Metabolic Changes in the Infant with Respiratory Failure

Metabolic Changes in the Infant with Respiratory Failure THOMAS E. OPPE, MoBo BETTY L. PRIESTLEY, MoB. DAVID REDSTONE, MoB.

Respiratory failure or, more properly, respiratory insufficiency exists when there is a reduction in arterial blood oxygen tension (p02) and an elevation of arterial blood carbon dioxide tension (pC0 2). The metabolic changes thereby induced depend upon (a) the severity and duration of the respiratory insufficiency, (b) the pre-existing metabolic and respiratory state of the patient, and (c) the efficiency of compensating mechanisms and resistance to deviations from normal homeostasis. Ultimately respiratory failure causes a dislocation of many metabolic processes within body cells, but these cannot at present be measured clinically. It is therefore in a practical discussion necessary to refer mainly to changes seen in the extracellular fluid, realizing that they do not indicate precisely the disturbance in intracellular metabolism. Both hypoxia and hypercapnia increase the hydrogen ion concentration in body fluids. Retention of carbon dioxide (elevated pC0 2 ) causes a so-called respiratory acidosis, the actual decrease in blood pH being dependent upon (a) the buffering capacity of the body, (b) the ability of the infant to conserve base and excrete hydrogen ions, and (c) the simultaneous presence of anoxaemic acid accumulationmetabolic acidosis. During the perinatal period acid-base disturbances are characterized by their variability and rapid fluctuations. Mostly they cannot be reliably evaluated by clinical examination, and it is essential to measure at least two of the main parameters, pH, pC02 and bicarbonate. Only then, and together with the clinical history, is it possible to distinguish between primary respiratory acidosis and acidosis due to excess nonvolatile acid production; often combinations of these conditions will be found. Oxygen lack, acidosis and hypercapnia produce widespread electrolyte, circulatory and endocrinological changes which are critical for the

723

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infant's survival and influence the course of the primary disease process. Critical levels have not yet been determined for human infants, but there is little doubt that they, like the newborn of many species, are more resistant to total anoxia34 , 61 and severe hypoxia 4 than adults. Clinical evidence suggests that infants also tolerate greater variations in pH and pC02. This biological capability is not due to more effective compensation, because the renal mechanisms for acid-base regulation are relatively poorly developed,19 and the newborn has also been shown to be precariously placed in regard to glycogen reserves. 48 The main aim of treatment for respiratory failure must be· the restoration of respiratory efficiency, and the methods adopted to attain adequate oxygenation and removal of carbon dioxide depend upon the cause of the respiratory difficulty and the resources available. It is, however, reasonable also to support the infant by the provision of materials necessary to correct acid-base disturbances and replenish energy stores. Such supportive measures could be critical in severe asphyxial states and are likely to be helpful in other situations in which the infant's recovery is handicapped by its disturbed internal environment. U sher55 was the first to recognize the importance of the biochemical consequences of the respiratory distress syndrome and to recommend a treatment schedule based on bringing the pH toward normal levels and providing glucose. 56 , 57 In further studies 58 he has demonstrated that these measures result in a significant lowering of mortality. Hutchison and his colleagues 22 , 23 also claim good results with an approach to therapy similar in principle, but differing in detail from Usher's regimen. Although the evidence that metabolic control of the acid-base disturbance in the respiratory distress syndrome does save lives is not yet conclusive, there is no doubt that the major premises on which it is based are sound. It may well be that the perinatal period offers other and perhaps more important opportunities for the correction of severe metabolic disturbances associated with respiratory failure, and some of these will be presented in this article. As there is much controversy concerning the terminology used in acid-base disturbances, it is proposed to discuss this at the outset.

ACID· BASE TERMINOLOGY

An unforeseen accompaniment of the technicological revolution in the field of micro determinations of blood acid-base parameters has been the introduction of a new terminology as an alternative to that in use since about 1920. An attempt, in 1948, by Singer and Hastings 49 to provide an alternative to the classic system failed to achieve general acceptance. In 1960, when Astrup and his co-workers3 introduced a new analytical method, the dose association between the technology

METABOLIC CHANGES IN THE INFANT WITH RESPIRATORY FAILURE

725

and the terminology led to the adoption of their terminology on a remarkable scale. At present all three systems are used in the literature, often without qualification. An adequate understanding of the various terminologies used in the description of acid-base disorders is of course essential to a proper understanding of the disorders themselves, and it is in the historic context that a grasp of these matters is most easily attained. In 1908 Henderson2o gave the first unified explanation of the physiological and physiochemical mechanisms by which the body maintains normal acid-base balance. He showed the unique importance of the carbonic acid-bicarbonate equilibrium in the maintenance of the hydrogen ion concentration of body fluids and described a general mathematical relationship for the components of the equilibrium. This relationship was later put into logarithmic form by HasseibalchI8 to accommodate the convenient Soerensen50 concept of pH. It states essentially that the pH of the blood is determined by the ratio of bicarbonate to .. . f h . [HCO g ] carbonIc aCId. The denommator 0 t e ratIO [ 0] depends on the H2C g carbon dioxide tension of the solution, and in the body this is determined by the rate of carbon dioxide production compared with its rate of respiratory elimination. The bicarbonate concentration depends on the amount of base in the body which is not combined with acids other than carbonic. Because bicarbonate in the body is available for the neutralisation of invading acids, Van Slyke and Cullen59 called it the alkaline reserve. They realised, however, that the amount of bicarbonate generated in the body fluids at a particular pH is very dependent on pC0 2 , so that in a solution such as plasma the term ''bicarbonate'' has a quantitative meaning only for a definite concentration of free carbonic acid, i.e. for a definite pC0 2 • Then, and indeed for another 40 years, means of measuring pH or pC02 in blood were not readily available. Because of this limitation, it was proposed that the pC0 2 be fixed at a definite level in the blood or plasma sample before the bicarbonate was determined. Thus where bicarbonate was the only one of the three variables of the Henderson-Hasselbalch relationship actually measured, one of the others, by definition, was known. This quantity, by usage, became known as the alkali reserve and was generally determined on separated plasma. Van Slyke himself later emphasized the limitations of this procedure. 40 Davenport,IO after examining the concept in detail, concluded that it gave no more information than the actual bicarbonate concentration, and as blood pH measuring equipment became available, there was no point in continuing to use the term "alkali reserve." In 1948 a new concept,49 the whole blood buffer base, was introduced as a parameter for the measurement of metabolic (nonrespiratory) acid-base disturbances. It is pertinent to mention here that neither

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Henderson nor Van Slyke ever claimed that either the actual bicarbonate concentration or the alkali reserve could be used as an exclusive index of pure metabolic deviation. Others incorrectly implied this meaning later. The object of the buffer base concept was to take account of all the buffer anions present in whole blood, including the bicarbonate in plasma and red cells, haemoglobin, plasma proteins and phosphate in plasma and red cells. The sum of the concentrations of these anions is about 50 mEq. per litre in normal blood, and the bulk of the buffer capacity is related to the bicarbonate and haemoglobin. When whole blood is equilibrated in vitro with different tensions of carbon dioxide, the sum of the buffer anions remains constant, so it was thought that buffer base precisely defined metabolic as distinct from respiratory disturbances. Another alternative was proposed by Astrup and Andersen 3 in 1960. Their system was allied to a technicological advance in the determination of whole blood pH and pC0 2 • A capillary micro-electrode as first described by Sanz46 is used to determine blood pH anaerobically and the whole blood log. pC0 2 /pH in-vitro carbon dioxide titration curve9 used to derive pC0 2 • The deviation of buffer base from the normal range which the authors called base excess, shown as a negative value for acid excess (base deficit) and as a positive value for acid deficit (base excess), and plasma standard bicarbonate could all be derived from the procedure. Standard bicarbonate is essentially the same as alkali reserve, but performed in a more elegant way, in the presence of the red cells and at a specific temperature and carbon dioxide tension. With this procedure the haemoglobin in the sample is fully saturated irrespective of the original saturation in vivo; however, this was accommodated in the new definition of standard bicarbonate proposed by the authors. There is little difficulty in regarding pH as representing the resultant of the balance of function between respiratory and nonrespiratory vectors. Likewise pC0 2 , although not an exclusive index of primary respiratory disturbances, is at least acceptable as a satisfactory measure of alveolar ventilation. The term best used to describe the nonrespiratory component is less easily defined. All alternatives to the actual bicarbonate depend on artificial alteration of the pC0 2 of the blood sample in the laboratory. They imply that if the blood underwent the same change of pC0 2 in the intact subject, the same change in its composition would result. But the in-vitro and in-vivo changes are not the same, and this is one of the main criticisms levelled at the base excess-standard bicarbonate concept by Schwartz and Relman. 47 In a detailed examination of the various proposed parameters they conclude that terms such as standard bicarbonate and base excess are both unnecessary and misleading. They emphasise the importance of assessing acid-base disorders in the light of the whole organism's known physiological reactions to various disturbances and show how this, in terms of the classic values

METABOLIC CHANGES IN THE INFANT WITH RESPIRATORY FAILURE

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of pH, pC0 2 and bicarbonate, together with the appropriate clinical data, allows rational evaluation of the most complex acid-base disorders. No single term for the exclusive description of a pure metabolic or respiratory deviation exists. Unfortunately, in the past most studies of human reactions to single primary acid-base deviations were made in clinical situations in which complicating factors such as electrolyte disturbances, themselves often having a profound effect on acid-base balance, were present. The effect of this has been to obscure, for many years, the uniformity of the whole body reaction to a single primary deviation. Recent experimental work8 has shown that when the organism is subjected to pure hypercapnia (without hypoxia) of varying intensity, its reaction is remarkably uniform. The duration of exposure to the primary deviation is an important factor, as has already been shown in the case of hypercapnia. Much work remains to be done in defining the human reactions to single primary acid-base deviations, in relation to primary metabolic as well as primary ventilatory disturbances. This applies particularly to the newborn, in whom the complexity of the reaction to a ventilatory disorder makes the evaluation of anyone component of that reaction and physiological therapy very difficult.

CLINICAL APPLICATIONS

Respiratory function is more critically altered at the moment of birth than any other physiological system.24 Before birth the lungs play no part in gas exchange, the placenta performing that function, and the umbilical vessels are the analogues of the airway. When the placenta separates and the umbilical cord is occluded, there is a period, usually brief, in which gas exchange is impossible until the first breaths are taken. Subsequently pulmonary ventilation provides gas exchange, and the lungs become an essential mechanism for acid-base regulation. Traditionally, the clinical manifestations of respiratory failure occurring in the perinatal period are differentiated according to the phase in which signs are shown: (a) foetal distress, (b) asphyxia neonatorum, and (c) respiratory distress. This clinical distinction is valuable just so long as it is appreciated that many of the complex changes secondary to respiratory failure can be understood only by considering the cumulative and overlapping effects of events taking place throughout this continuous process.

FOETAL DISTRESS

The undisturbed normal foetus at the end of pregnancy is no longer thought to be in a state of relative hypoxia and hypercapnia. 12 • 27, 43

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Certainly the oxygen tension of blood perfusing the foetus is lower than that of the mother mainly because of the placental oxygen gradient63 and also because of the mixing in the foetal circulation of venous with arterial blood. This does not mean that the foetus is deprived of oxygen, nor that there is difficulty in eliminating carbon dioxide and maintaining acid-base equilibrium. Numerous pathological events affecting maternal oxygenation, placental sufficiency and the integrity of umbilical blood flow can interfere with this equilibrium. At present foetal respiratory failure is detected clinically by the crude signs of changes in heart rate and meconium staining of liquor amnii. When labour is advanced and the presenting part of the foetus accessible, capillary blood can be drawn for measurement of pH and acid-base parameters. 44 , 45 Therapeutic intervention is for practical purposes limited to immediate delivery of the distressed foetus. The condition of the infant at birth is related to the severity and duration of any preceding episodes of hypoxia, but it is difficult to assess this accurately by either clinical or biochemical examination. 25 Arterial oxygen desaturation, hypercapnia and acidaemia may be as great in a baby recently and transiently asphyxiated during the birth process as in one who has suffered prolonged or recurrent hypoxia prenatally. As lactic acid levels return to normal more slowly than the blood gases after a bout of asphyxia, it has been suggested that blood lactate and especially the "excess lactate"21 calculated from the lactate-pyruvate ratio may give an indication of previous anaerobic hypoxic metabolism. The concept of excess lactate has been questioned, however, and in part the high lactate levels found in cord blood can be maternal in origin.33, 60, 65

ASPHYXIA NEONATORUM

The metabolic effects of neonatal apnoea without preceding hypoxia have been systematically studied in many animals. The experimental work which most closely parallels asphyxia neonatorum in man is the recent work of Dawes and his colleagues. 2 ,11 They delivered Rhesus monkeys by Caesarean section and asphyxiated the newborn by immersing the head in a saline-filled bag and tying the umbilical cord. Spontaneous respiratory movements started in about 30 to 45 seconds. Within minutes these movements ceased-primary apnoea-to be followed some moments later by a period of gasping which faded into terminal apnoea. At the same time the blood pH fell, reaching a level of about 6.77 at the time of the last gasp. Arterial pC0 2 rose rapidly, as did the blood lactate. Systemic arterial blood pressure rose initially, but fell as asphyxia proceeded, while the heart slowed throughout, but did not stop until asphyxia had continued for 10 to 15 minutes. Resus-

METABOLIC CHANGES IN THE INFANT WITH RESPIRATORY FAILURE

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citation was possible during the interval between the last gasp and circulatory arrest. The most effective method of restarting breathing was endotracheal intubation and intermittent positive pressure oxygen administration. Dawes et al. have shown also that survival time is prolonged if rapid intravenous infusion of bases such as 0.5 M. of THAM at pH 8.85 with 3.5 per, cent glucose is used in order to correct the arterial pH. These experiments are close to but not exactly analogous with the human situation. Until their experimental asphyxiation the baby monkeys were in good condition, whereas many apnoeic newborn infants are already in a precarious state when delivered. This, however, adds force to the argument that endotracheal intubation and use of buffers and glucose are the most rational treatment available for asphyxia neonatorum. The following case demonstrated the successful use of THAM in a severely asphyxiated human infant. CASE 1. J.G., a male infant, birth weight 1870 gm., was delivered normally at 38 weeks by a 24-year-old primigravida. The mother had hypertension in later pregnancy, and the foetus failed to grow from the thirty-fifth week onward. At birth he was limp and cyanosed, with a heart rate of 40 per minute, and no spontaneous respiratory efforts. Endotracheal intubation and positive pressure respiration produced a good improvement in colour and heart beat, and spontaneous respiration began. But removal of the tube was rapidly followed by a deterioration in the child's condition. At 30 minutes of age he was limp and deeply cyanosed, with an apex rate of 90 per minute. There were no apparent respiratory efforts, but the chest was maintained in a position of inspiration. Reintubation and positive pressure ventilation were carried out, but this time improvement in colour and heart rate was slow, without significant expansion of the chest. Air entry was just detectable in the left hemithorax. The baby began gasping intermittently, and finally feeble but regular respirations started. Withdrawal of the endotracheal tube was again followed by deterioration and gradual cessation of spontaneous breathing. He was then one hour old. A diagnosis of right-sided pneumothorax was made, and a needle attached to an underwater seal inserted. Air under considerable tension was released with immediate clinical improvement. Spontaneous respiration again became established, and air entry was audible over the left hemithorax, and faintly over the right. The thoracentesis needle was removed, and the child was transferred from the labour ward to the Special Care Baby Unit, still in poor general condition. At the age of 1112 hours he suffered a sudden cardiac and respiratory arrest, which fortunately responded rapidly to external cardiac massage, intubation and intermittent positive pressure ventilation. A severe degree of acidaemia was anticipated, and an umbilical artery catheterisation was therefore performed and treatment initiated. Acid-base studies are described below. At three hours his general condition was much improved, but the tension pneumothorax had recurred. This was again released by a temporary drain, and subsequently a small polyethylene catheter attached to an underwater seal was inserted into the right pleural space. His condition thereafter remained satisfactory, and a repeat radiograph at 19 hours of age showed almost complete re-expansion of the right lung.

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Figure 47. Clinical and acid-base data in J.C. (case 1) showing correction of severe metabolic and respiratory acidosis. The acid-base balance of the arterial blood is represented diagrammatically. pH is shown as the point of contact between the columns, the upper column representing the base (HC03) component, the lower the respiratory (pC02) component. The normal balance with pH at 7.40 is shown at the left of the diagram. Biochemical and clinical data are also shown on the graphs, with pH ordinate and time abscissa. The columns are drawn in proportion to those showing the normal state, and the measured values are indicated above and below the columns. The initial acid-base values, immediately after the cardiac arrest, showed a severe metabolic acidosis with a plasma bicarbonate level of 6 mEq. per litre and pH of 6.74. The near-normal pC0 2 at this stage is attributed to the artificial ventilation which was applied for a few minutes after the arrest. THAM, 4.5 mM. in two doses, was given over the next half-hour (see Fig. 47), but the pneumothorax was reaccumulating, and the next arterial analysis showed a gross hypercapnia with pC0 2 of 125 mm. Hg. But bicarbonate had also risen, and pH was virtually unchanged at 6.79. The second pneumothorax aspiration, together with the administration of a further 12.0 mM. of THAM over the next four hours, resulted both in a steady improvement in ventilation, pC0 2 falling to about 50 mm. Hg, and maintenance of bicarbonate levels despite the period of respiratory insufficiency. Subsequent analyses showed continuous improvement, and normal values were reached at 26 hours. An asymptomatic hypoglycaemia occurred during the second day, the blood sugar level falling to 10 mg. per 100 ml. (total reducing substances) at 48 hours. This responded to oral glucose feeds. Birth weight was low for gestational age, which may well have been associated with the transient hypoglycaemia,36 but the relatively large quantities of THAM used may have been contributory.6 His subsequent progress has been entirely satisfactory.

METABOLIC CHANGES

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731

Some infants born in poor condition show a severe metabolic acidosis due probably to preceding hypoxic anaerobic metabolism. These are suitable patients for the use of buffers and glucose, since, provided the damaging effects of acidosis can be overcome, they may have little or no underlying pulmonary pathology. Such a case is illustrated. CASE 2. M.W., a female infant, birth weight 1870 gm., was delivered normally after spontaneous onset of labour at 33 weeks. Membranes had ruptured three weeks previously, and labour had subsequently "threatened" on several occasions. At birth she was greyish blue and limp, without spontaneous respiratory efforts. She was given oxygen, using intermittent positive pressure via an Ambu resuscitator and face mask; regular and shallow respirations were established after five minutes, but her colour remained poor, despite continued oxygen. At one hour she was worse, with grey pallor and gross expiratory grunting. Respiratory rate, however, was only 36 per minute, air entry was good without recession, and chest X-ray showed clear lung fields. She continued to deteriorate, and at two hours umbilical catheters were passed, and a 10 per cent dextrose infusion supplying 60 ml. per kilogram per 24 hours was established via the umbilical vein. A course of intramuscular ampicillin and cloxacillin was commenced. The initial arterial sample showed a gross metabolic acidosis (see Fig. 48) with bicarbonate of 8.0 mEq. per litre and pR of 6.91. Ventilation at this time was normal with pC0 2 of 40 mm. Rg. TRAM, 2.5 mM., was given during the hour following the first sample, but the second arterial analysis at Blood Lactet. 149mEq/L

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four hours showed an increasing acidaemia due to a rise in pC0 2 to 65 mm. Hg. pH was 6.70, and the arterial whole blood lactate level 14.9 mEq. per litre (normal 1.0 to 1.5 mEq. per litre). At this time she was gravely ill and in peripheral circulatOlY failure. In view of this deterioration larger doses of THAM were used, 5.1 mM. being given over a period of 1* hours. It will be seen that thereafter the acid-base status steadily improved, normal values being attained at 25 hours. Apnoeic attacks occurred at nine and 11 hours reflected by slight lowering of bicarbonate and pH. The clinical state improved concurrently, and at 36 hours her general condition was satisfactory. Umbilical catheters were therefore removed, and gavage feeding was instituted. Her subsequent course was complicated only by jaundice, reaching a maximum bilirubin level of 16 mg. per 100 mI. at four days. She was last seen for followup at the age of four months, when she weighed 5.4 kg., had been smiling for one month and showed no abnormal neurological signs.

The paediatrician faced with an infant in poor condition at birth does not know whether the infant will recover spontaneously, with airway clearance and oxygen, or whether the infant is beyond the last gasp and in imminent danger of death. As speed is essential, reliance must be placed largely on clinical judgement, after taking into account the history of labour and delivery and the physical examination. Biochemical analysis of cord blood and infant's arterial or, less satisfactory, "arterialised" capillary blood for pH, bicarbonate and lactic acid may be helpful, but in severe cases initial therapy must be based on clinical findings. Subsequent management is far easier if serial measurements of blood gas and acid-base status are available. Normal vigorous infants and also mildly depressed ones frequently show deviations from the normal adult range of pH, pC0 2 , lactic acid and bicarbonate. These changes are transient, expressing brief episodes of hypoxia, slight difficulty in establishing pulmonary ventilation, or disturbances in maternal biochemical homeostasis. No treatment is required, and the majority achieve normal acid-base values within a few hours of birth. 15 . 25,29,31,38,45.64 Some even show a brief respiratory alkalosis,41 demonstrating a capacity for hyperventilation.

RESPIRATORY DISTRESS

Difficulty in maintaining pulmonary ventilation results from many disease processes in the newborn. Accurate diagnosis is a prerequisite for specific treatment, and there have been several good recent reviews 5, 13, 52 on the clinical aspects of respiratory distress. Whether the basic condition is idiopathic respiratory distress syndrome of prematurity or other more specific causes of respiratory embarrassment, the same principles of metabolic treatment are applicable. In respiratory distress there is often a combined respiratory and metabolic acidosis in what is primarily a disorder of ventilation. The "metabolic" component is frequently severe and cannot wholly be ac-

METABOLIC CHANGES IN THE INFANT WITH RESPIRATORY FAILURE

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counted for by the difference between in-vitro and in-vivo blood changes as described in acute hypercapnia. s In some cases the acid accumulation probably indicates a pre-existing acidosis due to foetal distress or asphyxia neonatorum; in others it indicates hypoxic anaerobic metabolism resulting from pulmonary and circulatory insufficiency. It is clear, however, that acute, progressive hypercapnia is associated with a poor prognosis, infants rarely surviving when pC02 levels rise continuously above 75 mm. Hg.22, 54, 56 If these levels are combined with a pH below 7.10, metabolic therapy is unlikely to be successful. Many small immature infants dying with progressive hypercapnic acidosis are shown to have gross intraventricular haemorrhage and are not at present salvageable. Larger babies may show progressive ventilatory failure associated with traumatic intracranial haemorrhage, sustained at birth, as occurred in the following case. CASE 3. N.K. Pregnancy was uncomplicated until 34 weeks, when severe pre-eclamptic toxaemia developed and failed to respond to bed rest and strong sedation. Labour was therefore induced at 35 weeks by artificial rupture of the membranes followed by a Pitocin drip. Forty-eight hours later, in view of failure to advance in the first stage, an emergency lower-segment Caesarean section was performed, and a live male infant was delivered, birth weight 1875 gm. The child was limp and blue at birth, with no spontaneous respiratory efforts. He responded slowly to suction, facial oxygen and analeptics, regular respirations becoming established after eight minutes. His colour improved temporarily, but 1 Yz hours after birth, despite 70 per cent oxygen, he was dusky, with expiratory grunting, subcostal recession, poor air entry and generalised crepitations. Chest radiograph showed extensive loss of translucency with appearance of an air bronchogram. Umbilical catheters were passed, and a 10 per cent dextrose infusion was commenced via the umbilical vein. Initial acid-base studies (see Fig. 49) at three hours showed a combined metabolic and respiratory acidosis. Shortly afterwards a severe cyanotic attack occurred which responded slowly to aspiration and increased oxygen. The next arterial analysis showed a deterioration in ventilation; pC0 2 had risen to 80 mm. Hg, and pH was 6.97. Sodium bicarbonate, 12.5 mM. (25 mI. of 4.2 per cent), was given via the umbilical vein catheter over 45 minutes. Fifteen minutes after the end of this infusion pC0 2 had risen to 91.5 mm. Hg, but bicarbonate had also risen to 21.6 mEq. per litre, so that pH remained essentially unchanged at 7.0. A further 15 mM. of sodium bicarbonate were given over the next hour. But ventilation continued to deteriorate, and pC0 2 was 125 at 9Yz hours. Again a rising bicarbonate concentration prevented a further fall in pH. Thereafter the clinical condition deteriorated progressively with frequent apnoeic attacks. Intubation and intermittent positive pressure ventilation following an attack at 9Yz hours probably accounted for the fall in pC0 2 and rise in pH at 12 hours. Death occurred at 15 hours. Post-mortem examination showed a tear of the right tentorium cerebelli, with considerable haemorrhage around the pons and medulla spreading forwards over the base of the brain. The lungs showed gross congestion, but no hyaline membrane formation.

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734

In other cases of respiratory distress with respiratory and nonrespiratory deviations of moderate severity, a near-complete correction of pH may well be achieved with base administration. The following case history illustrates this, although the infant subsequently died of one of the recognised complications of gross prematurity. CASE 4. B.W. was delivered by the breech, the first of twins, after spontaneous onset of labour at 28 weeks. He was limp and cyanosed at birth, but responded rapidly to simple resuscitative measures. Birth weight was 820 gm. At one hour he showed signs of respiratory distress, with deep expiratory grunting, mild subcostal recession and poor air entry. His colour was satisfactory in 50 to 60 per cent oxygen. Umbilical arterial and venous catheters were passed, and a 10 per cent dextrose infusion was commenced. Arterial analysis at 2Yz hours showed (see Fig. 50) a combined respiratory and metabolic acidosis of moderate degree. Sodium bicarbonate, 4 mM. (4 m!. of 8.4 per cent), was given, and the next analysis, at four hours, showed little change in ventilation, but bicarbonate concentration had risen to 22 mEq. per litre and pH to 7.14. A further 5 mM. of bicarbonate again resulted in a rise in bicarbonate and pH, although pC0 2 had risen to 75 mm. Hg. The clinical condition began to improve, and at nine hours bicarbonate was 28.4 mEq. per litre, pC0 2 58.4 mm. Hg, and pH 7.3l. Thereafter his general condition was satisfactory with good colour, minimal retraction and better air entry. The acid-base status remained stable, although a moderate elevation of pC0 2 , to about 55 mm. Hg, persisted. At 33 hours the umbilical catheters were removed, and gavage feeding with expressed breast milk was introduced. A few hours later he collapsed 30

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METABOLIC CHANGES IN THE INFANT WITH RESPIRATORY FAILURE

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suddenly with apnoea and cyanosis. Milky fluid was aspirated from the oropharynx, but he failed to respond to resuscitation. Post-mortem examination showed a very premature baby with haemorrhage filling the posterior horn of the left ventricle, and involving the brain substance underlying the ependyma of the ventricle. The lungs were patchily expanded. Histological examination showed no evidence of hyaline membrane formation or of aspiration of milk.

DISCUSSION OF THERAPY

Metabolic treatment of respiratory distress is based on the assumption that the lethal effects of the disease are due in large part to the disturbances secondary to the pulmonary failure rather than being caused directly by oxygen deficiency per se. It is argued that correction of the pH, and the provision of readily metabolisable carbohydrate, will enable the infant to survive while the pulmonary disorder improves either spontaneously or with treatment. Usher,55 who pioneered this approach, was originally impressed by hyperkalaemia as potentially the most lethal result of respiratory distress, and his regimen was proposed as an attempt to restore intracellular and extracellular electrolyte balance by the intravenous administration of glucose, bicarbonate and insulin. He recognised the importance of changes in hydrogen ion concentration and based alkali dosage on the degree of acidaemia. Hyperkalaemia is probably not such a constant feature of the respiratory distress syndrome as initially thought,28,37 but Usher57 has shown, in a controlled trial of

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alkali and glucose therapy, that the mortality of the respiratory distress syndrome in his unit has been significantly reduced. The only other large series of cases which has been reported is that of Hutchison et al.,22 who have claimed a considerable increase in survival with treatment using sodium bicarbonate or THAM, and glucose or fructose as intravenous carbohydrate. They prefer to calculate alkali dosage on the ''base excess" value rather than on blood pH and advocate rapid correction rather than continuous infusion of alkali. Published evidence has not yet shown conclusively that the prognosis is greatly improved by metabolic therapy, and certainly no one method has been shown to be superior to another. Since Gairdner and Warley62 demonstrated the need, a more liberal use of high oxygen concentrations has gained general acceptance, and this may well have influenced the prognosis in recent years. In conditions such as respiratory distress syndrome in which the prognosis is not readily predictable, evaluation of treatment is difficult even when carefully controlled. As used at present, metabolic therapy involves not only the intravenous administration of fluids, alkalis and carbohydrates, but also close observation of the infant. Choice of Base Sodium bicarbonate has been used since 1832 in the treatment of metabolic acidosis,30 and it continues to offer the simplest and most direct means of restoring bicarbonate depletion. Its use is somewhat limited by the amount of sodium and water which must be introduced at the same time. Sodium lactate, the metabolism of which effectively donates bicarbonate to the body fluids, was introduced in 1932 by Rartrnann17 as an alternative. Bicarbonate is more slowly released from lactate, so that the danger of too rapid alkalinisation is avoided. But in situations in which lactate elimination may be impaired, such as respiratory and circulatory insufficiency, its use is contraindicated. Amine buffers were introduced in biology in 1959 and have since been extensively investigated. Trishydroxymethylaminomethane (TRAM) is the most widely used in clinical medicine. Descriptions of its effects are often attended by perpetuation of a curious misconception with regard to its action in body fluids. This seems to stern from the title of the original article,35 which mentions the use of an organic carbon dioxide buffer in vivo. Of course a buffer with respect to anything other than a proton cannot exist, and the persistence of this idea is even more remarkable in view of the accepted reaction of TRAM with carbonic acid:(HOCH2)sC-NH2

+ H2C03;;::=: HC0 3 + (HOCH2)gC-NH3

Jorgensen26 has pointed out that TRAM, in the concentrations used therapeutically, has little or no effect on the buffer capacity of blood

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with respect to nxed acids or bases, or to carbonic acid, and that the amount of THAM required to double the buffer capacity of normal blood would also increase its osmolarity twofold. As a base, however, THAM is strong enough to be useful, and this is its main biological action. In the body, in common with all bases, THAM is effectively converted into bicarbonate, and it is as bicarbonate ion that its alkalinising effect is achieved. Since THAM is more rapidly distributed in the intracellular space than bicarbonate,42 there are theoretical reasons why its action in a given time may be favourable compared to that of bicarbonate. Starling5! pointed out that cardiac output in the heart-lung preparation was closely related to the acid-base state of the perfusate and that output fell with increasing acidaemia. There are also indications that vascular tone in the pulmonary circulation may be related to the pH of the perfusing blood. 7 In this site, therefore, where the vascular resistance is known to be increased in hypercapnic acidosis,32 THAM may be more effective than bicarbonate. The property of rapid distribution in the intracellular space may be responsible for undesirable effects on ventilation, for if THAM enters the cells of the respiratory centre, the consequent rise in pH may produce hypoventilation, as reported occasionally in adults.! Quantitative Aspects of Base Therapy Calculations of base or bicarbonate dencit involving the use of the terms "standard bicarbonate" or 'base excess" refer specincally to a blood in which pC0 2 is 40 mm. Hg. Correction dosage based on such calculations will restore bicarbonate only to the extent that the plasma bicarbonate level is returned to approximately 24 mEq. per litre. If pC02 is elevated whilst the bicarbonate is at this level, pH will remain below the normal value. When ventilation is impaired as in respiratory distress, bicarbonate and THAM dosage based on these criteria can achieve only a partial correction of pH. Obviously much depends on what is happening to ventilation and also on whether or not assisted ventilation is contemplated. If it is considered that ventilation is so improving that pC02 will shortly approach or achieve 40 mm. Hg, then alkali therapy calculated to restore the "standard bicarbonate" or "base excess" values to normal will suffice. If, however, a period of sustained hypercapnia is anticipated, larger amounts of base will be needed to achieve normal or near-normal pH values. There are limits to the degree of hypercapnia which can be balanced in practice by increased bicarbonate concentration. Under optimum conditions the body seldom achieves bicarbonate concentrations in excess of 45 mEq. per litre in response to sustained hypercapnia with pC0 2 levels in the region of 80 mm. Hg. Though the precise reactions of the newborn to sustained hypercapnia are not well denned, it would be reasonable to assume that pC02 values of 75 mm. Hg or above, particu-

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larly if rising, are unlikely to be tolerated for long periods. At and above these levels some means of improving ventilation are the prime necessity. The volume distribution of base deficit in the body is difficult to define in individual clinical situations, but it has been known for many years that the base deficit in metabolic acidosis behaves as though it were distributed in a volume approximately equal to that of the total body water 39 (i.e. about 60 per cent of body weight). The quantitative correction of base deficit by this approach is probably the most realistic guide to the complete correction of metabolic acidosis, although in practice it is safer to attempt a half-correction initially. When pC0 2 is elevated, the bicarbonate dosage is determined by calculating the plasma bicarbonate level necessary to achieve a normal pH (7.40) at the actual pC0 2 of the patient. This is easily done by using one of the many available nomograms. The difference between this and the actual plasma bicarbonate represents the bicarbonate deficit. Assuming that this is distributed in the total body water and that pC0 2 remains unchanged, the deficit in milliequivalents per litre multiplied by 60 per cent of the body weight in kilograms represents a total correction: half this quantity is given and the clinical and biochemical state then reassessed. This was the basis of bicarbonate administration in cases 3 and 4. Of course no method at present can take account of the variations in the rates of endogenous acid production and elimination which may occur in prolonged hypoxic states. In view of the distribution differences between bicarbonate and THAM previously referred to, precise calculation of THAM dosage does not appear to be warranted at present. The solution used in our cases was 0.3 M. at a pH of 8.4, 1 mM. per 3 ml., and dosage was empirical. If the baby is severely ill, 5 ml. of solution are given immediately. In less extreme situations we prefer to await the result of the initial pH measurement; if it lies below 7.1, we give 3 to 5 ml. to infants under 2 kg. in weight and 5 to 7 ml. for those over that weight. Subsequent doses are adjusted according to the response. When the initial pH lies between 7.1 and 7.2, it is necessary to make serial estimations in order to assess progress. If the pH improves, metabolic therapy can be withheld, but deterioration is an indication for instituting treatment. Use of alkalis is not advised unless frequent monitoring of acid-base status is possible. For this, regardless of the equipment used, consideration must be given to the obtaining of blood samples. Sampling Procedures The most satisfactory sample for acid-base determination is true arterial blood, but if this is not easily obtainable, arterialised capillary blood offers a possible alternative, since it bears a reasonably close correlation with coincidentally drawn arterial blood. Although Gandy et aJ.16 confirmed this correlation for healthy neonates over three hours

METABOLIC CHANGES IN THE INFANT WITH RESPIRATORY FAILURE

739

of age, they found that before this age, and in sick infants, the agreement was unsatisfactory. It is of course precisely in this group of neonates that acid-base studies are most needed. The favourite site for obtaining arterialised capillary blood is the heel, which is warmed for 10 to 15 minutes before sampling. Various methods of applying heat have been used, but immersion of the whole foot in water at 40° to 50°C. has proved satisfactory. The heel is then stabbed, using the tip of a scalpel blade, and blood collected by one of the accepted methods for anaerobic sampling. If the blood is drawn separately into a number of heparinised capillary tubes, some waste is inevitable, owing to the intermittent nature of the collection, and there is also the opportunity for exposure to air, and a consequent readjustment in gaseous tensions. A more satisfactory method involves continuous collection into a heparinised Mantoux syringe, as described by Gambino. 14 True arterial blood may be obtained from an umbilical or peripheral artery. Umbilical artery catheterisation is carried out under full sterile precautions. The cord is sectioned transversely at 2 to 4 cm. from the umbilicus. A small metal dilator is introduced into the artery, and slowly advanced until a sudden "give" is felt. A plastic umbilical catheter is then passed along the artery until a free How of blood is obtained. This usually occurs when the tip of the catheter lies in the common iliac artery or abdominal aorta, and approximately 5 to 7 cm. of catheter then lie within the abdomen. A silk suture is inserted into the cord, to anchor the catheter in position, and the distal end of the catheter connected via a two-way tap to a syringe containing heparinised saline. Blood samples may then be taken at intervals as required into heparinised syringes and the catheter then washed through with heparinised saline. Antibiotics are routinely given. It has been found in practice easiest to insert the arterial catheter within the first two to three hours of birth, but the method has also proved satisfactory during the first 24 hours. Possible dangers include haemorrhage at the time of withdrawal, infection and thrombosis. A temporary "white leg" has been known to occur, although the signs have disappeared within hours of removing the catheter. This should not be left in situ for longer than 36 to 48 hours, since difficulty may be experienced in removal after this period. After withdrawal, a suture is inserted through the cord and then tied around the vessel. Femoral artery puncture has also been used as a method of getting arterial samples, but thrombosis in the neonate has been reported following the procedure. The temporal artery appears to provide a more satisfactory alternative route, but again much practice is required before repeated samples can be obtained with ease. The method has been described in detail by Thomsen53 and seems to be free from serious complications.

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CONCLUSION

In this paper we have dealt with only one aspect of respiratory failure, that concerned with disturbances of acid-base balance and therapeutic eHorts to correct acidaemia. In emphasising this one aspect, discussion of the electrolyte, circulatory and hormonal changes has been avoided, and we have not dealt with the problem of providing suitable substrate for the maintenance of glycolysis. The results show that correction of the acidaemia in these circumstances probably aids recovery, although ultimate survival depends upon the ability of the infant to achieve and maintain adequate pulmonary function.

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17. Hartmann, A. F., and Senn, M. J. E.: Studies in the Metabolism of Sodium r-Lactate. 1. Response of Normal Human Subjects to the Intravenous Injection of Sodium r-Lactate. J. Clin. Invest., 11 :327, 1932. 18. Hasselbalch, K. A.: Die Berechnung der Wasserstoffzahl des Blutes auf der freien und gebundenen Kohlensaure desselben, und die Sauerstoffbindung des Blutes als Funktion der Wasserstoffzahl. Biochem. Z., 78: 112, 1916. 19. Hatemi, N., and McCance, H. A.: Renal Aspects of Acid-Base Control in the New Born. Acta Paediat. (Stockholm), 50:603,1961. 20. Henderson, L. J.: The Theory of Neutrality Regulation in the Animal Organism. Amer. J. Physiol., 21:427, 1908. 21. Huckabee, W. E.: Relationships of Pyruvate and Lactate during Anaerobic Metabolism. J. Clin. Invest., 37:244, 255, 264, 1958. 22. Hutchison, J. H., Kerr, M. M., Douglas, T. A., Inall, J. A., and Crosbie, J. C.: A Therapeutic Approach in 100 Cases of the Respiratory Distress Syndrome of the Newborn Infant. Pediatrics, 33:956, 1964. 23. Hutchison, J. H., and others: Studies in the Treatment of the Pulmonary Syndrome of the Newborn. Lancet, 2:465,1962. 24. James, L. S., and Adamsons, K., Jr.: Respiratory Physiology of the Fetus and Newborn Infant. New England J. Med., 271:1352,1403,1964. 25. James, L. S., Weisbrot, I. M., Prince, C. E., Holaday, D. A., and Apgar, V.: The Acid-Base Status of Human Infants in Relation to Birth Asphyxia and the Onset of Respiration. J. Pediat., 52:379, 1958. 26. J~rgensen, K., and Astrup, P.: The Effect of 2-Amino-2-Hydroxymethyl-l, 3-Propanediol on Blood-Buffering Capacity. Ann. New York Acad. Sc., 92:491,1961. 27. Kaiser, I. H.: Some Factors Bearing on Gas Exchange between Fetus and Mother. Amer. J. Obstet. & Gynec., 90:638, 1964. 28. Kerpel-Fronius, E., Varga, F., and Bata, G.: Blood Gas and Metabolic Studies in Plasma Cell Pneumonia and in Newborn Prematures with Respiratory Distress. Arch. Dis. Childhood, 39:473, 1964. 29. Kildeberg, P.: Disturbances of Hydrogen Ion Balance Occurring in Premature Infants. Acta paediat., 53:505, 1964. 30. Latta, T.: Letter from Dr. Latta to Secretary of Central Board of Health, London. Lancet, 2:274, 1831-32. 31. Levison, H., and others: Maternal Acid-Base Status and Neonatal Respiratory Distress in Normal and Complicated Pregnancies. Amer. J. Obstet. & Gynec., 88: 795,1964. 32. Ligou, J. C., Le Tallec, Y., Bernadet, P., Broue, A., and Calazel, P.: Effects of 2-Amino-2-Hydroxymethyl-l, 3-Propanediol on the Pulmonary Hypertension of Hypercapnic Acidosis. Ann. New York Acad. Sc., 92:617, 1961. 33. Marx, G. F., and Greene, N. M.: Maternal Lactate, Pyruvate and Excess Lactate Production during Labor and Delivery. Amer. J. Obstet. & Gynec., 90:786, 1964. 34. Mott, J. C.: The Ability of Young Mammals to Withstand Total Oxygen Lack. Brit. M. Bull., 17:144, 1961. 35. Nahas, G. G.: Use of an Organic Carbon Dioxide Buffer in Vivo. Science, 129:782, 1959. 36. Neligan, G. A., Robson, E., and Watson, J.: Hypoglycaemia in the Newborn: A Sequel of Intrauterine Malnutrition. Lancet, 1: 1282, 1963. 37. Nicolopoulos, B. A., and Smith, C. A.: Metabolic Aspects of Idiopathic Respiratory Distress (Hyaline Membrane Syndrome) in Newborn Infants. Pediatrics, 28: 206,1961. 38. Oliver, T. K., Jr., Demis, J. A., and Bates, G. D.: Serial Blood-Gas Tensions and Acid-Base Balance during the First Hour of Life in Human Infants. Acta paediat., 50:346, 1961. 39. Palmer, W. W., and Van Slyke, D. D.: Studies of Acidosis. IX. Relationship between Alkali Retention and Alkali Reserve in Normal and Pathological Individuals. J. Biol. Chern., 32:499,1917. 40. Peters, J. P., and Van Slyke, D. D.: Quantitative Clinical Chemistry. London, Bailliere, Tindall and Cox, 1931, Vol. 1. 41. Prod'hom, L. S., and others: Adjustment of Ventilation, Intrapulmonary Gas Ex-

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55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65.

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St. Mary's Hospital Medical School London, W.2 England