Transcutaneous monitoring in the newborn infant

T H E J O U R N A L OF

PEDIATRICS DECEMBER

1983

Volume 103

Number 6

Comment:We believe our readers will find this state-of-the-art summary useful. All experienced clinicians can ruefully recall an instance when the laboratory or some instrument led them astray, sometimes to the detriment of the patient. Dr. Cassady gives a fresh and authoritative look at where we are. The particular emphases on misleading results and reasonable applications seem especially welcome at this time.--R.E.M.

Transcutaneous monitoring in the newborn infant George Cassady, M.D. B i r m i n g h a m , A l a .

THE CONCEPT OF TRANSCUTANEOUS MEASUREMENT of physiologic gases is not new. I n 1793, Abernathy ~ recorded that gas exchange took place through human skin, and a half century later, Gerlach 2 confirmed and extended these observations by noting that absorption and elimination of both oxygen and carbon dioxide by skin were measurable. Another century passed before Baumberger and Goodfriend3 showed that the oxygen tension of warm water in which a finger was immersed reflected the alveolar oxygen tension of the human subject. Rapidly thereafter, the physiologic observations of Evans and Naylor .6 and the development by Clark 7 of an oxygen electrode led to the development by Liibberss in the late 1960s of a skin sensor to accurately measure oxygen tension. Clinical evaluation, primarily in newborn infants, promptly followed. 9-H By 1972, experience in Germany led to commercial availability. Since then, an explosion of information has confirmed the usefulness of the technique, and transcutaneous monitoring of oxygen tensions is now clinically used in most neonatal centers throughout the world. Major advances in medicine always carry a potential for

From the Department of Pediatrics, University of Alabama School of Medicine. Reprint requests: George Cassady, M.D., Department of Pediatrics, University of Alabama School of Medicine, Birmingham, AL 35294.

mischief. The use of transcutaneous oxygen monitors in the care of newborn infants demands sound knowledge of how the method works. A wealth of information is now available in several excellent monographs and reviewS,11-~7 although these works are seldom on the bookshelves of those who use this technique. Clinical experience frequently suggests a failure to understand the underlying princiPacoz Pao2 pHa Po2 TBs tcBI tcPco2 tcPo2

Arterial carbon dioxide tension Arterial oxygen tension Arterial pH Oxygen tension Total serum bilirubin concentration Transcutaneous bilirubin index Transcutaneous carbon dioxide tension Transcutaneous oxygen tension

pies required for safe and effective use. My purpose is to summarize these principles and provide a selective overview of current clinical applications of transcutaneous oxygen monitors. As space precludes detailed discussion of many points, the reader is urged to examine the underlying evidence that provides the physiologic and biophysical bases. TRANSCUTANEOUS

OXYGEN TENSION

Basic principles. There is an intimate, linear relationship between transcutaneous oxygen tension, as measured by commercially available instruments, and arterial oxygen

TheJournalofPEDIATRICS

837

8 38

Cassady

The Journal of Pediatrics December 1983

Table I. Factors that affect tcPoJPao2 Causes of poor correlation Requirements for good correlation

Proper sensor preparation and application

In sensor

In infant

Membrane Air bubbles Zeroing solution retained Thickness/character incorrect for electrode size Electrode Calibration error Surface damage during cleaning Cable broken Sensor off skin Application not gentle

Appropriate comparisons

System permeable to oxygen

Membrane thickness or permeability mismatched to skin character

Maximum hyperemia

Temperature <43.5 ~ C

No interfering agents

Halothane present/N20 present

tension. Although values are more often discrepant at very high (or low) Pao2 levels, 1~ correlation coefficients range from +0.85 to +0.99 in most studies? 5' ~7 All regression analyses of this relationship, to date, are flawed by the inclusion of multiple samples from individual patients. 19 Although tcPoz and Pa02 are not the same, in most circumstances the values for the two are similar, because events in the sensor and the skin counterbalance each other. The normal P O 2 of skin in term infants and adults is near zero, regardless of the Poz of the underlying tissue. In preterm infants, skin Poz is much higher, and is related to the degree of immaturity,z~ although even with extreme prematurity, skin Poz is seldom more than one third the arterial Poz. 2t Skin P02 approaches Pa02 as hyperemia is induced.46 Hyperperfusion of the skin, with vasodilation and block of local microvascular autoregulation, is therefore a prerequisite to transcutaneous oxygen monitoring.~2 Available commercial instruments use heat to achieve this. There are other consequences of heat. Subcutaneous fat is altered and becomes more permeable to oxygen, and the oxygen dissociation curve is sb~ted to the right, so that hemoglobin binding of oxygen is reduced and oxygen release into the tissue is increased,z3 These heat-related events raise tissue oxygen tension. Simultaneously, several factors lower tissue oxygen

Site not changed often enough

Sites inappropriate Failure to correct for lag time Inaccurate blood gas measurements Thick skin Scarring Edema Pressure ischemia Shock Acidemia Anemia Hypothermia Tolazoline

levels. Heat increases tissue oxygen consumption, and the electrode consumes oxygen in amounts directly proportional to electrode size and temperature and inversely proportional to membrane thickness.24 Electrode density also affects oxygen consumption. In most newborn infants and in most situations, the algebraic sum of these events is zero; they almost exactly counterbalance each other. The wary clinician must clearly understand the nature of these events and be alert to disturbances that may alter this delicate balance. A discussion of certain common events that disturb tcPoJPa02 correlation follows and is summarizedSn Table I. The sensor must be properly prepared and applied. Trapped air bubbles, retained zeroing solution (an oxygenreducing material used in calibration), and inappropriate choice of membrane material, well-known potential problems, are often overlooked in busy units. Calibration errors, especially the failure to appropriately adjust the high P02 reading for barometric pressure and humidity, as well as damage to the electrode surface by inappropriate cleaning, are also common. Kinked or cracked cables are seldom overlooked. More often, an insecure seal of sensor to skin may result in wide, erratic deflections. Most of these problems may be confounded by lack of gentleness in sensor application. Even with proper preparation, failure to change application sites often enough may result in poor

Volume 103 Number 6

Transcutaneous monitoring

torr L

1l/rain, 75

r

t 0

~'x

t ePO2/PaO2

%

.

Initial Value

"~

50

30

""~I

..... @--* tcP02

~

0--0 CARDIACOUTPUT " ~ , I I 150

• si~ 300

I 450

I 600

C o --I C'13 - 0 "-I

SUBCU[ 20 TISSUEPO2 (torr)

25

0~o~40

/ ;'01

839

I0

-I

ml

HEMORRHAGE VOLUME

Fig. 1. Mean tcPo2 and cardiac output vs volume of blood loss. (Redrawn from Tremper KK, Waxman K, Shoemaker WC: Crit Care Med 7"526, 1979.)

correlation. How long the sensor should remain in place is not certain, but most data suggest four hours, although change may be necessary every hour if the skin is very fragile or perfusion is compromised.

Appropriate comparisons between transcutaneous and arterial values must be made. Dramatic differences may be found if preductal and postductal values are compared in a baby with a significant right-to-left duetus shunt. Even if appropriate sites are used, wide and rapid fluctuations in Poz may occur from moment to moment. Changes are first evident in the arterial blood and then in the tissues. Although this delay is brief, it may be augmented by skin character or thickness and altered tissue perfusion, as well as by instrument factors including membrane thickness, electrode size, direction and extent of P02 change, and sensor temperature. 25,26 This delay amounts to only a few seconds in most cases, but certain combinations of these factors may lead to lag times of up to 100 seconds, which must be recognized. Finally, if tcP02 and Pa02 are discrepant, it is not always the transcutaneous value that is in error. If inconsistent quality control procedures are common (as when P02 measurements are made by inexperienced house officers or nurses) or if the capillary P02 is incorrectly assumed to represent arterial P02, it is likely that the tcPoz value is the correct one.27,28

The transcutaneous measurement system (sensor membrane and skin) must be permeable to oxygen. Variations in skin thickness or character related to gestational age, birth weight, weight for gestational age, postnatal age, skin edema, and scarring may alter permeability to 05 and thereby affect the correlation of tcPo2 with PAD2.2~ Less well recognized is that wide variations in skin thickness may require adjustments in sensor membrane thickness or permeability. If such changes are required, in vivo calibration of tcPo2 with appropriately comparable PaD2 values may be advantageous.

0

I 0

I o I0 20 30 40 % BLOOD LOSS

0

Fig. 2. Changes in mean tcPoJPa02 (0) and subcutaneous tissue P02 (e) during graded, acute hemorrhage. (Drawn from data in Matsen FA, Wyss CR, King RV, Simmons CW: Pediatrics 65:881, 1980.)

Local hyperemia, to almost the physiologic maximum, is essential. As this is a basic requirement if tcPo/ measurements are to be comparable to Paoz values, it is not surprising that there is a direct relationship between sensor heat and tcPo> 26,3~ Although this obviously varies depending on electrode type and size as well as Pao~, operating temperatures of 43.5 ~ to 45 ~ C are required with commercially available instruments. Use of lower temperatures will consistently alter the correlation.

Several clinical factors prevent development of sufficient local hyperperfusion despite adequate electrode heat. One common problem is pressure ischemia when the sensor is placed over a site where its weight,22the weight of the infant, or the method of attachment blanches the skin underneath. Compromised or altered blood flow and changes in regional distribution are also important. Severe hypothermia, marked acidemia (pHa <7.10), serious anemia (hematocrit <30%), and shock may all impair skin perfusion and thereby alter tcPo2/Pa02. 32-34 Data that relate cardiac output, blood pressure, and local perfusion to tcPo2 (and its relation to Pa02) deserve careful attention. Tremper et al. 35 studied the consequences of graded hemorrhage in a canine model. As blood was removed, cardiac output declined, but arterial P02 remained stable; meanwhile tcPoz declined, slowly at first and then more rapidly (as cardiac output was reduced), to levels 25 torr or more below control values (Fig. 1). Using a similar model in rabbits, Matsen et al. 36 demonstrated dramatic changes in tcPoz/Pa02, which closely paralleled measured subcutaneous tissue PO2 as blood loss increased (Fig. 2). Similar results are recorded by Rowe and Weinberg,37 who found, using 35% volume depletion in piglets, that tcPoJPa02 not only reflected altered cardiac output but also predicted survival following resuscitation. These animal studies clearly show that once the local hyperperfusion required for transcutaneous 02 monitoring can no longer be achieved because of faltering cardiac output, toP02 ceases to reflect Paoz.

840

Cassady

The Journal of Pediatrics December 1983

6211sec 487 3057secl ~79

N

NUMBER

DURATION

Fig. 3, Number and duration of apneic episodes charted by nurses using observation plus cardiorespiratory monitors compared with those recorded poiygraphically using transcutancous oxygen monitors. [ ] Nurses; 9 polygraph. (From Peabody JL,

Gregory GA, Willis MM, Philips AGS, Lucey JF: Birth Defects 15:275, 1979.)

Matching data are available from human subjects. Eickoff and Wimberly3s studied the relation between changes in mean arterial pressure and tcPo~ in five term and five preterm infants. Assuming a constant relationship between height of limb elevation and mean arterial pressure, they found a significant decline of 0.22 torr in foot tcP02 with each decrease (ram Hg) in arterial limb pressure in term infants. No such relationship was found in preterm infants. More impressive are their data from adultsfl 9,4~ as well as similar data from Gbthgen and Jacobson; 4t these studies showed a direct relation between changes in mean arterial pressure and tcPo2. The imaginative, meticulous studies of Peabody et al. 29 provide persuasive evidence for a direct relationship between arterial blood pressure and tcP02 in neonates. They reasoned that the cooling effect of blood at ~ 37 ~ C flowing under a sensor at 44 ~ C would be reduced by diminished flow and that these changes should be reflected by reduced energy required to maintain a stable sensor temperature. Recognizing the crucial role that thermal changes in the environment contribute as well, they carefully insulated the sensors. The results show a clear linear relation between changes in incremental heating power and blood pressure. They also showed that, with added compromise to perfusion (by tolazaline), local vasoconstriction may override the vasodilation induced by heat. Selective overview of clinical applications. Although transcutaneous oxygen monit9ring has been possible for nearly a decade, commercial~available equipment has allowed clinical application in the United States for about only five or six years. During that time, most users have

praised the technique while demonstrating its usefulness in the management of a variety of neonatal disorders. Serendipitous, new information about several disease states has also been a product of its use. With few exceptions, these reports are anecdotal, descriptive, and biased, and prospective, randomized, controlled trials are necessary to test the apparently obvious but surprisingly unproved benefits. We must keep in mind the difference between opinions of scientists (apparently logical hypotheses, speculatively applied to diagnosis and care before they are proved to be correct) and scientific opinion (the collected fund of scientifically proved hypotheses, which should form the foundation for sound patient care). Because it appears that tcPoz values provide estimates of oxygenation that are quicker, probably safer to acquire, and comparable to those obtained from blood samples, clinical attention has focused primarily on the use of this technique in the management of compromised ventilation in the newborn. Most of us are convinced that the tcP02 monitor provides more prompt and precise estimates of oxygen needs and allows the choice of safer and more effective ventilator settings than do conventional methods. We are also convinced that duration and complications of assisted ventilation are reduced. These clinical judgments imply that pulmonary, neurodevelopmental, and other complications of treatment are consequently reduced. Clinical bias is strong that use of transcutaneous oxygen monitors is indispensible in current care for infants with respiratory disorders. Studies that demonstrate improved survival, diminished air leak episodes, reduced duration of artificial ventilation, less chronic pulmonary disease, and better neurodevelopmental outcome in survivors are needed before we become too certain about the extraordinary value of this technique. This evidence is necessary because we have so often been wrong. 42 As a start, "undesirable time" has been defined as the cumulative proportion of time a baby is hypoxic or hyperoxic(~ Noting that more than three fourths of these episodes were iatrogenic, Long et al. .3 showed a sevenfold reduction in undesirable time when transcutaneous oxygen data were made available to caretakers. By showing the potential harm of such common interventions as chest physiotherapy, tracheal suctioning, 43,44 excessive noise, 45 percutaneous blood samplingfl7 exchange transfusion, 46 and feeding,47.4s these authors have made us more aware of how exquisitely sensitive these patients are and of how important gentleness is. Such common events as position change, diapering, and interrupting sleep states may also affect toP0249. By reduction in the number of potentially harmful interventions, which may add up to hundreds or thousands daily in many busy units, we may also reduce

Volume 103 Number 6

the personnel time as well as the number of laboratory tests, radiographs, and other procedures, and thereby cut the costs of care? ~ Proof of these benefits, an essential prerequisite to clinical acceptance, is not yet available. Transcutaneous monitors also hold great promise in the detection and management of apnea. Conventional methods couple careful observation with continuous heart rate monitors and impedence pneumography, but they fail to detect more than half of the apnea-related episodes of hypoxemia5~ (Fig. 3). Disorganized breathing, during which intermittent but ineffective gasps occur during a prolonged apnea-hypoxemia spell, may not be detected by impedence monitors if bradycardia is delayed. Obstructive apnea, in which chest excursion continues but air flow ceases, is another common and important example. The duration of apnea, presence of bradycardia, and cummulative severity of hypoxemia are not as directly related as was once supposed? ~As a research tool, therefore, the transcutaneous monitor has opened a new window, through which our view of apnea has markedly changed. But does the tcPo2 monitor used on babies at risk for or with demonstrated apnea reduce the total amount of hypoxemia these babies experience? Does it reduce the long-term impact, such as upper motor neuron damage, a known consequence of hypoxemia? Or does it diminish the risks of hyperoxemia consequent to prolonged and aggressive resuscitation? Preliminary data 52 suggest that retrolental fibroplasia is less frequent in babies at risk in whom tcPo2 monitors were used (four of 55, or 7%) compared with those monitored by conventional methods (12 of 46, or 26%). We must know more, however, before we accept the technique as standard and necessary in the management of neonatal apnea. There is an important potential role for transcutaneous oxygen measurement in the clinical assessment of cardiovascular disturbances. Transcutaneous measurements at two sites permit the detection of right-to-left ductal shunts in infants with disturbed transitional circulation. Presence of such shunts is confirmed by tcPo2 differences >10 torr between preductal and postductal sites; both changes in magnitude as well as responses to intervention may be estimated accurately. Whether this improves outcome awaits a carefully designed trial. Early detection of cyanotic congenital cardiac disease is also possible?3' ~4 Changes in tcPo2 during a three-minute inhalation of t00% oxygen show that clear differences exist among normal babies, those with primary respiratory disorders, and those with cardiac malformation (Fig. 4). Whether survival is better, diagnosis quicker, management better, care less expensive, or morbidity reduced is uncertain. Changes in heating power and tcPoz/Pao2 potentially provide noninvasive measures of tissue perfusion. Clinical

Transcutaneous monitoring

84 1

tcPoIT~r 2 5 0 -

200 -

80.e *- 30.7 Tort

healthy neonates n=50 150"

100. 31.2 4- 23 Torr

I

neonateswith respiratory problems n .11 8.2 -+ 11.1 Totr

I 9

i

o,o.~ I

neonateswith cyanotic heart diseases n =10 lOin.

AtcPo 2 (l"l-2ndmin.) time betwenn start of 02-administration and increase of t c P 0 2

Fig. 4. Changes in tcPo2 early in the hyperoxia test in healthy and sick newborns. (From Schachinger H, Schneider H, Huch R, Huch A: Birth Defects 15:495, 1979.)

examples in humans are limited but quite promising. Although Peabody et al. 29 have shown a direct relation between incremental heating power and mean arterial blood pressure in the 15 infants they studied, proper sensor insulation was necessary to prevent the distracting influences of thermal events in the environment. Unfortunately, appropriate sensor insulation is not yet commercially available, and as we have no confirming data, we do not know whether heating power measurements are clinically useful. Buntain et al. 3a have provided retrospective data to show that changes in tcPo2/Pa02 in response to fluid management in babies with necrotizing enterocolitis are related to survival. Whether prospective management of fluid therapy based on this ratio will improve outcome has not been shown. Tremper et al. 55 in studies of six preterminally ill adults, suggested that tcPo2/Paoz was useful as an index of tissue oxygen delivery in assessing response to resuscitative maneuvers. To summarize, available transcutaneous instruments provide accurate and immediate indexes of arterial oxygen tension. Benefits are promising, but supporting evidence

842

Cassady

The Journal o f Pediatrics December ! 983

Table II. Selected data re t c P c o J P a c o 2 ~m-

Reference

59

60

61

64 66

65

63

67

Clinical details

Equipment

perature (~

28 to 44 weeks gestation, 1 to 7 kg; studied at 1 day to 15 too; mean arterial pressure 20 to 71 mm Hg (two infants hypotensive) 26 to 40 weeks gestation, 0.72 to 3.62 kg; studied at 1 to 24 days Preterm, mean 32 weeks gestation, 1.69 kg; term, mean weight 3.5 kg; studied at 1 to 28 days 31 infants (4 hypotensive)

Radiometer

44

1.37

2.3

0.98

In vitro 45 In vivo 120 63% responses

Radiometer

Radiometer

37 42 44 42

1.05 0.99 1.07 1.14

13.0 17.8 17.8 6.4

0.86 0.96 0.94 0.95

In vitro 168 In vitro 114 90% responses In vivo 60 to 90 % response unclear

Radiometer

43

l .;40

4,0

27 to 40 weeks gestation, 1 to 3.3 kg; studied at 1 to 12 days Mean 33 weeks gestation, 2 kg; studied at 1.76 days 26 to 44 weeks gestation, 0.7 to 4 kg Newborn infants

Novametrix

43

Novametrix

"heated"

Biochem

42 44

Roche

44

from properly designed randomized clinical trials is surprisingly sparse. In addition, the elements of available sensors that provide indirect measures of tissue blood flow and oxygen delivery beneath the sensor, as well as the use of discrepancies between ordinarily similar tcP02 and Pa02 values, hold even more promise, but are yet to be clinically proved. Finally, use of this new technology demands a clear understanding of the underlying principles of both the instrument and the disease state in which it is used, if clinical value is to be assured. TRANSCUTANEOUS TENSION

CARBON

DIOXIDE

Skin surface carbon dioxide tension relates in a linear manner to arterial carbon dioxide tension. The skin sensor consists of a pH-sensitive glass electrode with an adjacent silver chloride reference electrode, covered with a membrane permeable to CO2. 56 Carbon dioxide in the skin diffuses through the membrane and induces p H changes in an electrolyte solution contalneO between membrane and electrode. These changes are detected by the pH electrode and converted to appropriate Pc02 values. The tcPc02 is consistently greater than Pac02 for several reasons. First, because metabolic events in the skin produce CO2, net quantities of the gas may vary directly

tcPcoe = Slope X Paco2 + Intercept

(l.60) (7.0) Pacoz = 0~37 tcPcoz + 17.46

1.15

19.2

Pacoz = 0.5 tcPco2 + 15 Paco~ = 0.6 tcPco2 + 11 1.61

-7.l

r

Response time (sec)

--

0.79

In vitro 27 90% responses

0.76

0.62 0.80 0.95

(?) In vivo 77 (?) In vivo 115 % response unclear --

with metabolic activity. Second, circulatory disturbances that permit the gas to accumulate in the tissues are important. Third, when blood is warmed, the carbon dioxide tension is raised (the so-called anaerobic heating coefficient of blood). Fourth, measured CO2 tension is higher as electrode temperature increases and lower a s membrane temperature diminishes. Whether these thermal events within the sensor or on its surface counterbalance each other depends on the temperature chosen and the calibration techniques used. Although preliminary studies using unheated sensors were promising, 57,58 more recent work suggests a better correlation of tcPo~ with Pat02 when heated electrodes are used. Hansen and Tooley 59studied the relation of tcPc02 to Pac02 in 17 sick infants using a prototype tcP02 electrode calibrated in a specific manner and heated to 44 ~ C. Their data suggest that skin CO2 production is negligible in the sick infant (the mean intercept value o f 2.3 was not significantly different from zero). The mean tcPco2/Pac02 difference in their studies was 1.37 (that is, P a c o : = t c P c o J s l o p e of 1.37), exactly that predicted by the anaerobic heating coefficient. 23 Data from other authors (Table II) consistently show intercept values that vary greatly from zero. A wide variation in slope values has also been found. Herrell et

Volume 103 Number 6

Transcutaneous monitoring

,oo_

[

I

843

o

"-~80-

-8

o

~D

T,

-6

(~6o2 ,o-

"-

E_20-

.......t /

cRo,c OOT,.UT-'?''-..2

0 .....

0

I

I

300

600

I

I

...............

9"_ ~',--CARDIACOUTPUT -2

I

I

I

i

soo 1200 0 300 600 900 HEMORRHAGE VOLUME (ml) REINFUSION VOLUME (rnl)

"-

0

1200

Fig. 5. Relation of tcPco2 and Paco2 to cardiac output during active graded hemorrhage (left) and during recovery following graded reinfusion of blood (right) in dogs. Mean values and 1 SD are shown. (Redrawn from Tremper KK, Mentelos RA, Shoemaker WC: Crit Care Med 8:608, 1980.)

al., 6~using the same equipment as Hansen and Tooley at the same electrode temperature, found a mean intercept of 17.8. Others, using the same or different equipment at temperature ranging from 42 ~ to 44 ~ C, reported intercepts ranging from about +20 to "20. Major discrepancies in equipment performance and electrode calibration may be responsible for these differences,59,6~ as may variations in electrode temperature. 6~ As in the oxygen studies, regression relationships have been calculated using multiple samples from individual patients in all studies. ~9 Response times are clearly temperature sensitive. Response is 150% slower at 37 ~ C than at 42 ~ C using Radiometer equipment,6~ and more than 400% slower at 37 ~ C than at 44 ~ C with Novametrix equipment.62 Electrode temperature also determines the extent to which heat-induced local vasodilation overrides vasoconstrictive autoregulatory changes in the skin microcirculation. Although physiologic reasoning predicts that low flow states may also lead to restricted removal of tissue CO2, the precise point at which local vasoconstriction induced by shock overcomes the local vasodilation and blunted autoregulation produced by heat is uncertain. Tremper et al. 6z produced graded hemorrhage in dogs and examined the tcPcoJPac02 as cardiac output declined. The Pac02 remained stable throughout the experiments, but as cardiac output diminished below 50% of the control value, a striking increase in tcPc02 was observed (Fig. 5, left). Graded reinfusion of shed blood resulted in changes that mirrored these findings (Fig. 5, right). Their studies clearly indicate that tissue CO2, and consequently tcPc02, are affected by major changes in blood flow and suggest that the extent of impaired tissue perfusion as well as response to therapy may be monitored by changes in tcPco2/Paco2. Limited clinical data in ill human infants are available. Shock was said not to affect the relation of tcPco2/Paco2

in the series of Hansen and Tooley,59 but only two of their 17 infants were clearly hypotensive. On the other hand, the four infants in shock studied by Peabody and Emery64 had much higher tcPc02 values relative to Pac02, a finding confirmed by Cabal et al. 58 and by Kashyap et al.65 Profound anemia may also alter tcPcoJPac02. While Merritt et al.66 could find no such effect, the lowest hematocrit in their patients was 33%. Data concerning the clinical application of transcutaneous COs monitoring in ill newborns are limited and preliminary, but certain facts seem well established. The Pac02 is linearly reflected by tcPc02 using commercially available instruments. The tcPcoz electrode has a slower response time than its oxygen counterpart. In most instances, response times are quicker at warmer electrode temperatures. As drift is usually negligible, the technique may be used in ordinary clinical settings. The tcPc02/ Pafoz does not appear to be affected by variations in Pac02 within the range seen in clinical medicine. The relationship is altered by variations in electrode temperature, calibration techniques, and design. Well-designed animal studies as well as most reports in humans also suggest a significant impact of seriously impaired perfusion on tcPc02 measurements and tcPco2/Pac02. Although all authors have agreed that skin character (indirectly estimated by gestational age, birth weight, or postnatal age) does not affect the relationship, definitive studies have yet to be performed. These observations suggest that use of tcPc02 measurements in the management of disordered or compromised ventilation in neonates or in those requiring assisted ventilation is now possible. Whether the clinical benefits are o f value is yet to be proved. Studies of the use of the tcPc02 monitor as a trend indicator of the effectiveness of spontaneous or assisted ventilation and as an instrument to more promptly and properly modify methods of respiratory support are urgently needed. The balance between cost and

844

Cassady

The Journal o f Pediatrics December 1983

Table III. Selected data re tcBI/TBs Bilirubin test

Reference

74

AO bilirubinometer86

Forehead

75

White et al.87

Sternum

78

AO bilirubinometer or Gambino88

Forehead

77

Abbott Bichrornatic Forehead Analyzer (ABA-100)

76

Clinical details

Site

Dupont Automatic Clinical Analyzer (ACA-IIt)

Forehead Sternum

Japanese; birth weight (gm) >2500 2001 to 2500 1501 to 2000 1001 to 1500 <1000 Gestation (wk) White, term Black, term White, >38 34 to 37 Black, -->34 White, >38 33 to 38 <33 Black, >38 33 to 38 <33 White, term

benefits must also be examined carefully. Finally, the use of altered tcPco2/Pac02 to evaluate the presence, extent, and response to management of serious disorders of perfusion needs careful, prospective clinical evaluation. TRANSCUTANEOUS

BILIRUBIN

ESTIMATES Visible detection of jaundice is usually followed by laboratory measurement of bilirubin level. Need for therapy is then based on unconjugated bilirubin values. Although seemingly straightforward, management of jaundice in the neonate is seldom this simple. First, several variables affect visual estimates of jaundice. Clinical experience of the observer, intensity and spectral characteristics of environmental light, and skin color or race of the baby may alter the bilirubin level at which jaundice is detected. Plethora may mask or anemia accentuate jaundice. The match between the serum bilirubin value and visible jaundice also varies with site; facial jaundice may be detected at levels of 4 to 6 mg/dl, whereas concentrations may reach 8 to 15 mg/dl before jaundice is evident in the legs or feet. 68 Second, laboratory estimates of serum bilirubin level vary remarkably, depending on the test used, how the specimen is handl6~ after collection, and how carefully quality control procedures are applied. 69,7~ At best, any single bilirubin value is only accurate to within 10%. Finally, objective estimates of bilirubin levels require blood samples. Collection of these samples is usually by

tcB1 = Slope • TBs + Intercept

1.08 1.13 1.32 1.46 1.24

7.22 11.92 11.76 11.65 16.23

0.95 0.89 0.92 0.98 0.71

--1.25 1.30 0.97

7.0 15.0 9.63 7.57 13.49 7.8 10.2 12.5 14.0 14.9 6.6 7.96 7.44

0.90 0.92 0.90 0.88 0.71 0.71 0.52 0.32 0.52 0.57 0.91 0.93 0.93

1.00

0.76 0.45 0.53 0.53 1.70 1.33 1.35

heel stick or venipuncture, and complications of these invasive procedures, although uncommon, are related to how often and how carefully the samples are obtained. For these and other reasons, there has been a continuing search for safer and simpler methods for estimating neonatal bilirubin levels. Attempts to better quantify visual estimates with so-called icterometers have not gained wide acceptance because of problems with interobserver variation.7~ Spectral reflectance methods have more recently received considerable attention, following the observations by Ballowitz and Avery72 in 1970. Now, a decade later, instrumentation that permits clinical application of a reflectometric technique is commercially available. The instrumefi( is hand held, battery operated, weighs about 9 oz, costs more per ounce than gold,73 and is deceptively simple to use. Strobe light, generated by a xenon tube, is flashed through a fiberoptic bundle and through the underlying, blanched skin into the subcutaneous tissue. The scattered light returns through a second fiberoptic bundle, is filtered at 460 and 550 m#, and enters a gpectrophotometric module, where the intensity of yellowness, corrected for hemoglobin and translated into arbitrary units, is displayed. The number is not the same as the total serum bilirubin value, but is an index of that level. The relation between this transcutaneous bilirubin index number and the total serum bilirubin, and those factors that affect this relationship, have been studied by several investigators.

Volume 103 Number 6

Transcutaneous monitoring

g45

Table IV. Accuracy of transcutaneous bilirubin index as device to separate infants with total serum bilirubin levels 13 m g / d l or more from those with levels <13 m g / d l

Reference

Clinicaldetails

74 75 78 77 77 76

Japanese, term White, term White, term White, term Black, term White, term

75 71 96 43 95 104 157

Action line* 19 23 24 20 19 24

Specificity~" 25/39 47/71 37/42 67/89 53/101 145/150

= = = = = =

64% 66% 88% 75% 52% 97%

Sensitivity~ 31/32 25/25 1/1 5/6 3/3 7/7

= = -= = =

97% 100% 100% 83% 100% 100%

t

Prediitive value Positivew Negativel[

31/45 25/49 1/6 5/27 3/51 7/12

= = = = = =

67% 51% 17% 19% 6% 58%

25/26 47/47 37/37 67/68 53/53 145/145

= = = = = =

96% 100% 100% 99% 100% 100%

*lcBl at or above which TBs 13 mg/dl or more and below which TBs <13 mg/di. tProportion of instances in which teBI below action line correctly predicts TBs <13 mg/dl. ~Proportion of instances in which tcBl at or above action line correctly predicts TBs 13 mg/dl or more. w of instances in wbich TBs 13 mg/dl or more is correctly predicted by tcBl at or above action line. IIProportion of instances in which TBs <13 mg/dl is correctly predicted by tcBI below action line.

Several facts seem well established. First, measurement of tcBI is quick, easy and reproducible. Coefficients of variation are less than 5% (half that of the best-controlled laboratory bilirubin assays). Although equivocal data suggest reduced reproducibility at higher bilirubin levels, 74,75 the most convincing evidence suggests there is no relation between the coefficient of variation and the serum bilirubin values. 76 Second, it seems clear that tcBI is related in a linear manner to the total serum bilirubin value, but variations in this relationship are common, often with wide differences in slopes and intercepts (Table III). Skin color and character (related to race, 75,77.78 gestational age and birth weight, 74'vT,v8 weight for dates, 79 and site of measurement 74-76) are responsible for these variations, as are therapeutic maneuvers (phototherapy and exchange transfusion) that change tissue or serum bilirubin concentrations.V4.75.78 The effect of phototherapy is prompt, with the tcBI decreasing 14% and 21% within one and two hours of treatment, respectively, d~ The more confounding variables that are present, the poorer the correlation and more discrepant the slopes and intercepts. It seems clear that tcBI is consistently higher than TBs and that it is even higher (larger intercept values) in black than in white babies. Site of measurement also affects tcBi/TBs.74.75 T h e precise nature of the effect of several other variables on this relationship is less certain. Significant intercept differences have been found in more premature, low-birth-weight babies, but the extent and direction of these differences is inconstant. Because the t c B I / T B s is currently uncertain in preterm babies, immediate application to their care is seriously limited. We must also know more about the effects of nursery illumination levels, concurrent therapy, differences between instruments, infant manipulations during measurement, s~ and postnatal age. W e also need to know whether opaque skin patches

protect a window, through which tcBI may be measured in infants who receive phototherapy. 8~ Perhaps most important, it is essential to recognize the scarcity of data relating tcBI to TBs exceeding 13 m g / d l . These observations suggest that clinical use of this technique requires caution and skepticism. 78,83 Advice that the relation of tcBI to TBs should be assessed for each instrument in each institution for each population by each investigator 77,83,84 should not be disregarded. With these reservations clearly in mind, initial objective analyses look promising. 76 Specificity, sensitivity, and predictive value are provided in Table IV, based on available scatterplot data. As suggested by the manufacturer, ~4 an action line has been arbitrarily selected that identifies babies with a TBs of 13 m g / d l or more (about 5% of all infants). Data are from reports that provide a sufficient number of points to allow the value of the test to be assessed with reasonable accuracy. A tcBI of 24 or more for forehead measurements and 23 or more for sternal measurements from white term infants has been arbitrarily chosen on the basis of examination of the plots from H a n n e m a n et at., TM Maisels and Conrad, 76 and Hegyi e t al. 75 A tcBI of 20 or more seems a better choice for the forehead measurements for white term infants, provided by Goldman et al., 77 and of 19 or more for the data of Yamanouchi et al. TM and Goldman et al., 77 based on Japanese and black infants, respectively. Sensitivity seems very good; in five of the six series, a tcBI at or above the action line correctly predicted TBs of 13 m g / d l or more in 97% to 100% of instances. Specificity seems less good; in five of the six series, tcBI below the action line correctly predicted TBs <13 m g / d l only 52% to 88% of the time. Calculated predictive values suggest a powerful negative predictive value; TBs <13 m g / d l was correctly predicted by tcBI below the action line in 96% to 100% in all six series. Predictive values, however, vary with the incidence of the condition sought, .5 in this case,

846

Cassady

excessive j a u n d i c e with TBs of 13 m g / d l or more. As most series contain very few data from infants with high bilirubin levels who are not receiving phototherapy, positive predictive ability is presently uncertain. These data support the conclusion t h a t the t r a n s c u t a n e ous bilirubin index m a y be a valuable tool to help distinguish t e r m babies with a total serum bilirubin value < 13 m g / d l from those with higher levels. As a screening test, the tcBI shows great promise as long as user knowledge keeps pace with new information concerning factors t h a t alter t c B I / T B s . On the other hand, replacement of serum bilirubin determinations by the tcBI technique in more j a u n d i c e d infants, particularly in populations of infants with variations in skin c h a r a c t e r or in w h o m serum-tissue bilirubin distribution m a y be altered, is m u c h less certain and has a real potential for mischief. In these infants, meticulous assessments of t c B I / T B s as well as specificity, sensitivity, a n d predictive values of the new technique are absolute requirements before the test can be routinely used in clinical settings.

REFERENCES 1. Abernathy J, editor: Surgical and physiological essays. II. London, 1793, p 107. 2. Gerlach JV: 1]ber das Hautathmen. Arch Anat Physiol Lpz Wissenschaft Med 431, 185 I. 3. Baumberger JP, Goodfriend RB: Determination of arterial oxygen tension Jn man by equilibration through intact skin. Fed Proc 10:10, 1951. 4. Evans NTS, Naylor PFD: Steady states of oxygen tension in human dermis. Respir Physiol 2:46, 1966. 5. Evans NTS, Naylor PFD: The systemic oxygen supply to the surface of the human skin. Respir Physiol 3:21, 1967. 6. Evans NTS, Naylor PFD: The oxygen gradient across human epidermis. Respir Physiol 3:38, 1967. 7. Clark LC: Monitor and control of blood and tissue oxygen tension. Trans Am Soc Artif Intern Organs 2:41, 1956. 8. Liibbers DW: Methods of measuring oxygen tensions of blood and oxygen surfaces. In Payne JP, Hill DW, editors: Oxygen measurements in blood and tissue. London, 1966, J & A Churchill, p 103~ 9. Huch A, Huch R, Liibbers DW: Quantitative polarographische Sauerstoffdruckmessung auf der Kopfhaut des Neugeborenen. Arch Gynakol 207:443, 1969. 10. Huch A, Huch R, Arner B, Rooth G: Continuous transcutaneous oxygen tension measured with a heated electrode. Scand J Clin Lab Invest 31:269, 1973. 11. Huch R, Huch A, Liibbers DW: Transcutaneous measurement of P O 2 (tcPo2): Method and application in perinatal medicine. J Perinat Med 1:183, 1973. 12. Friederichsen GH, Kopotic R ~ .Mannino FL: Transcutaneous oxygen (tcPo2) monitoring in the 80's. J Calif Perinat Assoc 2:41, 1982. 13. Huch A, Huch R: Transcutaneous, noninvasive monitoring of Poz. Hosp Pratt 11:43, 1976.

The Journal of Pediatrics December 1983

14. Huch A, Huch R, Lucey JF, editors: Continuous transeutaneous blood gas monitoring. Birth Defects 15:1, 1979. 15. Huch R, Huch A, Liibbers DW: Transcutaneous Po~. New York, 1981, Thieme-Stratton, p 170. 16. Lucey JF: Transcutaneous diagnosis in the high-risk neonate. Hosp Pract 16:108, 1981. 17. Lucey JF: Clinical uses of transcutaneous oxygen monitoring. Adv Pediatr 28:27, 1981. 18. Duc G, Frei H, Klar H, Tuchschmid P: Reliability of continuous transcutaneous Po2 (Hellige) in respiratory distress syndrome of the newborn. Birth Defects 15:305, 1979. 19. Weller SC: Statistical problems in the analysis of blood gas data. Working papers in Social Science, No. 2. Irvine, Calif., 1983, University of California. 20. Versmold HT, Tooley WH, Severinghaus JW: Increase of skin 02 diffusion resistance with birthweight. Birth Defects 15:271, 1979. 2t. Versmold HT, Holzmann M, Linderkamp O, Riegel KP: Skin oxygen permeability in premature infants. Pediatrics 62:488, 1978. 22. Liibbers DW: Cutaneous and transeutaneous Po2 and Pco2 and their measuring conditions. Birth Defects 15:13, 1979. 23. Bradley AF, Stupfel M, Severinghaus JW: Effect of temperature on Pco2 and Po2 of blood in vitro. J Appl Physiol 9:201, 1956. 24. Severinghaus JW, Tbunstrorn A: Problems of calibration and stabilization of tcPo2 electrodes. Acta Anaesthesiol Scand [Suppl] 68:68, 1978. 25. Abu-Osba YK, Thach BT, Brouillette RT: Evaluation of response time of a transcutaneous oxygen tension electrode. Pediatr Res 15:143, 1981. 26. LCfgren O, Jacobson L: The influence of different electrode temperatures on the recorded transcutaneous Po2 level, Pediatrics 64:892, 1979. 27. Graham G, Kenny MA: Changes in transcutaneous oxygen tension during capillary blood-gas sampling. Clin Chem 26:1860, 1980. 28. Hochberg HM: An introduction to methods for blood gas and pH monitoring. In Lauersen NH, Hochberg HM, editor: Clinical perinatal biochemical monitoring. Baltimore, 1981, William & Wilkins, p 3. 29. Peabody JL, Willis MM, Gregory GA, Severinghaus JW: Reliability of skin (tc)Po2 electrode heating power as a continuous noninvasive monitor of mean arterial pressure in sick newborns. Birth Defects 15:127, 1979. 30. Al-Siaidy W, Hill DW: The importance of an elevated skin temperature in transcutaneous oxygen tension measurement. Birth Defects 15:149, 1979. 31. Eickhoff JH, Jacobsen E: Correlation of transcutaneous oxygen tension to blood flow in heated skin. Scand J Clin Lab Invest 40:761, 1980. 32. Versmold HT, Linderkamp O, Holzmann M, Strohhacker I, Riegel K: Transcutaneous monitoring of Po2 in newborn infants: Where are the limits? Influence of blood pressure, blood volume, blood flow, viscosity, and acid-base state. Birth Defects 15:285, 1979. 33. Peabody JL, Willis MM, Gregory GA, Tooley WH, Lucey JF: Clinical limitations and advantages of transcutaneous oxygen electrodes. Acta Anaesthesiol Scand [Suppl] 68:76, 1978. 34. Buntain WL, Conner E, Emrico J, Cassady G: Transcutane-

Volume 103 Number 6

35.

36.

37. 38.

39. 40.

41.

42. 43. 44.

45. 46.

47.

48.

49.

50. 51.

52.

53.

54.

ous oxygen (tcPo~) measurements as an aid to fluid therapy in necrotizing entercolitis. J Pediatr Surg 14:728, 1979. Tremper KK, Waxman K, Shoemaker WC: Effects of hypoxia and shock on transcutaneous Po2 values in dogs. Crit Care Med 7:526, 1979. Matsen FA, Wyss CR, King RV, Simmons CW: Effect of acute hemorrhage on transcutaneous, subcutaneous, intramuscular and arterial oxygen tension. Pediatrics 65:881, 1980. Rowe MI, Weinberg G: Transcutaneous oxygen monitoring in shock and resuscitation. J Pediatr Surg 14:773, 1979. Eickhoff JH, Wimberly PD: The influence of changes in arterial blood pressure on transcutaneous oxygen tension (tcPo2) in the newborn. Acta Paediatr Scand 71:365, 1982. Eickhoff J, Ishihara S, Jacobsen E: Pao2 by skin electrode. Lancet 2:1188, 1979. Eickhoff JH, Ishihara S, Jacobsen E: Effect of arterial and venous pressures on transcutaneous oxygen tension. Stand J Clin Lab Invest 40:755, 1980. G6thgen I, Jacobsen E: Transcutaneous oxygen tension measurement. II. The influence of halothane and hypotension. Acta Anaesthesiol Scand [Suppl] 67:71, 1978. Silverman WA: Russian roulette in the nursery--again. Pediatrics 69:380, 1982. Long JG, Philip AGS, Lucey JF: Excessive handling as a cause of hypoxemia. Pediatrics 65:203, 1980. Raval D, Yeh TF, Mora A, Pildes RS: Changes in transcutaneous Po2 during tracheobronchial hygiene in neonates. Perinatol Neonatol 4:41, 1980. Long JG, Lucey JF, Philip AGS: Noise and hypoxemia in the intensive care nursery. Pediatrics 65:143, 1980. Monin P, Vert P, Andre M, Vibert M : Transcutaneous Po2 monitoring (tcPo2) in the newborn during apneic spells, convulsions, cardiac catheterizations and exchange transfusions. Birth Defects 15:469, 1979. B6defeld E, Schachinger H, Huch A, Huch R, Lucey JF: Continuous tcPo2 monitoring in healthy and sick newborn infants during and after feeding. Birth Defects 15:503, 1979. Burroughs AK, Asonye UO, Anderson-Shanklin GC, Vidyasagar D: The effect of nonnutritive sucking on transcutaneous oxygen tension in noncrying, preterm neonates. Res Nurs Health 1:69, 1978. Long JG, Philip AGS, Lucey JF: A comparison of transcutaneous oxygen (tcPo2) monitoring and conventional techniques for detecting hypoxemia and hyperoxemia. Birth Defects 15:347, 1979. Lucey JF, Dehner LR: TcPo: monitoring reduces costs for blood gas monitoring (abst). Pediatr Res 14:604, 1980. Peabody JL, Gregory GA, Willis MM, Philips AGS, Lucey JF: Failure of conventional monitoring to detect apnea resulting in hypoxemia. Birth Defects 15:275, 1979. Yamanouchi I, Igarashi I, Ouchi E: Incidence and severity of retinopathy of prematurity in low-birth-weight infants monitored by continuous transcutaneous oxygen monitoring. Retinopathy of Prematurity Conference syllabus, vol 2. Columbus, Ohio, 1981, Ross Laboratories, p 505. Schachinger H, Schneider H, Huch R, Huch A: Interpretation of tcPo2 recordings for quick evaluation of postpartum adaptation. Birth Defects 15:495, 1979. Tateishi K, Yamanouchi I: Noninvasive transeutaneous oxy-

Transcutaneous monitoring

55.

56.

57.

58.

59. 60.

61.

62.

63.

64.

65.

66.

67.

68.

69. 70.

71. 72. 73.

847

gen pressure diagnosis of reversed ductal shunts in cyanotic heart disease. Pediatrics 66:22, 1980. Tremper KK, Waxman K, Bowman R, Shoemaker WC: Continuous transcutaneous oxygen monitoring during respiratory failure, cardiac decompensation, cardiac arrest and CPR: Transcutaneous oxygen monitoring during arrest and CPR. Crit Care Med 8:377, 1980. Severinghaus JW, Stafford M, Bradley AF: TcPco2 electrode design, calibration and temperature gradient problems. Acta Anaesthesiol Scand [Suppl] 68:118, 1978. Cabal L, Cruz E, Siassi B, Waffarn F, Hodgeman JE: Skin surface P c o J P o : in preterm infants with RDS without cardiovascular compromise (abst). Clin Res 28:121A, 1980. Cabal L, Siassi B, Cruz H, Yeh S, Hodgeman JE: Dual functions of transcutaneous O2/CO2 in neonates with and without shock (abst). Pediatr Res 14:593, 1980. Hansen TN, Tooley WH: Skin surface carbon dioxide tension in sick infants. Pediatrics 64:942, 1979. Herrell N; Martin R J, Pultusker M, Lough M, Fanaroff A: Optimal temperature for the measurement of transcutaneous carbon dioxide tension in the neonate. J PEDIATR 97:114, 1980. Martin R J, Herrell N, Pultusker M: Transcutaneous measurement of carbon dioxide tension: Effect of sleep state in term infants. Pediatrics 67:622, 1981. Tremper KK, Mentelos RA, Shoemaker WC: Effect of hypercarbia and shock on transcutaneous carbon dioxide at different electrode temperature. Crit Care Med 8:608, 1980. Sun S, Aranda Z, Ruiz N, Baldomero A, Castillo M: Transeutaneous Pco~ (tcPco~) monitoring in neonates (abst). Pediatr Res 16:311A, 1982. Peabody JL, Emery JR: Does shock affect the transcut~neous-arterial Pco2 gradient (abst). Pediatr Res 16:302A, 1982. Kashyap S, Stefanski M, Schulze K, James LS: Effects of changes in circulation on transcutaneous Pco2 (tc Pco2) (abst). Pediatr Res 15:666, 1981. Merritt TA, Liyamasawad S, Boettrich C, Brooks JG: Skinsurface COl measurements in sick preterm and term infants. J PEDIATR 99:782, 1981. Willard D, Eberhard P, Messer J, Erny P: Continuous noninvasive measurement of blood carbon dioxide pressure (Pco2). In Lauersen NH, Hochberg HM: Clinical perinatal biochemical monitoring. Baltimore, 1981, Williams & Wilkins, p 249. Ebbesen F: The relationship between the cephalo-pedal progress of clinical icterus and the serum bilirubin concentration in newborn infants without blood type sensitization. Acta Obstet Gynecol Scand 54:329, 1975. Schreiner RL, Glick MR: Interlaboratory bilirubin variability. Pediatrics 69:277, 1982. Shennan AT, Cherian AG, Angel A, Bryan MH: The effect of intralipid on the estimation of serum bilirubin in the newborn infant. J PEDIATR 88:285, 1976. Gossett IH: A perspex icterometer for neonates. Lancet 1:87, 1960. Ballowitz L, Avery ME: Spectral reflectance of the skin. Biol Neonate 15:348, 1970. Engel RR: Nuances of nuisances for cutaneous bilirubinometry? Pediatrics 69:126, 1982.

8 48

Cassady

The Journal of Pediatrics December 1983

74. Yamanouchi 1, Yamauchi Y, Igarashi I: Transcutaneous bilirubinometry: Preliminary studies of non-invasive transcuraucous bilirnbin meter in the Okayama National Hospital. Pediatrics 65:195, 1980. 75. Hegyi T, Hiatt IM, Indyk L: Transcntaneous bilirubinometry. I. Correlations in term infants. J PED1ATR 98:454, 1981. 76. Maisels M J, Conrad S: Transcutaneous bilirubin measurements in full-term infants. Pediatrics 70:464, 1982. 77. Goldman SL, Pefialver A, and pefiaranda R: Jaundice meter: Evaluation of new guidelines. J PEDIATR101:253, 1982. 78. Hanneman RE, Schreiner RL, DeWitt DP, Norris SA, Glick MR: Evaluation of the Minolta bilirubin meter as a screening device in white and black infants. Pediatrics 69:107, 1982. 79. Wu PYK, Edwards NB, Chan L, Lee G, Wareham C: Transcutaneous bilirubinometry and factors affecting the transcutaneous bilirubin index (abst). Pediatr Res 16:315A, 1982. 80. Cifuentes RF, Nelson A J, Levine J, Engel RR: Cutaneous bilirubinometry during phototherapy (abst). Pediatr Res 16:282A, 1982.

81. Pasnick M, Lucey JF: Transcutaneous bilirubinometry can be used during phototherapy (abst). Pediatr Res 16:302A, 1982. 82. Tolentino T, Zanni R, Gertner I, Hiatt IM, Hegyi T: Transeutaneous bilirubinometry: Correlations during phototherapy (abst). Pediatr Res 16:312A, 1982. 83. Hegyi T: Transcutaneous bilirubinometry: A new light on an old subject. Pediatrics 69:I24, 1982. 84. Minolta/Air-Shietds Jaundice Meter 10I. Operators manual. Generating action levels (Appendix A). Hatboro, Pa., 1981, Narco Scientific Air-Shields Division, p 14. 85. Feinstein AR: Clinical biostatistics. St. Louis, 1977, CV Mosby, p 214. 86. Walker T, Brown MC: A direct-reading bilirubin meter for pediatric use. Clin Chem 15:802, 1969. 87. White D, Hardar GA, Reinhold JG: Spectrophotometric measurements of bilirubin concentrations in the serum of the newborn by the use of a microcapillary method. Clin Chem 4:21 I, 1958. 88. Gambino SR: Bilirubin (modified Jendrassik and Grof). Stand Meth Clin Chem 5:55, 1965.

BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the 1983 issues of TrtE JOURNAL OF PEDIATRICS are available to subscribers (only) from the Publisher, at a cost of $42.00 ($55.00 international) for Vol. 102 (January-June) and Vol. 103 (July-December), shipping charges included. Each bound volume contains subject and author indexes, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram, with the Journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C, V. Mosby Company, Circulation Department, 11830 Westline Industrial Dr., St. Louis, MD~-63146, USA/800-325-4177, ext. 351.

Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.