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THE PROTEASE INHIBITOR, APROTININ, REVERSES ACUTE HEMODYNAMIC CHANGES IN EXPERIMENTAL SEPTIC SHOCK (SS) GR Nimmo, AD Cumming

INCREASED CARDIAC OUTPUT AND RENAL BLOOD FLOW AFTER VOLUME LOADING DOES NOT PREVENT RENAL ULTRASTRUCTURAL DAMAGE IN AN ANIMAL MODEL OF SEPSIS

The plasma kallikrein-kinin system is activated by endotoxin. In SS, kinins could be mediators of hypotension, systemic vasodilatation, and capillary leak. In high doses, aprotinin (Trasylol, Bayer) inhibits plasma kallikrein. In ovine experimental SS due to peritonitis, we found beneficial effects of aprotinin infused from 30 minutes after surgery'. We report here the effect of

G.Lamb, D.Tighe, R.Moss, G.Hayward, A.Wilson, D.Bennett

aprotinin given late in SS. Ovine surgical peritonitis was induced as previously described 2 (n =5). Once volume-resistant hypotensive SS developed, (fall in mean arterial pressure >40 mm Hg, mean 8.5±1.3 hours postsurgery), aprotinin 10 6 KIU was given as an intravenous bolus, followed by 10 6 KIU /hour.

Change in MAP from Change in SVR from baseline (dyne/sec/cm -5 ) baseline (mm Hg) Pre-aprotinin Aprotinin Post - aprotinin

- 53.8 ± 4.6

- 714 ± 75

- 28l±36* - l2.6±5.0* - 636 ± 180 ** - 49.8 ± 10.8 ** ** p<0.01 vs aprotinin * p <0.01 vs pre-aprotinin

Aprotinin produced a rapid increase in MAP and systemic vascular resistance, with no change in cardiac output. This did not persist after infusion was stopped, suggesting that high plasma levels are necessary. Urine output, sodium excretion, and creatinine clearance also improved during aprotinin infusion. If reproduced clinically, these effects of aprotinin could prove useful in SS.

This study was undertaken to document the possible protective effect on renal ultrastructure of maintaining high cardiac output(CO) and renal blood flow(RBF) in a pig peritonitis model. In 9 anaesthetised animals routine haemodynamic measurements were made. In addition renal blood flow was measured using a thermodilution catheter placed in the left renal vein. There were 4 animals in the placebo(P) and 5 in the high volume(H) group. P were given hetastarch to maintain CO at baseline levels, H to increase CO by 30%. RBF increased by 57% and MABP by 36% in H compared to P. Renal tissue was acquired at 8 hrs and the animals were then culled. Tissue was processed for histological examination, photographed and the pictures randomised. Individual structures were independently scored blind by 3 people (0 =normal,10=grossly abnormal). In the P group the proximal nephron(PT) showed considerable vacuolation(PTv) and mitochondria) damage(PTm) with little loss of microvilli(PTmc) but marked loss of patency of the tubular lumen(PTIp). In the glomeruli(GL) there was leukostasis(GLIk) with capillary lumen occlusion(GLvo)with reduction of the urinary suace(GLus). Statistical significance (*) was tested by ANOVA. PTmc PTlp PTv PTm 2.8±0.2 Placebo 5.3±0.2 5.0±0.3 4.9±0.3 5.9±0.2 5.5±0.2 3.0±0.2High 7.1±0.3* GLIk GLvo GLus 2.2±0.5 3.6±0.5 4.0±0.5 Placebo High 4.8±0.4 5.2±0.3* 3.8±0.5* In the H group there was no improvement, in fact glomerular and tubular luminal occlusion was significantly worse. We conclude that increasing renal perfusion offers no protection from structural damage as seen with electron microscopy. St. Georges Shock Group, St. Georges Hospital Med Sch, LONDON, UK, S W 17 ORE.

1. Cumming AD, Nimmo GR. Crit Care Med, in press. 2. Cumming AD et al. Crit Care Med, 1988; 16: 1132. Department of Medicine, University of Edinburgh, Royal Infirmary

of Edinburgh, EH3 9YW, UK.

Pediatrics I. Respiratory 31

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COMPARISON OF RESPIRATORY MECHANICS MEASUREMENTS DURING VOLUME AND PRESSURE CONTROLLED VENTILATION IN NEONATES L Stürme, Y

SEQUENTIAL RESPIRATORY MECHANICS IN TERM INTUBATED NEONATES RECEIVING MUSCLE RELAXANTS M. Durand, S. Sardesai, C. McEvoy, M. Alvarado

Riou, F Leclerc, N Kacet, JP Dubos, S Rousseau, P Lequien It has recently been demonstrated that respiratory mechanics of infants could be evaluated during volume controlled ventilation either by the "pulse" method or the interrupter method (Pediatr Pulmonol. 12; 203212, 1992); however, these methods cannot be used during pressure controlled ventilation that is the subject of a new interest. The aim of the study was to measure compliance and resistances during pressure controlled ventilation (part I) and to compare the results with those obtained by the interrupter technique during volume controlled ventilation (part II). Flow, volume, and pressure were measured at airway opening in 16 neonates (age 12,4 +1- 16,75 days; B.W. 2400 +/- 720 g) mechanically ventilated with a Servo-ventilator 9000; flow/volume, flow/pressure, and volume/pressure were displayed on a X/Y table. In the part 1, the method is based on the statement that, when applying constant inspiratory pressure (Pao) during passive inflation, the equation of motion of the respiratory system is : V(t)= (Pao-PEEPrs,infl) x Crs,infl-(Rrs,infl x Crs,infl) x' (t), where 1/Crs,infl is the total elastance of the respiratory system, V(t) the volume, Rrs,infl. the resistance, PEEPrs,infl the total end-expiratory pressure. Pao being constant, the relationship between inspiratory volume and flow is then a linear function of the type Y = a + bX, in which the slope (b) defines the time constant (T) of the respiratory system.When flow is equal to zero, at the end of inflation, equation is Crs,infl.=tidal volume/(Pao-PEEPrs,infl). We verified in each test that inspiratory flow was equal to zero at the end of inflation on the P /V loops. Rrs,infl. is then defined by T/Crs,infl. In the part II, Compliance (Crs,occl) and resistances (Rrs,occl) were also measured by the occlusion technique during volume controlled mode (Kochi et al. J Appl Physiol. 64: 441-450, 1988). We found a strong correlation between Crs,infl. and Crs,occl. (r =0.86; p<0.001) and between Rrs,infl and Rrs,occl (r=0.84; p<0.002). Intrinsic PEEP calculated during the two modes of ventilation by using end-expiratory occlusion were comparable (r =0,92; p<0.001). We concluded that pulmonary mechanics can be simply estimated in infants during pressure controlled ventilation . Neonatal, Pediatric intensive care and Respiratory physiology wtits.CHRU de LILLE

Term neonates in severe respiratory failure often receive muscle relaxants in an attempt to optimize mechanical ventilation. An increase in pulmonary resistance has been reported with pancuronium. Measurements of pulmonary mechanics in term neonates receiving vecuronium (Norcuron) are not available. We evaluated the cumulative effects of Norcuron on pulmonary mechanics in 10 infants (BW 2680-4285g, GA 38-41 wks, age 0.5-2 days); 8 patients had meconium aspiration and 2 pneumonia. The initial dose of Norcuron was 0.2 mg/Kg IV, followed by 0.1 mg /Kg as needed. Respiratory mechanics and 1-hr monitoring of computerized pulse oximetry were obtained 1-hr prior to and 1-hr after the initial dose of Norcuron, and at 24-hr intervals for the duration of the paralysis (72 hours). At comparable mean airway pressure and FIO2, we monitored airway pressure, flow and tidal volume (VT) and only mechanical breaths were analyzed. Respiratory resistance (Rrs) and compliance (Crs) were calculated (PeDS). Oxygen saturation (Sa02) was measured with the Nellcor N-200 monitor and a computer operating an oximetry software. <85% Sa02<90% Rrs Crs % OF TIME ml/cmH2o/Kg cmH2O/L/sec 0.7 1.6 0.35 59 1 HR BEFORE 0.4 0.7 70 1 HR AFTER * 0.39 * p > 0.05 In addition, there were no significant changes in Crs, Rrs, oxygenation, heart rate or blood pressure, measured daily during Norcuron therapy (ANOVA). Our findings indicate that Norcuron does not significantly affect Rrs and Crs in term neonates. Norcuron appears to be well tolerated in infants who require muscle relaxants. Dept. of Pediatrics, LAC +USC Medical Center, University of Southern California, 1240 N. Mission Road, Los Angeles California 90033, U.S.A.

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ADULT RESPIRATORY DISTRESS SYNDROME (ARDS) IN IMMUNOCOMPROMISED CHILDREN L.Bindl. U.Herberg.S.Buderus.U.Bode.M.Lentze

111(31 FRItU FNOY l ILLATMY VENI'IIATICN AND EF1RAQJRFOREAL MEMBRANE OXYC.MT1Ct IN NIINA'IFS AND INFANTS WTII SEVERE R PIRA1U Y FAlIJJRF. V. Varnholt, P. Lasch, G. Suske, W. Kachel, H. Wirth*

We retrospectively investigated the clinical course in 7 immunocompromised children with ARDS, we saw in a 2-year period. Diagnosis of ARDS was made if a triggering event was followed by severe respiratory distress with a lung injury score of> 2,5 (.1). Pt-No MainDiagnosis irnminoconprorni>ing event tiggering event 1 2 3 4 5 6 7

Cushing's Syrdrorne hypercortisolisrn Diabetes mell'tus Nephrwlastona therapy induced reutrop?nia steroid trEatmenLeucen- ia Leucemia theraN induced reutropenia ACTH-treatment Infantile spasms Purtilo S'yndr;me apl.a=tic n.€utr - openia Hemophilia A, AID: steroid treatment Crohn's Dise.e.e

I:etoacilosis sepsis syndrome sepsis (Streploc.vir ) qiant cell pneumonia sepsis CIT hemorrhage
Treatment folowed the recommendations of Royall at el( 2), permissive hypercepnia(3) was applied in 3 patients.Mean duration of ventilator therapy was 16,1 days. Mean peak oxygenation index was 42. The out come was uniformely fatal. Multiple organ failure developed in all patients with respiratory failure as fatal event in 2 patients. Recovery from neutropenia in these 2 patients was accompanied by severe worsening of pulmonary function. To our knowledge this is the largest published series of immunocompromised children with ARDS. Our experiences are in accordance to those in comparable adult patients and in the few published pediatric patients with this condition. Neither high steroid levels nor neutropenia are protective in children at risk for ARDS. (1) Murray JF. AmRevRespirDis 1977,115: 1071-8. (2) RoyaliJA at el. JPediatr 1988.112: 335-347. (3) Hickling KG el al. IntensiveCareMed 1990.16:372-7. L.Bindl, Univ.- Kinderklinik, Adenauerallee 1 19, 63 Bonn I , RIG.

35 INTRATRACHEAL PULMONARY VENTILATION (ITPV) IN CHILDREN - A PRELIMINARY REPORT J. Pfenninger*, Th. Kolobow** ITPV may have a considerable potential as a technique of ventilation which, by eliminating anatomical dead space minimizes volo-(baro-) trauma. The current study has been conducted in order to evaluate clinical applicability. Methods: For delivery of a constant flow of fresh gas a capped catheter with side holes ("reverse thrust') is advanced through a standard ET tube just above the carina. The ET tube is connected via a Y piece to a Siemens Servo 900 C respirator which is merely used for opening and closing the expiratory valve and measuring tidal volumes. Expired gases are ccntinuously monitored for mixed CO2 concentration. With this set-up ventilation can be changed rapidly from conventional mechanical (CMV) via a hybrid form (CMV+ITPV) to pure ITPV. Results: Five patients with a variety of underlying diseases have been studied, the time on ITPV ranging from 1 to 18 h. Mean tidal volume was reduced from 15.1 ml/kg (CMV) to 5.1 ml/k (ITPV), Whereas respiratory rate was increased from 32.7/ min. to 91.3/min. During ITPV PaCO2 rose from 29 to 35, and Pa02/FIO2 fell from 420 to 382 mm Hg (ITPV 1 h vs CMV just before institution of ITPV). biscussion: These first human data are encouraging. Surprisingly minute ventilation was higher during ITPV with a less effective washout of CO2. It was our impression that on the long run problems with tracheo-bronchial toilet might play a substantial role. University Childrens Hospital, Inselspital, CH-3010 Bern ** National Institutes of Health, Bethesda, MD,USA

Extracorporeal membrane oxygenation (EDD) is a possibility of treatment for infants with severe respiratory failure, that now has been used successfully in more than 5000 cases. But this invasive method has several major risk, therefore other forms of therapy are subject for research until now. We report on 73 neonates (gestational age > 33 weeks, birth weight > 180) g) and infants (age < 3 months) with severe respiratory insufficiency who were treated in our hospital after failure of maxim m conventional treatsent (February 1987 - April 1992). All children had pa09 ( 45 mit Hg, when ventilated with peak inspiratory pressure) 38 an 1120 and Fi02 = 1.0, thus seeting FIM) entry criteria. High frequency oscillatory ventilation (HFOV) was tried in all patients. If sufficient oxygenation couldn't be achieved (pa02 <40 nun Hg for ) 2 h), 1(H) therapy was begun, which was the case in 38 children. Infants responding to I-IFOV (n = 35) were less hypoxaeric before HRN (paO2 38.3 vs. 312 nun Hg; p ( 0.01), their POD2 was lower (32.1 vs. 47.5 nun Hg; p ( 0.05); during HFOV there was a significant rise in pa02 (j 200 mit Hg) and a fall in pOD2 to 20.8 mit Hg. Children with lung hypoplasia as a result of diaphragmatic hernia or other reasons or with cyanotic heart disease (total anomalous pulmonary venous return) did not improve with HFOV, whereas HEW tended to be successful in cases of prithunry pulmonary hypertension, neconiiun aspiration, sepsis and pneumonia, In these diseases success or failure of HR)/ couldn't be reliably predicted by any parameter. Mean duration of HR)V was 38.3 h vs. 87.5 h of DI"D (only survivors). Weaning fron HFOV/TD[) was possible in 91 %/74 of the infants; the overall survival rate was 71 %. There were no significant differences between HRN/DAD groups with regard to duration of ventilation following HF0V/1[1), rate of bronchopulnonary dysplasia, neurological complications (intracranial haerrorrhage, brain infarction) and rate of mentally handicapped children. About 50 % of neonates and young infants with severe therapy-resistant respiratory failure can be treated successfully with IiF7V, thus avoiding EDO. By applying both therapies the survival rate of these severely ill children can be increased fron an estimated rate of < 10 % up to 75 - 80 %. Departments of Pediatrics and Pediatric Surgery', Universitäts- Klinikfan, Thecdor-Kutzer-Ufer, N 6800 Mannheim 1, cenn3nv

36 NONINVASIVE MEASUREMENT OF SYSTEMIC OXYGEN TRANSPORT (SOT) IN TERM AND PRETERM NEONATES W. Lindner Adequate oxygen supply is a major problem in critically ill ventilated neonates. Routine oxygen monitoring includes Pa02 and arterial 02-saturation (Sa02), but invasive measurement of cardiac output is not available in these patients. Tissue oxygenation however depends on SOT. Using the pulsed Doppler method we measured left ventricular output (LVO) in 32 health term and preterm neonates (gestational age 23-41 wks) in the f rst week of life and calculated SOT according to the equation: SOT = LVO x [(1.34 x hemoglobin x Sa02) + (0.003 x Pa02)x10' 2 ]. 18 additional measurements were made in three critically ill neonates [Follow u after heart transplantation (Htx), air leak syndrome (ALS, pericardial tamponade (PT)]. Results: I. Normal Infants: SOT was 52 (30-132) in preterm (n=26) and 120 (97-201) in term (n=6) neonates. OT/kg bodyweight was 51 (43-71) in preterm and 42 38-50) in term neonates. SOT was related to gestational age (r=0.80, p<0.001) and body surface area (r=0.84, p<0.001). II. Sick infants: Htx: A low LVO (170 ml/kg/min) at 4h after Htx was compensated by high Pa02, SaO2 and hemoglobin (Hb), resulting in a normal SOT (36-46 mi/kg/min). No metabolic acidosis occured in the postoperative course. ALS: PaO2, SaO2 and Hb were normal but LVO (108 ml /kp/min) was decreased due to a high mean airway pressure, resulting in a low SOT (26 ml/kg/min). SOT increased by 21 % with decreasing mean airway pressure (15%) and increasing LVO (25%) inspite of decreased, subnormal PaO2 and SaO2. PT: SOT (12 ml/kg/min) was below the 02consumption of stressed neonates (19 ml/kg/nun) inspite of normal Sa02 due to an extremly low LVO (74 ml/kg/min). The resulting metabolic acidosis normalized with increasing LVO (200 ml/kg/min) and SOT (38 ml/kg/min) after pericardial drainage. Conclusion: SOT in neonates is higher than in older children and adults. Our data of SOT in neonates, calculated by noninvasive measurements agree well with invasive data in the literature (Lister G et al: SOT in neonates 33 ml/kg/min; Semin Perinatol 8:192, 1984). Knowledge of SOT provides additional, clinically relevant information on tissue oxygenation in critically ill neonates. Department of Pediatrics, University of Munich, F.R.G.