References 1. Leading Article, Brit. Med. J., 1,1 91, 1967 (April 22). 2. ODriscoll, B.J.: Potassium Chloride with Diuretics, Br. Med. J., Vol. 11, pg. 348,1966.
CIBA
DoRvAL, QUEBEC H9S1B1
c-4073
CMA JOURNAL/OCTOBER 18, 1975/VOL. 113 763
