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Closed-loop control of the partial pressure of arterial oxygen in neonates

This article has been downloaded from IOPscience. Please scroll down to see the full text article. 1988 Clin. Phys. Physiol. Meas. 9 291 (http://iopscience.iop.org/0143-0815/9/4/001) View the table of contents for this issue, or go to the journal homepage for more

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Clin. Phys. Physiol. Meas., 1988, Vol. 9, No. 4, 291-305. Printed in Great Britain

Closed-loop control of the partial pressure of arterial oxygen in neonates

R E Dugdalef, R G Cameron+ and G T Lealmans
tDepartment of Medical Physics, and Department of Paediatrics, Bradford Royal Infirmary, Bradford, West Yorks, UK +Department of Control Engineering, University of Bradford, Bradford, West Yorks, UK Received 23 December 1987, in final form 27 April 1988

Abstract. A closed-loop control system has been developed to regulate automatically the partial pressure of arterial oxygen (P,o,) to a pre-set level in neonates with RDS (Respiratory Distress Syndrome). A microcomputer-based system is described which uses the Pao, value from an indwelling umbilical artery electrode as the input to a robust control algorithm. T h e derived control signal is used to modify the position of a motor driven oxygeniair blender, thus regulating the percentage of oxygen delivered in the inspired gas mixture. T h e parameters of the control algorithm were conservatively chosen, and the safety aspects of the system are discussed. A total of 48 h of closed-loop control were recorded on seven pre-term infants with mild-to-moderate RDS being nursed in headboxes. Ten separate closed-loop control intervals were recorded, and overall the results showed a marked improvement over comparable periods of manual control. T h e percentage of time for which the recorded Pao2 within 1 kPa of was the chosen target value (10 kPa) was 74.9 i 10.2% when averaged over the ten closed-loop control periods. T h e corresponding figure for the comparable manual control intervals was 45.2 k 16.0%.

1. Introduction
One of the principal problems associated with premature infants is the respiratory distress syndrome (RDS). h e definition of RDS is rather imprecise and estimates of the incidence of T the condition vary. Chamberlain er aZ(1975) in the British Births survey found that 20% of all infants weighing less than 2.5 kg had breathing difficulty. T h e diagnosis of RDS is made by observation and x-ray. When no other specific cause of respiratory difficulty can be identified, the infant is assumed to have RDS due to Hyaline Membrane Disease. The condition is caused by a deficiency of pulmonary surfactant, a substance normally present in the alveolar walls. Surfactant (consisting mainly of of phospholipids) lowers the surface tension in the alveoli, reducing the pressure required for their inflation, and permitting alveoli of differing diameters to coexist. A deficiency results in alveoli remaining collapsed and this in turn leads to impairment of gas exchange between the blood and lung. The object of therapy in RDS is to support the infant over the period taken for biochemical maturation to occur. Particular concerns are the maintenance within certain limits of the partial pressures of oxygen (Pao2) carbon dioxide (P,co,). This is'achieved and by nursing the infant in increased concentrations of oxygen and, where necessary, assisting respiration by the use of a ventilator. Care has to be taken to avoid prolonged periods of hypoxia and hyperoxia, both of which may prove damaging to the infant. T h e incidence of long term problems due to these conditions is difficult to assess as insults to
0143-08151881040291 + 15 $02.50 0 1988 Institute of Physical Sciences in Medicine

29 1

292

R E Dugdale et al

the pre-term infant are usually multiple. High Pao2levels have long been considered one of the causes of Retinopathy of Prematurity (ROP), which may result in partial or complete loss of vision. Yu et al (1982) reported a 2.4% incidence of retinal scarring (resulting in partial blindness) in infants weighing less than 1.5 kg at birth. Prolonged hypoxia may result in brain damage or, in the worst cases, death, but the effects are similarly difficult to quantify. It has been estimated however that 20 000 unnecessary deaths occured in England between 1951 and 1970 due to excessive restriction of oxygen administration (Bolton and Cross 1974). This was attributed to the concern about ROP at a time when there were no facilities for continuously monitoring PaoP. Continuous monitoring of Pao2. either intra-arterially or transcutaneously is now routine, having been made possible by the development of miniature polarographic electrodes (Parker and Souter 1975, Rolfe 1976, Gregory 1982). Using this technique, in conjunction with regular formal blood-gas analysis (for calibration purposes), the twin dangers of hypoxia and hyperoxia can be largely avoided. This is achieved by manually adjusting the fractional inspired oxygen concentration Fio2in response to Pao2levels outside the acceptable range. In view of the high incidence of RDS in premature infants, and of the dangers associated with hypoxia and hyperoxia, it was considered worthwhile that automation of the above process should be considered. T h e aims of this work were: (1) T o develop an algorithm suitable for implementation in a microcomputer-based closed-loop control system designed to maintain P,o, at safe and acceptable levels by adjustment of the 50,. (2) T o construct such a system and perform an evaluation of its performance in preliminary clinical trials under strictly defined and continuously supervised conditions.

2. Background A previous attempt to regulate Pao2 automatically in pre-term infants with RDS was performed at the Hammersmith Hospital in 1979 (Beddis et a1 1979, Collins et al 1979). T h e apparatus developed was a hard-wired servosystem which used the continuous Pao2 reading from an indwelling umbilical artery electrode as its input. Desired upper and lower were pre-set by means of dials on the instrument, and the measured PaO, limits for Pa02 was compared with these limits at one minute intervals using voltage comparators. If the Pao2fell within the limits, no action was taken. If the Pao2fell outside the limits the F,02 was incremented or decremented by 0.05 (5%) using a mixer valve controlled by a servoamplifier and motor. T h e apparatus was used on 12 pre-term infants with RDS, recording the Pao2and F,o, each time. Overall the Pao2was outside the limits (7.3-10.7 kPa) 12.2% of the time under servocontrol and 27.6% under manual control. More recently, an adaptive feedback control system was proposed to determine the optimal Fio2 that must be introduced into an incubator in order to maintain the Pao2within normal limits for pre. term infants with RDS (Sano and Kickuci 1985). A simple static linear model was assumed response dynamics for oxygen inspiration, and a first order differential to describe the PaoZ equation to describe oxygen diffusion in the incubator. The validity of the control scheme was examined using a mathematical model of the respiratory system of a newborn infant with RDs which was adapted from that proposed for normal adults by Grodins et a1 (1967). In addition, experiments were carried out on anaesthetised animals in various low ventilation conditions, but no clinical trials were reported. Techniques designed to assist in the management of oxygen therapy, under manual control, have been suggested for adults with respiratory problems. Benatar et a1 (1973) and

Control of Pao2 in neonates

293

Lawler and Nunn (1984) suggested a graphical method for determining the optimal Fio2 required to produce a desired P,o, under the prevailing conditions of the patient, by assuming a constant arteriovenous shunt during the therapy period. Gross and Israel (1981), sought also to achieve this aim by the use of a nomogram based on the assumption that the ratio of the partial pressure of alveolar oxygen to that of arterial oxygen remained constant over a wide range of 60, values. A closed-loop control system based on this principle was described by Kawakami et al(1981) and tested on 23 normal adults. In the case of neonates and sick children, Jones and Owen-Thomas (1971) suggested a manual therapy management technique based on an assessment of the arterial blood gas partial pressures. Theoretical plots of P,co, against Pao, were presented for twelve levels of shunt and five levels of the partial pressure of alveolar carbon dioxide (PAco2), equivalent to five levels of alveolar ventilation. Separate plots were derived for a subject breathing air and 100% oxygen. Paired measurements of P,02 and Paco2in both of these respiratory states were used to derive shunt and PAcoZvalues in each case. The shunt value in 100% oxygen was taken to be the anatomical or true shunt, and the difference between this and the greater value in air was attributed to ventilation-perfusion ( I Q )inequalities. This was PA extended to predict the 50, needed to restore the Paoz to some required value in the presence of the derived anatomical shunt. The assumptions made in the calculations associated with this type of approach contain several sources of potential error which were discussed by Gupta et al(l967) for the case of pre-term infants with RDS. They concluded that the magnitude of these errors could be so great that the results derived should be treated as an approximate guide to the correct values. In addition the administration of 100% oxygen, used in this assessment, may be deemed unwise for reasons previously stated. T h e conclusion that this type of approach is not effective in the treatment of RDS by oxygen therapy was endorsed and amplified by Corbet and Adams (1978). They noted that oxygen therapy in RDS is effective despite the presence of large true right-to-left shunts because high concentrations relieve both alveolar hypoxia and vasoconstriction in small air spaces for which the PA/Qratio is very low. As a result, the right-to-left shunt is reduced and oxygenation improved. Because of this they reasoned that the magnitude of the change in P,o, with inspired oxygen was very difficult to predict since the size of the low PA/Q compartment and its distribution, together with the regional vascular response, were variable. They concluded therefore that the use of iso-shunt curves similar to those used by Benetar et al(1973), and described above, was inappropriate since the approach.ignored this open low PA/Qratio compartment. In view of the above, no analytical technique designed to assist in the regulation of PaoZ, manual adjustment of Fioz alone, has been widely adopted for pre-term infants by with RDS. Consequently the basis for an effective conventional control algorithm does not appear to arise from standard clinical practice, experience and diligence remaining the major requirements for effective therapy. If mechanical ventilation is required to assist in the regulation of arterial blood gas pressures for pre-term infants, multiple user-variable parameters are available to optimise gas exchange. The strategies adopted in the treatment regimen are largely based on clinical studies of infants with RDS and on common practice. Efforts to assist this therapy by the use of a computer have been described (Waldemar et al 1986), however the closed-loop control of Pao2(and P,co,) using a mechanical ventilator remains a complex, and as yet unattempted, control problem for neonates with RDS. In view of this, the work presented here addresses the problem of controlling the Paozby 40, alone, and the technique was not applied in situations where the need for mechanical ventilation was indicated.

294

R E Dugdale et a1

3. The proposed control strategy

3.1. Choice of control strategy

T h e control problem to be considered is to regulate the P,02 automatically in a sick preterm infant within predetermined limits (typically 8-12 kPa) and, ideally, to attempt to maintain it close to some chosen target value (typically 10 kPa). This is to be achieved by adjusting the concentration of oxygen in the inspired gas (40~). the dynamic Clearly characteristics of the system involved (namely the sick infant) alter over a period of time, for example as the infant matures or recovers. Furthermore, differences between individuals can lead to significant differences in response dynamics. Bearing this in mind there are, broadly speaking, two different approaches to the design of a feedback controller: one possibility is to design an adaptive controller, whose characteristics change so as to follow the changes taking place in the infant in an adaptive manner; the other is to design a robust controller, where changes in the infant are tolerated without significant loss of control quality, and without changes to the controller parameters. A concise summary of the various aspects of adaptive control is given in Singh (1987). Although adaptive control has the otential for high quality control, at the time of writing several practical problems remain. strom (1987) lists these as follows: The closed loop system obtained with adaptive control is non-linear and difficult to analyse, particularly if there are random disturbances. . . .Stability proofs are only available under very restrictive assumptions. The problem of convergence rate is poorly Regulators based on adaptive understood, as are consequences of modelling errors. ... techniques are more complicated than conventional regulators. Robust control is defined precisely by Davison (1976). A controller is said to regulate a system if the closed loop controlled system is stable, and differences between the system output and the desired set point decay asymtotically for all disturbances or reference inputs associated with the system. A controller is said to be a robust controller if asymtotic regulation takes place for all process perturbations in a given set (in Davisons definition, in a hypercube in the parameter space).

3.2. The control algorithm

T h e robust approach is adopted in this work. The control algorithm used was described by Astrbm (1981), and developed by Cameron and Li (1985). It requires only two items of information related to the system to be specified, and both of these may be derived from the response of the system to a step-wise change at the input. T h e first requirement is for a measure of the steady state gain of the system and the second is for a measure of the time elapsing before 50% of the steady state gain is achieved. In the present case these measurements relate to the Pao2 response to a step-change in the position of the oxygenlair blender valve governing the Fio2. The assumption made in Astroms original work is that the system has a monotone unit step response (H(t)in figure 1). Wstrom suggested that this response should be represented by a simple model, namely a step function with gain b associated with it, and delayed by a time T (see figure 1). T h e output of such a model (say ym (t)),with input u(t), is given by: Y&) = w - T ) (1) A simple control algorithm for this system was proposed by h r o m by using a sampled dead-beat regulator with integral action. By choosing T as the sampling interval and letting y k = y,(kT) and uk = u(kT), from equation (1) it may be seen that: Yk Yk-1 = b ( u k - , k-2)

Control of Pao2in neonates

295

r
System response
H(t
L * /
,

, / ,

Model response

Figureo1. A monotonically increasing step response function, H(t), and the simple representational model used in the Astrom controller.

If it is now required that y should be equal to the set point yp after one sampling period (i.e. that yk = Y;-~), then the following control law is obtained:
uk = u k - 1 + (yk y,)lb (2) h t r o m proved that if the control law expressed in equation (2) is applied to the actualsystem (and not its model) then the corresponding closed-loop system will be asymptotically stable, if the free design parameters ( b and r ) satisfy the inequalities:

2b > H(m) 2 J Y q > H(4

where

(3) (4)

H(m) = lim H ( t )
1-oj

is the steady state response to a unit step input to the system. Furthermore, Cameron and Li (1985) demonstrated that the stability was guaranteed if a sector-bounded time-varying non-linearity is introduced into the loop, with the width of the sector being directly proportional to the ratio 2b/H(m).This control philosophy and several detailed controllers have been extensively tested in simulation, and the results proved encouraging (Ahmadi 1986). By selecting a suitable (compromise) value for the gain (b), the controllers proved capable of accomodating significant changes in the control parameters. For example u p to 300% variation in static gain was tolerated while still regulating the notional Pao2level against small fluctuations introduced into the feedback loop.

3.3 Monotonicity of response

Monotonicity of the Pao2response to a step change in Fio2 has been demonstrated in controlled experiments for adults and animals (Lange et a1 1966). In the case of neonates Riegel and Versmold (1979) demonstrated monotonic in vivo responses to step changes in 502using both intra-arterial and transcutaneous electrodes. Simultaneous recordings of these responses revealed similar curves, although as expected the skin exerted a damping effect with the transcutaneous electrodes, and the intravascular electrode responded more rapidly to changes in Paozdespite a longer in vitro response time. A more detailed study by Versmold et al (1978) examined the responses to step-changes in 402 for 16 neonates monitored simultaneously with four transcutaneous electrodes of differing manufacture. The range of birth weights and gestational age was from 0.95 kg at 27 weeks to 3.8 kg at full term, and five were identified as suffering from RDS. Again, monotonicity of tcP0,

296

R E Dugdale et a1

response was observed for step changes between the prevailing q o Z and 100% oxygen. Whilst large differences in response time between the electrodes were measured in vitro, these disappeared in vivo, as reflected in the close agreement between electrodes for the time taken to achieve 50% of the steady-state response ( T50). Large differences in response times between infants were noted, however, and attributed to variations in nitrogen washout and circulation times. For increasing Fio2,the mean value of T,, for the Radiometer electrode was, for example, 82.5 f 22.9 s for the sixteen infants tested, with the other electrodes exhibiting only small differences from this value. The lag between actual PaoZ and tcPo, was estimated at about one third of the response time at T50. In addition to the above observations, theoretical models of the neonatal respiratory system based on the physiological processes involved suggest a first order plus time delay input-output model (Sano and Kickuci 1985), giving rise to a monotonic step response.

3.4. Choice of control parameters T h e values of the control parameters were conservatively chosen by observing the P,02 response to a step change in the valve positon of the oxygedair blender for five infants with mild to moderate RDS being nursed without mechanical support in headboxes. These response dynamics reflect the cascaded effect of three processes: the mixing dynamics of the headbox, the physiological response of the infant, and the Pao2transducer response. T h e infants chosen were from a clinically similar group to those subsequently selected for closed-loop control trials, the Pao2being monitored using an intra-arterial electrode. The mean gestational age was 33 weeks (range 31-35) and the mean birthweight was 1.92 kg (range 0.99 to 2.82). T h e step-changes observed were those occuring in the normal course of the nursing process. Step-changes in the blender valve position resulting in changes between 0.05 and 0.10 in F,o, were observed, within an overall range from 0.3 to 0.6 in Fio2. T h e mean value of the static gain (H(c0)) derived from these responses was 0.11 k 0.03 kPa per 0 oxygen. This agrees well with the value inferred from the work of Sano and 7 Kickuci (1985) for infants with RDS. Their work also suggests a value of approximately 0.6 kPa per 7 oxygen for a normal infant, which may be compared with a value in the region 0 of 0.4 kPa per 7 oxygen for a term infant with birth asphyxia inferred from the work of 0 Versmold et a1 (1978). On the basis of the mean value estimate, the controller gain must be chosen to be in excess of 0.055 kPa per Yo oxygen in order to satisfy one of the stability criteria (equation (3)). T h e value actually used in the controller was 1 kPa per VO oxygen, a very conservative value for these preliminary trials, which allowed for both a significant spread in initial response gains and a marked improvement in the condition of the infant over the control period. With regard to the intervention interval, the mean time to attain half the static gain value was measured as 1.10 f 0.22 min in these five observations. A value in excess of this is required to satisfy the second of the stability criteria (equation ( ) ,and a value of 2 min 4) was chosen as a conservative estimate. This value was also greater than the tcPo, response time to 50% of the steady state value (T50) measured by Versmold er a1 (1978) (outlined above), confirming the conservative nature of the chosen value.
4. Instrumentation and software

For development purposes, a microcomputer software package has been designed and implemented on a BBC microcomputer to provide the facility for real-time control. A block diagram of the constructed instrumentation is shown in figure 2.

Control of Pao2 in neonates

297

Microcomputer

User port

Analogue input

Stepper conditioner

FIV

I
moiiiorl

02

Air+,

blender

"

, Headbox , ,

298

R E Dugdale

el

a/

Figure 3. T h e Modified ROC Quantiflex Blender, Neocath IO00 l,,O:.Uoniror and Interface Instrumentation.

of paozis performed manually. This enables retrospect ive comparison of the controlled
and manual modes to be performed from the stored data. T h e first requirement of the software is for calibration of the output from the P,02 monitor, using a dummy load to simulate the electrode. T h e patient identification, date and time are then requested. T h e principal display screen is then presented, which allows the last 50 controlled (or monitored) intervals to he observed. T h i s is shown in figure 4.

Figure 4. T h c principii di\pl,iy

\ c r C c r i 101

i l i c ~ ~ i i i ~ i \tvi \ ll r i n

By using the appropriate function keys, the following arc user sclcctable: (1) T h e choice of monitoring or control modes. (2) T h e target P,02 value. (3) The high-level Pao2alarm value. (4)T h e low-level Pao2alarm value. (5) The intervention interval. (6) T h e controller gain. T h e system initialises in the monitoring mode and the def:Jlllt values are: a target level Of 10 kPa, a high-level alarm of 12 kPa and a Iow-Ievel alarm of. 8 kPa. T h e intervention interval and controller gain default to the values chosen on the basis of the arguments

Control of Pao2in neonates

299

outlined in section 3.2. (2 min and 1 kPa per 9 oxygen respectively). Although the facility ' 0
t o alter the default values during the course of the program execution was available, in the

preliminary trials discussed here they were left unchanged. I n order that the control algorithm should act on representative rather than instantaneous values of P,o2, rudimentary smoothing is performed by taking the arithmetic mean from the preceding one minute of data (sampled at one second intervals). In the control mode this value is used by the algorithm, and for both the monitoring and control modes the last 50 of these values are displayed on the screen. T h e Pao2valde, time, valve position, set point, alarm values, Fio2 level and controller gain for each intervention interval are also stored on floppy disc for retrospective analysis.

5. Safety considerations
The requirement for patient safety is naturally of paramount importance in this type of application, and as a consequence, during these preliminary investigations, the system was continuously supervised during all closed-loop control intervals. T h e choice of the sensor system which continuously records the Paozreading is obviously vital, since the entire control-loop relies upon its accuracy and reliability. As has been mentioned, the continuous monitoring of Pao, is routinely performed by the use of instrumentation employing either transcutaneous or intra-arterial electrodes. T h e transcutaneous system uses a heated polarographic (Clark) electrode which is attached to the skin and causes the capillary blood under the electrode to be arterialised. Oxygen diffuses from the dilated capillaries through the skin into the electrode and a current proportional to the oxygen partial pressure is generated. A period of 10 to 20 min is required after electrode application for the current to stabilise. At 44OC and 45OC good correlation has been demonstrated between transcutaneous Po, (tcPo,) and Pao2 measured by both blood sampling (Huch et a1 1976) and intra-arterial sensors (le Souef et a / 1978) in sick infants. In conditions of cardiovascular shock or other impairments to oxygen transport, however, these correlations begin to weaken (Neuman et al 1983). At the temperatures indicated, repositioning of the electrode site is required every few hours to prevent skin damage, and each re-siting is followed by a restabilisation period when reliable tcPo, readings are unavailable. Care must also be taken to ensure that air is not introduced under the electrode, so leading to spurious readings. Despite these qualifications, however, this non-invasive technique has greatly widened the scope for the continuous estimation of Pa%. T h e main application of transcutaneous electrodes is usually in the long term monitoring of infants with mild respiratory problems or in the recovery phase Of RDS, but the technique has not generally replaced the use of intravascular catheter-tip electrodes for the continuous measurement of Pao2in infants with severe respiratory illness. T h e reasons for this are related to the ability of the catheter-tip electrodes to provide accurate, direct and uninterrupted measurement of Pao2 whilst simultaneously allowing access to the circulation for arterial blood gas analysis sampling and infusion purposes (le Souef et al 1978). In the longer term it may be worth considering the use of transcutaneous electrodes to provide an estimate of Pao2 the control loop since the majority of P,O, monitoring for in infants is carried out using this technique. In this pilot study, however, the intravascular catheter-tip electrode system was chosen as the more reliable and accurate option. T h e theoretical basis, development and construction of indwelling catheter-tip electrodes has been well covered by Parker and Soutter (1975), Rolfe (1976) and Hahn and Foex (1982). In addition, the accuracy of the electrodes over extended periods of use and the manner in which they fail has also been studied.

300

R E Dugdale et al

T h e design of the electrode used in this study consists of a miniature polarographic electrode mounted on the tip of a bi-lumen 5F catheter. One lumen carries the wires from the electrode, and the other is for blood sampling, blood pressure monitoring and the infusion of fluids via a lateral sampling hole postioned just below the tip. The electrodelcatheter combination is disposable and manufactured for use with the Neocath monitor by Biomedical Sensors Ltd. The electrode consists of a silver wire 1000 Paoz cathode and a reference electrode in the form of a silver cap. T h e assembly is fixed together with epoxy resin, and a rubber-modified polystyrene membrane is dip-coated onto electrolyte crystals deposited on the tip. When the electrode comes into contact with blood, sensor is water vapour diffuses through the diffusion membrane and a polarographic PaoZ formed. This particular style of Paozsensor is widely used and generally exhibits good stability during comparitively long-term use (Conway et al 1976). Regular calibration of the electrode reading against the results of formal blood gas analysis of arterial samples, drawn through the catheter, is obviously good practice in order to correct possible drift. In addition however, total electrode failure can occur. Conway et al (1976) found that 6 out of 32 electrodes failed after a mean time of 49 h, and attributed the cause to fibrin deposition on the electrode tip, electrical short circuits or the development of rapid zero drift. The deposition of fibrin can be minimised and the patency of the catheter maintained by constantly infusing through it heparinised clear fluids. The electrochemical mechanisms which cause this type of electrode to drift and fail were examined by Putnam et al(1984). They observed that the design of these electrodes was such that the restricted volume available for the storage of electrolyte could lead to depletion of chloride ions resulting in shifts in the operating characteristic (the polarogram), with an associated change in electrode sensitivity. In addition, they noted that silver dendrites may be formed at the cathode, caused by the anode material (silver) being transported to, and reduced at, the cathode. The formation of these dendrites led to signal instability, accelerated current drift and, ultimately, to electrode failure through short-circuiting. In the hard-wired Paozservo-control system described by Beddis er al (1979), the detection of electrode failure (or a sudden change in the condition of the infant) was attempted by activating an alarm if three steps, each corresponding to a 0.05 change in F,oZ, were consecutively requested in a single direction. With the additional flexibility available through microcomputer control of the control-loop this was refined to detect, after each intervention interval, three averaged Pao, values consecutively above the high-level, or below the low-level, alarm setting. These conditions actuated a visual and audible alarm, as did the detection of any single averaged Paoz reading above 16 kPa or below 4 kPa. Electrode failure or rapid drift did not occur in any of the controlled or monitored intervals encountered in the clinical trials and no alarm condition occured in any of the control intervals. Despite this, as the technique is developed the sophistication of the methods designed to detect such events must in our opinion be given as great a priority as the qualit7 of control achieved. Calibration of the Paoz electrode was performed every 3 h during control intervals by comparison with blood gas analysis results of arterial samples drawn through the electrode catheter. Finally, at any time the whole control system could, if necessary, be easily over-ridden by use of a switch on the Quantiflex blender which isolates the stepper-motor and allows manual control of the valve position to be accomplished.

Control of P,o,in neonates

30 1

6. Results

A total of 48 h of closed-loop P,o, control were recorded on seven pre-term infants being nursed in headboxes with mild to moderate RDS. T h e clinical characteristics of these infants are summarised in table 1, the mean gestational age being 31.8 weeks (range 27-35), and the mean birth weight being 1.94 kg (range 1.10-2.50). These infants were carefully chosen and clinically judged (with one exception) to be in an improving condition. Three of the infants were nursed solely in headboxes for the duration of their treatment. Three more were in the post-ventilation recovery phase of RDS and in one instance the control-loop was applied prior to both mechanical ventilation (IPPV)and CPAP, and immediately after it. T h e mean F,02 used in the control intervals lay in the range 0.29 to 0.69 (see table 2 below).
Table 1. T h e clinical details of the infants studied using closed-loop control.
~~ ~

Infant

Sex

Gestation (weeks)

Birth weight (kg)

Age at control period (days) Period 1 Period 2

Nursing history relevant to control period(s) Post

IPPV

1 2 3

F M F

4
5 6 7

M F M
M

35 32 27 32 31 32 34

2.50 1.87 1.10 1.95 2.02 2.19 2.20

4 1 1 1 6 2 1

4
2

Pre

& Post

CPAP & IPPV

Headbox alone Headbox alone Post IPPV Post IPPV Headbox alone

It is our routine clinical practice for infants in the first few days of life to be given mechanical respiratory support if they require an F,o,in excess of 0.6. Larger babies coping well in higher concentrations of oxygen are, however, often left in headboxes and closely observed. Ten separate closed-loop control intervals were implemented and following each of these an equal period of passive monitoring was recorded during which manual control of the Pao2was exercised. Normal nursing procedures pertained in both closed-loop and manual control periods with each infant being intensively nursed. Conventional blood-gas analysis was performed at three hourly intervals. During periods of manual control of Pao2 no special instructions were issued to the nursing or clinical staff, in order that these periods reflected normal clinical practice. During these periods the F1o2was adjusted by the clinical staff, if required, at the time that the blood-gas analysis was performed. Other than this the nursing staff adjusted the q o , as they considered appropriate. Taking both of these processes into account, during the periods of manual control monitored, the Fio2was adjusted at approximately two hourly intervals. T h e range of F,02 used in periods of manual control was between 0.72 and 0.25, and the maximal change in F,o, effected by the nursing or clinical staff was 0.08, but typically 0.05. The results of the trials are summarised in table 2. In each of the 10 periods the closedloop control interval result is shown paired with that of the manual control interval following it. The percentages of these intervals for which the recorded Pao2was within k 1 and k0.5 kPa of the target value are displayed (P(IEI < 1) and P(IEI <0.5) respectively). In addition, complementary to P(IEI < l), the percentages above 1 kPa and below 1 kPa are shown (P(E > 1) and P(E < 1)).

302

R E Dugdale et a1

Table 2 Tabulated results for paired closed-loop and manual control intervals. T h e mean and standard deviation . of the P,02are measured relative to the set point (10 kPa). T h e standard deviation for the 5 0 2 used in the manual control intervals has not been calculated due to the small number of changes effected. T h e range is, however, included.
Conirol lnfanr hlodr

P(IEIC1)

P(E>I)
(701

P ( E c -1)
(70)

P(IEI<O.5)

P,O?

'Vi
SD

~rme
Range
0.31-0.55 (h:min)

(%I
I
1
A"I0

?.kan
(kPa)
442 2i6 43.0 38.1

Mean 0.43
0.40 0.66 0.64 0.44 0.53 0.29 031 0.52 0 42 0 31 0.28 0.33 0.30

so
0.059

(kPa)
0.96

iO.5
55.2

Manual
2

16.6 20.3 12.i

0.9

12.9 24.5 99 44.8 26.5 61 i 8.5 33.8

0.03 -001

j,26

I.li
0 96 1.2i 1.40 1.62

0 34-0.45
0.070
0 54-0.i8 0.62-0.68 4:44

Auro Manual
AUlO

ii.4 54 3

-007
-0.98

51 3
31.2

Manual 4
3
hut0 hlmunl
<Auto

21.2 7.1
7.0

23.0
12 9
57.8 19.7

-007 - 1 35
-0.18 0.53

0.065

0.31-0.58 0 48-0.58

5.40

84.5 53.5
89 8 i 3 9
76. I

12 i
32 12.6

1.02 1.54
0.73 1.06 0.89 I 21 1.06 168 0.92 I 58

0.058

0.21-0.40 0.29-0.33
0.42-0.63 0 38-0.50 0.22-0.43 0.25-0.32

2:22

Manual
h

i.0 13.5
158 44.0 20.3 62 5

70.2

-0.08
-0.16

0.055

7.10

40.5
40.9 28.2 3j.Y 6.3 j2.8 29.2
493 16 2

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Manual
5
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51.4 75.0 li 2

8. I 46 4i
20 3

-0.05 -0.84 -0.3i -0.81

-0.18 -088
-0.06

0.043

8:38

0.084

Aianual

0.21-044 0.28-0.32
0.32-0.50 0.36-0.42 0.60-0.80 0.70-0 i 4

2.10

x
Y

.\Ut"

in.?
46.2

,\lanuil

85 85
11.0 59 19 7

13.2 45 I
11.0 55.9 13 6 32 2

0.40 0.40
0.69 0.72

0.04i

3:34

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.\idn~i

78.0 38.2
66 9 30 5

-I

18

1.11 I36 1.14 1.83

0.070

4:20

111

:\ma ,\lmurl

3i 3

3i.3 15.3

0.04 0 15

0.38 0.39

0.067

0.10-0 50 0.3i-042

3:51

T h e mean value of P(IEI < 1) for the 10 periods of closed-loop control was 74.9 k 10.2 compared with a manual control value of 45.2 f 16.0. The corresponding values for P(IEI <0.5) were 45.4 f 13.0 and 23.4 k 11.1 respectively. Paired t-tests were used to determine the significance of differences between periods of manual and closed-loop control. T h e values for P(IEI < 1) in each of the 10 cases are re-presented in figure 5(n),
P('El<l)
100 100. 80

P( i E 1 <0.5)

1 .o

Mean

d
2
4 6 8 Control period 10

05 0

r-05 -1 0 -1 5

_ .

__ - ---

(a)

4 6 8 Control period

1 0

(b)

(d

4 6 8 1 0 Control period

Figure 5 Histogram representations of paired results for: ( a ) P(IEI < 1). ( b ) P(IE1 < 0.5). (c) Mean values of the . distributions. Solid blocks are for closed-loop conrrol, shaded blocks for manual control.

the difference between closed-loop and manual control being highly significant = 7.32;P < 0.0001). T h e values for P(IEI < 0.5) are shown in figure 5(b) and again the overall difference is highly significant ( t = 6.45;P < 0.0001). The distribution of Paoz outside the chosen bands was studied and no significant difference was shown between the paired values of P(E > 1) for closed-loop and manual control ( t = 0.52;P = 0.31). For paired values of P(E < 1) the percentage of time spent
(t

Control of Pa,02in neonates

303

below - 1 kPa of the target value was significantly less for closed-loop than for manual control ( t = 7.01;P < 0.0001). In figure 5(c) the mean values of the entire distributions (relative to the set point of 10 kPa) are shown for both manual and closed-loop control, and the overall downward shift in the Pao2distributions for manual control (relative to closed-loop control), as reflected in the above results, is demonstrated. T h e dispersion about the mean, as measured by the standard deviation, also shows a consistent improvement for the control-loop intervals against the comparable intervals of manual control (see table 2). T h e poorest individual performance using the control-loop was for period number 3, the second control period for infant number 2. This control period followed both mechanical ventilation and CPAP, and the Pao2was particularly subject to large and frequent transient disturbance. Despite the closed-loop control figure being the lowest recorded (P(IEI < 1) = 52.3%), this was still greater than the corresponding manual result (31.2%), and indeed better than the average manual control figure.

7. Discussion
In the preliminary work described here, emphasis has been placed on the choice of a suitable (robust) Pao2 control algorithm and on the conservative choice of control parameters to ensure stability over a wide range of operating conditions. The quality of control achieved was considered, a t this stage, to be of secondary importance. Despite this however, the results achieved were very encouraging. In every instance in which the control-loop was implemented the percentage of time spent in the vicinity of the target value (as reflected in P(IEI < 1) and P(IEI <0.5)) was increased over the comparable value in the period of manual control which followed it. Overall the improvement was shown to be highly significant for both of these parameters. Comparison of the results achieved with those of Beddis et al (1979) is difficult since the approach used was to control the Pao2 between defined limits (7.3-10.7 kPa) rather than to a single target value (10 kPa). In general, however, the use of a microcomputer to implement this type of closed-loop control system has advantages over a hard-wired system. These are related to the flexibility with which the control algorithm may be implemented and improved, to the possibility of developing sophisticated inherent safety features, and to the high degree of monitoring which can be achieved. T h e control-loop as described here could be improved in several ways. Firstly, the choice of control parameters has been made with safety and conservatism very much in mind; the consequence is that large, frequent transient disturbances in the Pao2signal are tolerated by the controller (in the sense that the control-loop remains stable). This inherent stability is bought, however, a t the cost of heavily damped responses. One way to improve this would be to implement a degree of adaptability into the controller, whilst retaining its robust character. This could be achieved by using a non-parametric model of the process, identified from recent responses, together with a simple optimality criterion such as the minimisation of the future (predicted) errors (Cameron and Li 1987). This may be appropriate in the case of infants suffering from severe RDS, in order to track more closely the changes in Pao2 associated with an unstable condition. A second enhancement to the system could be made by the introduction of a parameter estimation algorithm designed to estimate the critical Parameters in a detailed physiological model of the sick infant. The information obtained could then be used not only for controller adaption, but also, in a suitably presented form, for a quantitive assessment of the condition of the baby.

304

R E Dugdale et a1

Designing a closed-loop control system for this type of application which might be left unartended implies a level of engineering sophistication which has not been presently attempted. We would observe however that if the system were developed to this level of sophistication it would be with the aim of improving care, and not as an alternative to observation by nursing and medical staff.

8. Conclusion
This preliminary work has demonstrated the feasibility of using a microcomputer to implement a closed-loop control system for the Pao2 of pre-term infants with mild-tomoderate RDS. The extension of the system to include infants suffering from severe RDS and undergoing mechanical ventilation, is now under consideration. It is considered feasible that the safety features of the system could be enhanced to a degree where the technique could be used routinely. In this way the technique could make a useful contribution to the techniques of respiratory support in neonatal intensive care.

Acknowledgements
We would like to acknowledge the assistance given to us by Ohmeda Ltd of Steeton, West Yorkshire, for their assistance in modifying the Quantiflex blender. We would also like to acknowledge Pergamon Press, Oxford, for kindly allowing us to quote from the Systems and Con t ro 1 Encyclopaedia.

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