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BJA Advance Access published February 24, 2009
British Journal of Anaesthesia Page 1 of 5 Maternal haemodynamics and lung water content during percutaneous fetoscopic interventions under general anaesthesia R. Hering1*, A. Hoeft1, C. Putensen1, K. Tchatcheva2, R. Stressig2, U. Gembruch2 and T. Kohl2 1Department of Anaesthesiology and Intensive Care Medicine and 2Department of Obstetrics and Prenatal Medicine, German Centre for Fetal Surgery and Minimally-Invasive Therapy, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany *Corresponding author: Department of Anaesthesiology and Intensive Care Medicine, Kreiskrankenhaus Mechernich GmbH, St Elisabeth Str. 2-6, D-53894 Mechernich, Germany. E-mail: Background. The purpose of our study was to evaluate the maternal cardiopulmonary func-tion and lung water content during percutaneous fetoscopic interventions under generalmaternal – fetal anaesthesia and continuous tocolytic medication.
Methods. We prospectively studied 13 women between 19 and 30 weeks of gestation under-going percutaneous fetoscopic procedures that were performed under general maternal – fetalanaesthesia and tocolysis using indomethacin. Invasive haemodynamic monitoring using pul-monary artery catheters and the transpulmonary indicator dilution technique was applied todetermine intrathoracic blood volume (ITBV), cardiac output, and extravascular lung water(EVLW). Pulmonary vascular permeability was estimated as the ratio of EVLW/ITBV.
Measurements were performed during and for 24 h after the interventions.
Results. Respective mean (SD) maternal ITBV and cardiac output were 894 (191) ml min21m22 and 3.29 (0.51) litre21 min21 m22 intraoperatively, and 843 (169) ml min21 m22 and 4.47(0.55) litre min21 m22 during the first postoperative day. EVLW was 7.9 (2.7) ml kg21 duringthe interventions and 7.7 (1.8) ml kg21 during the first postoperative day. The pulmonary vas-cular permeability index was calculated as 0.35 (0.06) during the interventions and 0.38 (0.14)for the first postoperative day. Clinically overt pulmonary oedema was not detected in anywoman while pulmonary gas exchange remained normal.
Conclusions. In mid-gestational women undergoing percutaneous fetoscopic interventionsunder general maternal – fetal anaesthesia, cardiopulmonary function remained stable. However,a moderate increase in EVLW and pulmonary vascular permeability indicates an increased riskfor maternal pulmonary oedema.
Keywords: anaesthesia, obstetric; complications, pulmonary oedema; fetus; heart, cardiacoutput; monitoring, cardiopulmonary Accepted for publication: January 15, 2009 The life-threatening consequence of a spectrum of fetal cardiac access, patch coverage of the exposed neural tissue malformations has prompted efforts to assess the feasi- in fetuses with spina bifida aperta, temporary tracheal bility of minimally invasive fetoscopic fetal surgical inter- occlusion in fetuses with diaphragmatic hernia, release of amniotic bands, and tracheal decompression in fetuses performed by members of our own group, fetoscopic tech- with congenital high airway obstruction syndrome.1 2 At the time of the clinical introduction of these mini- intra-amniotic access, partial amniotic carbon dioxide mally invasive fetoscopic techniques at our centre about insufflation, fetal posturing, fetal transoesophageal echo- 6.5 yr ago,3 maternal pulmonary oedema had been one of cardiography, and percutaneous uterine closure were the most feared problems. In an analysis by the pioneering developed in order to achieve or facilitate direct fetal San Francisco group, this complication was observed in # The Board of Management and Trustees of the British Journal of Anaesthesia 2009. All rights reserved. For Permissions, please e-mail: about one-fourth of women regardless whether an open Table 1 Patient characteristics. CHAOS, congenital high airway obstruction surgical or less invasive fetoscopic approach was used.4 At our institution, we observed a case of maternal pulmon- ary oedema after our first attempt at fetoscopic patch cov- erage of spina bifida aperta.5 Although the anaesthetic and tocolytic regimen for fetal surgery may promote maternal pulmonary oedema, the mechanisms of fluid accumulation in the maternal lungs have not been completely under- stood.6 Therefore, a systematic approach to determine the lung water content and pulmonary vascular permeability in pregnant women during fetal interventions would provide important, clinically relevant information.
We prospectively determined maternal systemic and pulmonary vascular haemodynamics, pulmonary water content, and pulmonary vascular permeability in mid- gestational women undergoing percutaneous fetoscopic interventions under general maternal – fetal anaesthesia.
Haemodynamic monitoring consisted of pulmonary artery catheterization and the transpulmonary indicator dilution method to determine cardiac output, pulmonary vascular pressures, intrathoracic blood volume (ITBV), and extra- Temporary tracheal balloonocclusion for diaphragmatichernia After approval by the local committee on human researchand in accordance with the ethical standards for humanexperimentation Helsinki, written informed consent was obtained from all stored on a computer at sampling intervals of 5 s. Arterial patients. We prospectively studied 13 pregnant women and mixed venous blood gases, haemoglobin, and pH were between 19 and 30 weeks of gestation undergoing percuta- determined with a standard blood gas analyzer (ABL 510, neous fetoscopic procedures (Table 1).
One hour before the procedure, all women received Advanced haemodynamic monitoring was performed indomethacin 100 mg rectally for tocolysis and ranitidine 150 mg orally as acid aspiration prophylaxis. Before AH-05050-PU, Reading, CA, USA) which was inserted induction of anaesthesia, sedating drugs were not adminis- through the right internal jugular vein, and a 4 F tered in order to avoid immobilization of the fetus before a thermistor-tipped artery catheter (Pulsiocath PV2024-4F, favourable fetal position was observed. Rapid sequence Pulsion Medical Systems, Munich, Germany) which was induction of anaesthesia was performed using i.v. remifen- advanced via the femoral artery into the descending aorta.
tanil (1 mg kg21), thiopental (5 mg kg21), cis-atracurium Mean arterial pressure, central venous pressure, and mean (0.015 mg kg21), and succinylcholine (1 mg kg21).
pulmonary artery pressure were transduced continuously Balanced maternal – fetal anaesthesia was maintained with (Combitransw, Braun AG, Melsungen, Germany), recorded remifentanil, and desflurane in oxygen. Mechanical venti- (CS/3, Datex-Engstro¨m, Helsinki, Finland), and stored on a lation was provided with a standard anaesthetic machine personal computer at sampling intervals of 5 s. Pulmonary (Julian, Dra¨ger Incorporation, Lu¨beck, Germany). PEEP was artery occlusion pressure was measured intermittently.
set at 5 cm H2O and peak inspiratory pressure was adjusted The transpulmonary indicator dilution method was used to the value corresponding to a tidal volume of 6 ml kg21.
to estimate cardiac output, ITBV, and EVLW.7 8 In brief, The inspiratory-to-expiratory time ratio was set to 1:1 and 15 ml iced saline was used as an indicator and injected the ventilator rate was adjusted to maintain a maternal arter- into the right cardiac atrium. The dilution curve of the ial carbon dioxide tension between 30 and 40 mm Hg.
indicator was recorded in the aorta with the thermistor- Ventilatory and gas-exchange data including tidal tipped artery catheter and a bedside computer (PiCCO, volume, minute ventilation, end-expiratory pressure and Pulsion Medical Systems) estimated cardiac output, ITBV, peak inspiratory pressure, inspired and expired concen- and EVLW.9 10 Pulmonary vascular permeability was cal- trations of oxygen and desflurane, capnography, and pulse culated as the ratio of EVLW/ITBV.11 – 14 Parameters were oximetry were taken from the anaesthetic machine and indexed for maternal body surface or body weight, where Fetal interventions: maternal haemodynamics appropriate. Standard formulae were used to calculate Table 2 Maternal cardiorespiratory variables. All values are mean (SD) stroke volume, systemic and pulmonary vascular resist- ance, and oxygen delivery and consumption.
Remifentanil infusion and concentration of desflurane were adjusted to maternal and fetal analgesic and hypnoticrequirements and a degree of uterine relaxation that would allow to technically execute the procedures and prevent con- tractions. Adequacy of maternal anaesthesia was judged by the bispectral index (target value 40 – 50), fetal anaesthesia was judged adequate if there were no fetal movements and heart rate increases after painful stimuli and adequacy of uterine relaxation was judged clinically and by tocography.
gas-exchange variables were started after induction of anaesthesia and insertion of catheters and continued during the first 24 postoperative hours in the ICU.
(dyne s cm25 m2)Extravascular lung water (ml kg21) Lactated Ringer’s solution was infused at a rate of 4 ml kg21 h21. In the case of haemodynamic instability (more than 20% reduction of mean arterial pressure when compared with the pre-anaesthetic period or a reduction of mean arterial pressure or cardiac output below 65 mm Hg or 3 litre min21 m22, respectively), a rapid infusion of 250 ml of hydroxyethyl starch 6% was allowed under close control of ITBV and EVLW. If hypovolaemia was ruled out (ITBV above 850 ml m22), vasoactive medication was allowed starting with a continuous infusion of 0.1 mg kg21 min21 of epinephrine. Continuous amniotic fluid exchangefor uterine distension was restricted to an amniotic infusionof 2 litre of crystalloid solutions.
Immediately after the intervention, extubation was During the intervention, mechanical ventilation with a planned in the case of stable cardiopulmonary status.
PEEP of 5 (1) cm H2O and a peak inspiratory pressure of During the first postoperative day, tocolysis using indo- 19 (3) cm H2O resulted in a tidal volume of 7 (1) ml kg21, methacin was continued and lactated Ringer’s solution was a minute ventilation of 78 (8) ml kg21 min21, and an end- infused at a rate of 120 ml h21. Postoperative opioid analge- tidal partial pressure of carbon dioxide of 34 (2) mm Hg.
sia was provided with bolus doses of piritramide (0.03 mg Maternal heart rate (P,0.05) and cardiac output kg21) as clinically needed. In order to detect and attend (P,0.01) were reduced during the intervention when com- potential maternal and fetal complications, patients were pared with the postoperative period, whereas stroke volume monitored in the ICU during the first postoperative day.
and ITBV remained unchanged throughout the study Data were expressed as mean (SD) and evaluated for (Table 2). Mean pulmonary artery, central venous pressure, normal distribution with the Shapiro – Wilks W test. The data obtained during the intervention and the first post- (P,0.01), and mean arterial pressure decreased during the operative day, respectively, were compared using the interventions (P,0.05). Intraoperatively, 1654 (591) ml of crystalloid infusions and 500 (299) ml of colloid infusions between EVLW and cardiac output, mean pulmonary were given i.v. In one case, epinephrine (0.03 – 0.07 mg artery and pulmonary artery occlusion pressure, and ITBV kg21 min21) was infused for 45 min to keep cardiac output using linear regression analysis. Differences were con- above 3.0 litre min21 m22 after hypovolaemia had been sidered to be statistically significant if P0.05.
excluded. After the interventions, no colloids were infused.
Mean urinary flow rates were 68 (43) ml h21 during and173 (42) ml h21 after the interventions.
Pulmonary gas exchange and haemodynamic parameters including cardiac output, ITBV and mean pulmonary arter- The mean duration of the interventions was 152 min ial pressure, pulmonary arterial occlusion pressure, and (range 60 – 645 min). Adequate transplacental fetal anaes- central venous pressure were within the normal range thesia was achieved in all procedures as indicated by the during general anaesthesia and mechanical ventilation. All absence of fetal movements and heart rate increases after women were extubated immediately after the procedure.
When compared with the intraoperative period, cardiac output and oxygen delivery and consumption increased gestational women under continuous tocolytic medication and mean pulmonary arterial pressure, pulmonary arterial who were undergoing fetal interventions under general occlusion pressure, and central venous pressure decreased anaesthesia. In the awake state, during the first postopera- after the interventions (P,0.01) (Table 2). Although clini- tive day, systemic and pulmonary vascular blood pressures cally overt pulmonary oedema and impairment of oxygen- were normal and cardiac output was within the upper ation were not observed in any of the patients, EVLW and normal range which confirms the previous findings of a pulmonary vascular permeability were above the normal hyperdynamic cardiovascular status in normal preg- range (Table 2). There was no significant correlation nancy.18 During anaesthesia, maternal haemodynamics between EVLW and cardiac output (r2¼0.0075), pulmon- were within normal ranges, as well. However, systemic ary artery occlusion pressure (r2¼0.0766), mean pulmon- arterial pressure and cardiac output were significantly ary artery pressure (r2¼0.1171), and ITBV (r2¼0.1155).
reduced when compared with the awake state. At the sametime, the reduction in cardiac output resulted in an overalldecrease in oxygen delivery. Since oxygen consumptionalso decreased and oxygen extraction remained unchanged indicating a markedly reduced oxygen demand, we suggest The purpose of our prospective study was to evaluate the that this was most likely caused by a reduced metabolic maternal cardiopulmonary function and lung water content rate during anaesthesia. Similarly, the reduced cardiac in mid-gestational women undergoing percutaneous feto- output was mainly caused by a lowered heart rate that scopic interventions under general maternal – fetal anaes- coincided with the infusion of remifentanil. In one case, thesia and continuous tocolytic medication. Whereas the heart rate reduction lowered cardiac output below 3.0 litre shortest procedures took about 60 min, an exceptional case min21 m22 and therefore, in the absence of hypovolaemia, of a very large thoraco-lumbo-sacral spina bifida aperta was treated with a low dose infusion of epinephrine to required 10.5 h for waterproof coverage in several layers.
stabilize maternal systemic and uteroplacental blood flow.
Maternal haemodynamics and pulmonary gas exchange However, stroke volume remained constant in all women stable during and after the interventions.
indicating no detrimental effects on maternal myocardial However, a moderate increase in EVLW and pulmonary function. In agreement with these results, remifentanil did vascular permeability indicates an increased risk for not produce further cardiovascular depression in a recent maternal pulmonary oedema in these patients undergoing study in women with severe pre-existing cardiovascular Maternal pulmonary oedema has been shown to be a major problem during fetal interventions4 15 16 occurring In this study, fluid administration was performed very in about one-fourth of women regardless of whether an carefully under close monitoring of ITBV and EVLW. The open surgical or less invasive fetoscopic approach was transpulmonary indicator dilution method to assess EVLW used.4 Before the series of patients reported, we also closely correlates with the gravimetric method, which is observed one case of maternal pulmonary oedema after the gold standard to determine lung water content.14 20 It our first attempt at fetoscopic patch coverage of spina has been validated both in animals8 and in patients,7 13 21 bifida aperta.5 Although the anaesthetic and tocolytic and is being routinely used for cardiopulmonary monitor- regimen for fetal surgery may promote maternal pulmon- ing of critically ill patients at the bedside in the ICU and ary oedema, the mechanisms of fluid accumulation in the during surgery.22 Normal values for ITBV have been pro- maternal lungs have not been completely understood.6 posed to be 850 – 1000 ml m22 body surface area and ,7 During fetoscopic interventions, significant amounts of ml kg21 body weight for EVLW.11 – 13 In addition, the fluids can be absorbed into the maternal circulation and, EVLW/ITBV ratio has been used as a measure of micro- consequently, may induce maternal fluid overload, if con- vascular pulmonary permeability,11 12 14 the normal ratio tinuous amniotic fluid exchange with crystalloid solutions of which is between 0.2 and 0.3.11 – 13 The rationale of is used for uterine distension in order to improve visualiza- using the EVLW/ITBV ratio as a measure of pulmonary tion. Therefore, current treatment strategies for fetal inter- microvascular permeability is based on the fact that ventions include maternal fluid restriction to avoid any EVLW may be increased by an abnormal vascular per- impairment of pulmonary gas exchange.4 15 16 However, meability or an increase in hydrostatic pressure. Since the volume depletion may impair maternal systemic blood increase in EVLW in hydrostatic pulmonary oedema is flow and as a consequence promote the risk of uterine due to an increase in pulmonary blood volume and hypoperfusion perioperatively.17 Therefore, balancing the pressure, the EVLW/ITBV ratio should be much lower benefits and the risks of fluid restriction is a challenge in In the present study, pulmonary gas exchange was We for the first time systematically investigated the normal during and after the fetoscopic interventions.
maternal lung water content and cardiovascular status However, EVLW was above the normal range, despite a restrictive infusion protocol which aimed at a relatively Fetal interventions: maternal haemodynamics low ITBV which has been shown to be an accurate surro- 9 Meier P, Zierler KL. On the theory of indicator-dilution method gate parameter of intravascular filling even during mech- for measurement of blood flow and volume. J Appl Physiol 1954; anical ventilation.23 24 Calculations of pulmonary vascular 10 Newman EV, Merrel M, Genecin A, et al. The dye dilution permeabiltity as the ratio of EVLW to ITBV resulted in method for describing the central circulation. An analysis of values being moderately increased in our patients. In factors shaping the time – concentration curves. Circulation 1951; addition, linear regression analysis did not show any sig- nificant correlation between systemic blood flow, mean 11 Honore PM, Jacquet LM, Beale RJ, et al. Effects of normothermia pulmonary arterial pressure, pulmonary arterial occlusion versus hypothermia on extravascular lung water and serum cyto- pressure, ITBV, and EVLW. These results may indicate kines during cardiopulmonary bypass: a randomized, controlled that hydrostatic mechanisms were unlikely to cause the trial. Crit Care Med 2001; 29: 1903 – 9 12 Matejovic M, Krouzecky A, Rokyta R, Jr, et al. Fluid challenge in slight increase in EVLW in our patients.25 patients at risk for fluid loading-induced pulmonary edema. Acta In conclusion, the moderate increases in lung water content and pulmonary vascular permeability confirm the 13 Groeneveld AB, Verheij J. Extravascular lung water to blood clinical observation that pregnant women are prone to volume ratios as measures of permeability in sepsis-induced ALI/ accumulate relevant amounts of water in the lung intersti- ARDS. Intensive Care Med 2006; 32: 1315 – 21 tium. However, percutaneous fetoscopic interventions under 14 Katzenelson R, Perel A, Berkenstadt H, et al. Accuracy of trans- general anaesthesia can be performed safely for mothers as pulmonary thermodilution versus gravimetric measurement ofextravascular lung water. Crit Care Med 2004; 32: 1550 – 4 concerns cardiopulmonary function. In technically difficult 15 DiFederico EM, Burlingame JM, Kilpatrick SJ, et al. Pulmonary and long-lasting procedures, the transpulmonary indicator edema in obstetric patients is rapidly resolved except in the pre- dilution method provides valuable information of the sence of infection or of nitroglycerin tocolysis after open fetal maternal cardiovascular status and lung water content surgery. Am J Obstet Gynecol 1998; 179: 925 – 33 which can be used to balance fluid therapy, intra-amnial 16 DiFederico EM, Harrison M, Matthay MA. Pulmonary edema in a fluid administration, and vasoactive medication.
woman following fetal surgery. Chest 1996; 109: 1114 – 7 17 Harrison MR, Adzick NS, Flake AW, et al. Correction of conge- nital diaphragmatic hernia in utero: VI. Hard-earned lessons.
J Pediatr Surg 1993; 28: 1411 – 7 18 Mabie WC, DiSessa TG, Crocker LG, et al. A longitudinal study This work was supported by departmental resources.
of cardiac output in normal human pregnancy. Am J ObstetGynecol 1994; 170: 849 – 56 19 Orme RM, Grange CS, Ainsworth QP, et al. General anaesthesia using remifentanil for caesarean section in parturients with criti- cal aortic stenosis: a series of four cases. Int J Obstet Anesth 2004; 1 Kohl T, Szabo Z, Suda K, et al. Fetoscopic and open transumbilical fetal cardiac catheterization in sheep. Potential approaches for 20 Kirov MY, Kuzkov VV, Kuklin VN, et al. Extravascular lung water human fetal cardiac intervention. Circulation 1997; 95: 1048 – 53 assessed by transpulmonary single thermodilution and postmor- 2 Kohl T. Fetoscopic surgery: where are we today? Curr Opin tem gravimetry in sheep. Crit Care 2004; 8: 451 – 8 21 Michard F, Schachtrupp A, Toens C. Factors influencing the esti- 3 Kohl T, Hering R, Van dV, et al. Analysis of the stepwise clinical mation of extravascular lung water by transpulmonary thermodi- introduction of experimental percutaneous fetoscopic surgical lution in critically ill patients. Crit Care Med 2005; 33: 1243 – 7 techniques for upcoming minimally invasive fetal cardiac interven- 22 Kuzkov VV, Kirov MY, Sovershaev MA, et al. Extravascular lung water determined with single transpulmonary thermodilution 4 Golombeck K, Ball RH, Lee H, et al. Maternal morbidity after correlates with the severity of sepsis-induced acute lung injury.
maternal – fetal surgery. Am J Obstet Gynecol 2006; 194: 834 – 9 5 Kohl T, Hering R, Heep A, et al. Percutaneous fetoscopic patch 23 Lichtwarck-Aschoff M, Beale R, Pfeiffer UJ. Central venous coverage of spina bifida aperta in the human—early clinical experience and potential. Fetal Diagn Ther 2006; 21: 185 – 93 thoracic blood volume, and right ventricular end-diastolic volume 6 Pratt S. Uterine relaxation. In: Myers LB, Bulich LA, eds.
as indicators of cardiac preload. J Crit Care 1996; 11: 180 – 8 Anesthesia for Fetal Intervention and Surgery. Hamilton, London: BC 24 Sakka SG, Bredle DL, Reinhart K, et al. Comparison between intrathoracic blood volume and cardiac filling pressures in the 7 Sakka SG, Ruhl CC, Pfeiffer UJ, et al. Assessment of cardiac early phase of hemodynamic instability of patients with sepsis or preload and extravascular lung water by single transpulmonary septic shock. J Crit Care 1999; 14: 78 – 83 thermodilution. Intensive Care Med 2000; 26: 180 – 7 25 Garcia-Delgado M, Colmenero-Ruiz M, Fernandez-Sacristan MA, 8 Neumann P. Extravascular lung water and intrathoracic blood et al. Effect of a catecholamine-induced increase in cardiac volume: double versus single indicator dilution technique.
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Ch 30

CHAPTER 30 Pharmaceutical Products 1. This Chapter does not cover: (a) Foods or beverages (such as dietetic, diabetic or fortified foods, food supplements, tonic beverages and mineral waters)other than nutritional preparations for intravenous administration (Section IV); Plasters specially calcined or finely ground for use in dentistry (heading 2520); Aqueous distillates or aqueou

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