European Journal of Cardio-thoracic Surgery 15 (1999) 742±746

Modi®ed ultra®ltration improves global left ventricular systolic function after open-heart surgery in infants and children

Rajiv R. Chaturvedia,1, Darryl F. Shoreb, Paul A. Whitea, Michael H. Scallanc, John W.W. Gothardc, Andrew N. Redingtona,*, Christopher Lincolnb Downloaded from https://academic.oup.com/ejcts/article/15/6/742/422511 by guest on 30 September 2021

aDepartment of Paediatric , Royal Brompton Hospital, Imperial College of Science, Technology and Medicine, London, UK bDepartment of , Royal Brompton Hospital, Imperial College of Science, Technology and Medicine, London, UK cDepartment of Anaesthesia, Royal Brompton Hospital, Imperial College of Science, Technology and Medicine, London, UK Received 26 October 1998; received in revised form 15 February 1999; accepted 11 March 1999

Abstract Objectives: Modi®ed ultra®ltration increases blood pressure and cardiac index following open-heart surgery in children, but it is unclear if this is secondary to an improvement in global left ventricular function. A previous report has suggested that left ventricular systolic function as assessed in a single chord is improved by ultra®ltration (Davies MJ, Nguyen K, Gaynor JW, Elliott MJ. Modi®ed ultra®ltration improves left ventricular systolic function in infants after . J Thorac Cardiovasc Surg 1998;115:361--370). The prominent vascular actions of modi®ed ultra®ltration necessitate left ventricular assessment using load-independent indices of systolic and diastolic function. Methods: In 22 consecutive infants and children undergoing open-heart surgery, left ventricular function was assessed following bypass and then 10 min later. Sixteen children (median weight 8.1 kg) underwent modi®ed ultra®ltration during this period, the remainder (median weight 7.3 kg) were controls for spontaneous recovery without ultra®ltration. Real-time pressure±volume loops, with transient inferior caval vein snaring were generated from conductance and microtip pressure catheters inserted through the LV apex. From these, load- independent (slope of the end-systolic pressure±volume [Ees] and end-diastolic pressure±volume [Eed] relationships) and load-dependent (Pmax, maximum LV pressure; Ped, end-diastolic LV pressure; maximum [dP/dtmax] and minimum [dP/dtmin] time derivatives of LV pressure; t, time constant of isovolumic relaxation) indices of left ventricular function were measured. Results: Haemoconcentration was achieved in all modi®ed ultra®ltration patients, median increase in haematocrit 34% (interquartile range 21%, 42%), ®nal haematocrit 0.40 (0.35, 0.41).

Ees increased 58% (9, 159, P ˆ 0:005). The changes in Eed, Pmax, Ped,dP/dtmax,dP/dtmin, and t were not signi®cantly different from the control group. Conclusion: Modi®ed ultra®ltration improves global left ventricular systolic function in infants and children following open-heart surgery. q 1999 Elsevier Science B.V. All rights reserved.

Keywords: Congenital heart disease; Cardiovascular surgery; Ventricular function

1. Introduction monary bypass is associated with a decrease in total body water [3,4], postoperative blood loss [3,5±8], alveolar±arter- Open-heart surgery in infants and children results in an ial oxygen gradient and duration of ventilation [5,6], increase in total body water that is mainly distributed to frequency of pulmonary hypertensive episodes [9] and interstitial tissue [2]. This is primarily related to the use of morbidity after cavopulmonary connections [7]. The cardiopulmonary bypass with haemodilution and the subse- haemodynamic effects of ultra®ltration are an elevation in quent in¯ammatory response. Tissue oedema leads to ¯uid arterial blood pressure [3,4,10,11], decrease in pulmonary accumulation in body cavities and can have adverse effects vascular resistance and increase in cardiac index with an on end organ function, especially of the lungs, heart and unchanged systemic vascular resistance [11]. However the brain. Ultra®ltration during rewarming or after cardiopul- effect of ultra®ltration on global left ventricular function has not been assessed, and in the presence of its prominent effect on loading conditions clearly requires evaluation by load- * Corresponding author. Royal Brompton Hospital, Sydney Street, Chel- sea, London SW3 6NP, UK. Tel.: 1 44-171-351-8546; fax: 1 44-171- independent indices of systolic and diastolic function. A 351-8545. recent important report has described an improvement in E-mail address: [email protected] (A.N. Redington) minor-axis left ventricular systolic function using single- 1 Current address: Great Ormond Street Hospital NHS Trust, Great Ormond St., London, WC1N 3JH, UK.

1010-7940/99/$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S1010-7940(99)00101-3 R.R. Chaturvedi et al. / European Journal of Cardio-thoracic Surgery 15 (1999) 742±746 743 chord indices analogous to global load-independent 5±10 min of cessation of bypass using the Great Ormond indices[1]. Street Hospital protocol [3] with a paediatric haemo®lter In infants and children undergoing modi®ed ultra®ltration (Paediatric Filtral 66, Gambro, Engstrom, Sweden). Flow (MUF) following corrective open-heart surgery we report an through the ®lter was maintained at 200 ml/min by an improvement in global left ventricular function, assessed inlet roller pump and outlet resistance varied to maintain a from the pressure±volume plane using a conductance and ®ltration rate of 100±150 ml/min. The previously optimized microtip pressure catheter. left atrial pressure was maintained during ®ltration by trans- fusion from the venous reservoir through the ®lter. Filtration was performed for 10 min aiming to achieve a haemoglobin 2. Methods concentration of 12 g/dl. Blood was taken for measurement of haemoglobin concentration and haematocrit immediately 2.1. Patients before and after ultra®ltration. Downloaded from https://academic.oup.com/ejcts/article/15/6/742/422511 by guest on 30 September 2021 The investigation was approved by the Royal Brompton Hospital Ethics Committee for Human Research. Informed 2.4. Assessment of left ventricular function consent was obtained for 22 children undergoing open-heart surgery (®rst 16 children had MUF, last six were controls). The conductance catheter has been extensively validated Diagnoses of the patients (numbers in brackets) were (a) for left ventricular volume measurement and details of the MUF: primum (1), secundum atrial theory [12] and our customized conductance catheter septal defect (1), ventricular septal defect (2), secundum system are presented elsewhere [13,14]. Left ventricular atrial septal defect and ventricular septal defect (2), atrio- function was assessed with the chest and pericardium ventricular septal defect (2), right ventricular out¯ow tract widely open and ventilation stopped at end-expiration, initi- obstruction (1), (5), tetralogy of Fallot ally 5±10 min after coming off cardiopulmonary bypass and and atrioventricular septal defect (2); and (b) control: then repeated after a further 10 min with or without primum atrial septal defect (1), ventricular septal defect (controls) an intervening period of modi®ed ultra®ltration. (3), tetralogy of Fallot (2). All patients were candidates Real-time left ventricular pressure±volume loops were for biventricular repair, were undergoing their ®rst open- generated using conductance catheter and microtip pressure heart operation and there were no residual shunts following catheter (2F, Millar) inserted through the left ventricular surgery. None of the patients had pre-existing ¯uid overload apex and secured with a pledget and purse-string suture. or renal impairment. The conductance catheters were custom built (NuMed Inc., Hopkinton, NY) single-®eld 3F (interelectrode 2.2. Cardiopulmonary bypass and myocardial protection distance 0.36±0.50 cm) or 5F (interelectrode distance All patients received a standardized protocol of iso¯urane 0.71 cm) catheters with eight platinum ring electrodes. gaseous induction, pancuronium, fentanyl and iso¯urane Conductance catheters of the appropriate size were selected maintenance. They underwent bicaval and ascending aorta based on the measured left ventricular long axis from the cannulation, and subsequently core cooling was begun on parasternal long-axis view of the pre-operative echocardio- bypass to 20±258C. The priming solution was a mixture of gram. The conductance catheter was manipulated until all whole blood and Hartmann's solution in a ratio calculated to ®ve segmental volumes were in-phase and a counter-clock- achieve a haemoglobin concentration of 8±9 g/dl. Each wise rotating pressure±volume loop was formed demon- patient received cold crystalloid cardioplegia (St. Thomas' strating that the conductance catheter was not in the left solution 1, 20 ml/kg) delivered by the perfusionist into the atrium or aorta, and therefore must lie within the long- aortic root at 40 mmHg, after aortic cross-clamping. Cardi- axis of the left ventricle. Preload was varied by transient opulmonary bypass ¯ow was 150 ml/kg per min (weight , (10 s) snaring of the inferior caval vein. All volume 10 kg) or 2.4 l/m2 per min (weight . 10 kg). At the end of measurements were corrected for blood resistivity and the procedure the cross-clamp was removed and rewarming parallel conductance, and each was determined before and begun on bypass. Ionized calcium was maintained at after ultra®ltration. Parallel conductance was determined by 1.0 mmol/l, boluses of calcium were given no closer than the hypertonic saline method [12] using an injection of 0.5± 20 min prior to the ®rst set of post-cpb measurements and no 2.5 ml of 20% NaCl into the pulmonary artery. Once a calcium was given between measurements. All patients stable position with good quality pressure±volume loops were in sinus rhythm and each patient remained on the was found there was no further catheter manipulation, and same dose of dopamine (5±10 mg/kg per min) post-bypass the dimensionless gain constant alpha was assumed to be and throughout the study period. unity and unchanged during the study period. The conductance catheter signal encoding volume and 2.3. Modi®ed ultra®ltration ECG data were fed to a stimulator/processor unit (Sigma - 5-DF, Cardiodynamics) and then to a committed microcom- Modi®ed ultra®ltration was performed for 10 min within puter, where it was integrated with the ampli®ed pressure 744 R.R. Chaturvedi et al. / European Journal of Cardio-thoracic Surgery 15 (1999) 742±746

Table 1 MUF group, two in the control group), and hence Eed values Comparison of control and modi®ed ultra®ltration groups (median[inter- are based on 15 patients. All other reported indices used all quartile range]) 22 patients. Linear regression determinations of the end- Control Modi®ed ultra®ltration systolic and end-diastolic pressure±volume relationships had a mean R2 ˆ 0:78 and 0.67, respectively. Haemocon- Weight (kg) 7.3 [4.0, 8.2] 8.1 [4.7, 13.2] centration was achieved in all MUF patients with a median Bypass time (min) 68 [59, 76] 74 [69, 101] Cross-clamp time (min) 40 [37, 45] 49 [39, 83] increase in haematocrit of 34% (interquartile range ICU stay (days) 1 [1, 4] 2 [1, 4] 21%,42%) and a median ®nal haematocrit of 0.40 (IQR 1 2 Ees (% change) 2 24 [ 2 39, 11] 58 [9, 159] 0.35±0.41). There was a weak positive correlation between Eed (% change) 44 [ 2 41, 170] 27 [ 2 13, 194] the degree of haemoconcentration achieved and the change Pmax (% change) 2 7[2 15, 1] 15 [ 2 11, 27] in Ees (Pearson correlation coef®cient 0.50, P ˆ 0:055). Ped (% change) 2 19 [ 2 35, 3] 2 4[2 13, 27] dP/dt (% change) 2 5[2 26, 3] 8 [ 2 14, 70] Importantly there was a highly signi®cant increase in Ees max (median increase 57.8%) in the MUF group as compared Downloaded from https://academic.oup.com/ejcts/article/15/6/742/422511 by guest on 30 September 2021 dP/dtmin (% change) 2 10 [ 2 27, 4] 8 [ 2 14, 64] t (% change) 2 [ 2 10, 24] 0 [ 2 21, 3] to the controls (P ˆ 0:005). Changes in indices of diastolic

a function (Eed,dP/dtmin, t) for the MUF group were not Abbreviations: Ees and Eed, slopes of end-systolic and end-diastolic signi®cantly different from controls (Fig. 1). pressure±volume relationship; Pmax, peak LV pressure; Ped, LV end-diasto- lic pressure; dP/dtmax and dP/dtmin, maximum and minimum values of the time derivative of LV pressure; t, time constant of isovolumic relaxation. b P , 0:05 (Mann±Whitney). 4. Discussion signals (Fylde Isotransducer Ampli®er) in custom designed In this study 10 min of modi®ed ultra®ltration cleared software.

2.5. Data analysis

The end-systolic and end-diastolic pressure±volume rela- tionships were derived from left ventricular pressure± volume loops generated under varying preload. Since the pericardium was widely opened and preload was varied over only a limited range, the end-diastolic pressure± volume relationship was ®tted with a straight line. Linear regression estimations of the end-systolic and end-diastolic pressure±volume relationships were excluded if R2 , 0:5. Load-dependent indices were also obtained from steady- state microtip pressure recordings: peak systolic pressure

(Pmax), left ventricular end-diastolic pressure (Ped), tau (t), the time constant of isovolumic relaxation; dP/dtmax and dP/ dtmin. Percentage change in each index of ventricular func- tion was calculated for each patient (pre-MUF compared to post-MUF, post-bypass compared to post-bypass 1 10 min for controls). The change in ventricular function in the ultra- ®ltration group was compared with that of the control group using the Mann±Whitney rank sum test. The null hypothesis was rejected if P , 0:05 (corrected for ties). Results are presented as median (interquartile range, IQR).

3. Results (see Table 1)

There was no signi®cant difference between the control and MUF groups in weight, bypass duration, cross-clamp time and intensive care unit stay. There were two deaths in the MUF group (patients 15 and 16 who died 0.3 and 3 days post-operatively) secondary to pulmonary hypertensive Fig. 1. Left ventricular pressure±volume loops during an inferior caval vein snare, in a 6.6 kg child before (1a) and after (1b) modi®ed ultra®ltration, crises. Technically adequate end-diastolic pressure±volume showing a 48% increase in E . Pre-ultra®ltration: E ˆ 7:7 mmHg/ml regression lines with R2 . 0:5 could not be obtained at es es (r ˆ 0:7); Eed ˆ 0:5 mmHg/ml (r ˆ 0:6). Post-ultra®ltration: either of the two time points in seven subjects (®ve in the Ees ˆ 11:4 mmHg/ml (r ˆ 0:8); Eed ˆ 0:5 mmHg/ml (r ˆ 0:8). R.R. Chaturvedi et al. / European Journal of Cardio-thoracic Surgery 15 (1999) 742±746 745 suf®cient plasma to achieve haemoconcentration, and was study [19]. However, in a randomized study of conventional associated with improved LV systolic function as assessed versus modi®ed ultra®ltration in neonatal pigs, MUF was by a load-independent index (median increase Ees ˆ 58%). superior in terms of decreasing total body and cardiac The weak relationship in this study between change in weight gain, increasing systemic blood pressure and haematocrit and Ees implies that plasma clearance is impor- improving LV function as demonstrated by an increase in tant, but does not discriminate between free water or cyto- preload recruitable stroke work, although cytokine levels kine clearance. Modi®ed ultra®ltration did not alter diastolic were not measured [4]. function in this study. The failure to detect a consistent High-volume haemo®ltration (median 4.97 l/m2) with no decrease in Eed with ultra®ltration could be related to the net ¯uid removal during rewarming, leads to lower cytokine study conditions (open-chest, open-pericardium) which levels immediately after haemo®ltration and 24 h later, and allowed a truer assessment of myocardial performance, reductions in postoperative blood loss, alveolar±arterial but removed the normal effects of pericardial restraint on oxygen gradient, time to extubation compared to controls chamber diastolic function. Alternatively, modi®ed ultra®l- [6]. Immediately after haemo®ltration tumour necrosis Downloaded from https://academic.oup.com/ejcts/article/15/6/742/422511 by guest on 30 September 2021 tration genuinely may not improve clearance of excess factor a, interleukin 10, C3a and myeloperoxidase were myocardial tissue water. This is unlikely as in a neonatal lower than controls whereas 24 h later interleukin 1, 6, 8 pig model of cardiopulmonary bypass with ischaemic arrest, and myeloperoxidase were lower. The authors suggested modi®ed ultra®ltration decreased cardiac wet weight and that haemo®ltration during rewarming, when cytokine increased the preload recruitable stroke work, but diastolic levels usually rise, may have attenuated the in¯ammatory indices were not reported [4]. Although myocardial oedema response. This study clearly shows that some effects of is associated with increased myocardial stiffness [15], the massive ultra®ltration are independent of free water clear- converse, of oedema clearance by ultra®ltration increasing ance. However both the haemo®ltration group and control compliance and by implication improving diastolic func- group received modi®ed ultra®ltration post-bypass, and so tion, has not been shown. the effects of free water clearance could not be assessed. A recent study in 21 infants suggested MUF improved left Only one negative study of the effects of intraoperative ventricular function based on changes in pressure±dimen- haemo®ltration has been published, and this was in a group sion loops i.e global left ventricular function was inferred of older children with median weight 17 kg [20]. Saatvedt et from changes in a single minor-axis chord [1]. Extrapolating al. [20] reported 18 children with half randomized to receive global chamber changes from the behaviour of a single ultra®ltration. Although 25 ml/kg ¯uid was removed there chord is potentially misleading, but is particularly proble- was no difference between the two groups in terms of matic in the immediate post-bypass period when incoordi- haemodynamics, in¯ammatory mediator levels and post- nate wall motion is frequently encountered. Indeed our operative course. The overall ¯uid balance for the ®rst group has previously demonstrated that M-mode derived 24 h was no different between the two groups, largely indices of ventricular function are critically dependent on because the ultra®ltration group required more colloid the axis examined [16]. The small decrease in end-diastolic replacement as compared to controls in the intensive care pressure, wall thickness, wall area and increase in minor unit, i.e. post-operatively they were forced to replace most axis length were interpreted as re¯ecting an increase in of the ¯uid that had been removed by ultra®ltration intra- compliance. Standard indices of diastolic function such as operatively. We have observed a similar high colloid time constant of isovolumic relaxation, dP/dtmin and the end- requirement post-operatively, in some but not all patients diastolic pressure±volume relationship were not reported that have undergone modi®ed ultra®ltration. and hence assessment of diastolic function was indirect. The increase in Ees produced by modi®ed ultra®ltration represents a moderate improvement in LV systolic function, 4.1. Effect of ultra®ltration on cytokines approximately comparable to the effects of 4±5 mg/kg per min dopamine in a non-cardiopulmonary bypass animal Ultra®ltration can potentially ameliorate increased total model [21]. Although our results have added improvement body water and in¯ammation following open-heart surgery. in systolic LV function to the list of bene®ts of modi®ed Although increased free water clearance whilst avoiding a ultra®ltration, we caution against unequivocal acceptance of hypercoagulable state seems worthwhile for overall post- cytokine network manipulation by this technique prior to a operative management, most attention has focused on the large randomized trial. The more extensive experience of effects of ultra®ltration on the in¯ammatory cascade. immunomodulatory therapies in sepsis has been disappoint- Our group [16] and others [5,6,17±19] have demonstrated ing, often initially encouraging at the small trial stage but ultra®ltration induced attenuation of the rise in cytokines when extended to larger populations have either failed or (tumour necrosis factor a; interleukins 1, 6, 8 and 10), increased morbidity and mortality [22,23]. complement (C3a, C5a) and neutrophil degranulation in children undergoing open-heart surgery. The method of 4.2. Conclusion ultra®ltration (MUF versus conventional) only improved the clearance of tumour necrosis factor in one clinical A signi®cant increase in global left ventricular systolic 746 R.R. 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