低体温对心血管功能的影响

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Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Author's personal copy Resuscitation 83 (2012) 760– 766 Contents lists available at SciVerse ScienceDirect Resuscitation j ourna l h o me pag e: www. elsev ier .com/ locate / resusc i ta t ion Experimental paper Cardiovascular and microvascular responses to mild hypothermia in an ovine model� Xinrong He, Fuhong Su, Fabio Silvio Taccone, Leonardo Kfuri Maciel, Jean-Louis Vincent ∗ Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Belgium a r t i c l e i n f o Article history: Received 15 September 2011 Received in revised form 20 November 2011 Accepted 29 November 2011 Keywords: Cardiac function Haemodynamics Microcirculation Therapeutic hypothermia Lactic acidosis a b s t r a c t Aims: Hypothermia is used for brain protection after resuscitation from cardiac arrest and other forms of brain injury, but its impact on systemic and tissue perfusion has not been well defined. The aim of this study was to evaluate the cardiovascular and microvascular responses to mild therapeutic hypothermia (MTH) in an ovine model. Methods: Seven anaesthetised, mechanically ventilated, invasively monitored sheep were cooled from a baseline temperature of 39–40 ◦C to 34 ◦C using cold intravenous fluids, ice packs and transnasal cooling. After 6 h of MTH, sheep were progressively re-warmed to baseline temperature. Positive fluid balance was maintained during the entire study period to avoid hypovolemia. In addition to standard haemo- dynamic assessment, the sublingual microcirculation was evaluated using sidestream dark-field (SDF) videomicroscopy. Results: MTH was associated with significant decreases in cardiac index and left (LVSWI) and right (RVSWI) ventricular stroke work indexes. There was a downward shift in the relationship between LVSWI and pulmonary artery occlusion pressure during MTH, indicating myocardial depression. During MTH, mixed venous oxygen saturation increased, in association with reduced oxygen consumption, but blood lactate concentrations increased significantly. There was a significant decrease in the proportion and density of small perfused vessels. All variables returned to baseline levels during the re-warming phase. Conclusion: In this large animal model, MTH was associated with decreased ventricular function, oxygen extraction and microvascular flow compared to normothermia. These changes were associated with increased blood lactate levels. These observations suggest that MTH may impair tissue oxygen delivery through maldistribution of capillary flow. © 2011 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Mild therapeutic hypothermia (MTH), with temperatures between 32 and 34 ◦C, has been shown to improve survival and neu- rological outcome after cardiac arrest and can also be beneficial in other forms of brain injury.1–3 In recent years, together with a better understanding of the mechanisms underlying its neuroprotective effects, important insights have been gained into the physiolog- ical and pathophysiological changes associated with cooling.1 In particular, hypothermia may contribute to peripheral vasocon- striction and potentially affect the microcirculation after cardiac arrest.4 The microcirculation is a major determinant of oxygen and � A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2011.11.031. ∗ Corresponding author at: Department of Intensive Care, Erasme University Hos- pital, Route de Lennik 808, 1070 Brussels, Belgium. Tel.: +32 2 555 3380; fax: +32 2 555 4555. E-mail address: jlvincen@ulb.ac.be (J.-L. Vincent). nutrient delivery to the tissues, and impaired microcirculatory flow and reactivity have been described in several critical illnesses, including cardiogenic and haemorrhagic shock, cardiac arrest and sepsis.4,5 These microcirculatory alterations are associated with the development of organ failure and with worse outcome.6 However, the relationship between changes in systemic haemo- dynamics and the peripheral microcirculation during MTH have not been well defined. Experimental observations on the cardiovascu- lar consequences of cooling have been conflicting with studies on isolated heart preparations showing that hypothermia can enhance the contractility of mammalian heart cells,7,8 but animal studies showing that MTH may depress ventricular function.9,10 More- over, clinical data are limited (Table 1), no specific evaluation of the effects on global and tissue perfusion has been conducted, and only specific clinical conditions, such as cardiac surgery or post-cardiac arrest, have been investigated. It thus remains unclear whether observed changes are related to a physiological adjust- ment to the balance between oxygen supply and demand, which are both reduced during hypothermia, or whether hypothermia per se has deleterious effects on tissue perfusion. 0300-9572/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2011.11.031 Author's personal copy X. He et al. / Resuscitation 83 (2012) 760– 766 761 Table 1 Summary of key experimental and clinical studies (in chronological order) that have evaluated the effects of hypothermia on cardiac function. First author, publication date, ref. Study Key findings Laboratory studies Saunders (1958)44 Isolated pig ventricular strips at 32 ◦C Increased contractility Shattock (1987)33 Isolated rabbit and rat ventricular muscles studied at 37 ◦C, 33 ◦C and 23 ◦C Increased contraction tension Suga (1988)45 Excised cross-circulated dog ventricle cooled to about 29 ◦C Emax increased by 46 ± 13% Greene (1989)9 Pigs on partial ventricular bypass, at 34 ◦C LV regional work decreased, diastolic relaxation impaired Schroder (1994)15 Sheep infused with low dose dopamine at 29 ◦C LV end-diastolic pressure increased. Contraction and relaxation velocity changed slightly Mattheussen (1996)7 Isolated rabbit hearts cooled to 30 ◦C At HR ≥90 bpm, systolic LV pressure was lower, diastolic LV pressure higher, and positive and negative LV dP/dt lower than in normothermia Tveita (1994)46 and (1998)26 Dogs at 25 ◦C Depressed functional LV variables Stowe (1999)27 Isolated and paced guinea pig hearts at 27 and 17 ◦C Increased intracellular Ca2+ and LV contractility Weisser (2001)19 Isolated ventricular myocardium from pig or patients after cardiac arrest, cooled from 37 ◦C to 31 ◦C Isometric twitch force increased by 50 ± 9% (pigs) and by 91 ± 16% (patients) Inoue (2003)8 Isolated ischaemia-reperfused rat hearts, cooled in ice at ≤4 ◦C for 3 min LV contraction increased to 105% of pre-ischaemia value Nishimura (2005)37 In situ dog’s hearts, surface-induced hypothermia to 32 ◦C Emax increased from 3.4 to 4.4. Cardiac output, HR and SV decreased Fischer (2005)10 Dogs at 35 ◦C LV diastolic function impaired but not systolic function Jacobshagen (2010)21 Isolated failing human myocardium, cooled from 37 ◦C to 33 ◦C Contraction force increased by up to 120% Chenoune (2010)22 Rabbits with coronary artery occlusion cooled to 32 ◦C using either total lung ventilation (TLV) or surface device Only cooling induced by TLV prevented transmural infarction and provided cardioprotection Ristagno (2010)20 Isolated ventricular myocytes exposed to normal perfusion or ischaemia-reperfusion in rats, cooled from 37 ◦C to 34 ◦C, 32 ◦C, and 30 ◦C Increased contractility Gotberg (2010)23 Ischaemic cardiogenic shock pig model cooled to 33 ◦C Cardiac output increased slightly, HR decreased, SV increased, acute mortality reduced Baumgart (2010)36 Mice cooled from 38 ◦C to 27 ◦C LV ejection fracture increased from 44% to 50% Post (2010)18 Pigs at 33 ◦C Decrease in diastolic function Filseth (2010)17 Pigs cooled to 25 ◦C for 1 h Reduced systolic but not diastolic ventricular function, (increase in troponin T levels during rewarming) Clinical observations in adult patients Moriyama (1996)47 Hypothermia (33 ◦C) combined with intra-aortic balloon pump support to low cardiac output state after open heart surgery Better outcome Kuwagata (1999)48 Patients with severe head injury with mild hypothermia (33.5–34.5 ◦C) for 48 h Attenuated peak velocity of LV posterior wall movement during systole and diastole Lewis (2002)34 Five patients undergoing coronary artery bypass grafting, cooled to 33 ◦C Improvement in systolic function with HR = 80 bpm but contractility decreased when HR = 120 bpm Hovdenes (2007)49 Out-of-hospital cardiac arrest −32 to 34 ◦C Better outcome Bergman (2010)35 Out-of-hospital cardiac arrest, 32.5 ◦C for 24 h Cardiac output and MAP decreased despite increased vasopressors and inotropes Jacobshagen (2010)21 Cardiac arrest survivors: mild hypothermia (∼35.4 ◦C) Stabilised haemodynamics LV: left ventricular; SV: stroke volume; HR: heart rate; MAP: mean arterial pressure. The aim of this study was, therefore, to evaluate, in a healthy ovine model, the cardiovascular and microvascular responses to MTH. 2. Materials and methods 2.1. Animals Experiments were performed on seven female sheep (31.1 ± 0.9 kg) that were fasted in a ventilated and controlled temperature chamber (20–24 ◦C) for 24 h before the study, with water ad libitum. Care and handling of the animals were in accor- dance with National Institute of Health Guidelines (Institute of Laboratory Animal Resources). 2.2. Preparation Each animal was intramuscularly premedicated with 0.25 mg/kg of midazolam (Dormicum, Roche SA, Belgium) and 20 mg/kg of ketamine hydrochloride (Imalgine, Merial, Lyon, France), then placed supinely on an operating table. The cephalic vein was cannulated with a peripheral venous 18G catheter (Surflo I.V Catheter, Terumo, Belgium). Fentanyl (Fentanyl, Janssen, Berchem, Belgium) (30 �g/kg) and rocuronium (Esmeron, Organon, Oss, the Netherlands) (0.1 mg/kg) were administered intravenously and the trachea was intubated (Tracheal Tube, 8.0; Hi-Contour, Mallinckrodt Medical, Ireland). Anaesthesia was then maintained with a continuous infusion of ketamine (10 mg/kg/h), morphine (0.5 mg/kg/h), midazolam (0.5 mg/kg/h) and rocuro- nium (0.1 mg/kg/h) through the cephalic vein. Boluses of fentanyl (15 �g/kg) were administered intravenously if anaesthesia was insufficient. During the surgical preparation, mechanical ven- tilation was administered in volume-controlled mode (Servo ventilator 900C, Siemens–Elema, Sweden) with a tidal volume of 10 mL/kg, a positive end-expiratory pressure (PEEP) of 5 cm H2O, an inspired oxygen fraction (FiO2) of 1, and an inspiratory time/expiratory time (I/E) of 1:2. The stomach was emptied with a 60 cm plastic tube (inner- diameter 1.8 cm) to avoid gastric reflux during ventilation and a Foley bladder catheter (14F, Beiersdorf AG, Germany) was placed to collect urine output. The right femoral artery and vein were surgically exposed and an arterial catheter (6F Vygon, Cirences- ter, UK) was implanted and connected to a pressure transducer (Edwards, Lifescience, CA, USA) zeroed at the midthorax level. An introducer was inserted through the femoral vein, and a 7F Swan-Ganz catheter (Edwards Life Sciences, Baxter, Irvine, CA, USA) was advanced into the pulmonary artery under mon- itoring of pressure waveforms. The animal was then turned Author's personal copy 762 X. He et al. / Resuscitation 83 (2012) 760– 766 to the prone position and allowed to reach a stable baseline condition. 2.3. Measured haemodynamic variables Monitored haemodynamic variables included heart rate (HR), mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), central venous pressure (CVP), pulmonary artery occlu- sion pressure (PAOP) and cardiac output (CO). HR, MAP, MPAP (Sirecust 404 Siemens, Germany), CO, core temperature (Vigilance Baxter, Edwards Critical-Care, USA) and ventilator parameters were continuously monitored; CVP and PAOP were measured at every observation point. Derived variables, including stroke volume (SV), systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), left ventricular stroke work index (LVSWI), right ventricular stroke work index (RVSWI) and oxygen extraction index (O2EI) were calculated using standard formulas.11 Oxygen consumption index (VO2I) was calculated using the Fick equation.11 The body surface area of the sheep was calculated from the equation BSA = 0.084 × [body weight (kg)]2/3.12 At every observation point, urine output (UO) was measured with a graduated cylinder; the infused fluid volume was recorded hourly and maintained above UO. 2.4. Sublingual microcirculation The sublingual microvascular network was visualised using sidestream dark-field (SDF) videomicroscopy (MicroScan, MicroVi- sion Medical, The Netherlands), with a 5× imaging objective giving 380× magnifications. At least 5 videos lasting 20 s were acquired at each time point. After all experiments, the videos were anony- mously randomised and analysed by two independent researchers (H.X. and F.S.) according to the procedure described by De Backer et al.13 The proportion of small perfused vessels (sPPV), the per- fused small vessel density (sPVD), mean flow index (MFI) and the heterogeneity indexes of PPV (htPPV) and MFI (htMFI) were evalu- ated according to the round table conference consensus.13 2.5. Experimental protocol After baseline measurements, each sheep received a 4 ◦C saline infusion at a rate of 1000 mL/h via the cephalic vein catheter. Simul- taneously, ice packs were placed around the sheep and a nasal cooling set (RhinoChill System, Benechill, CA, USA) was applied by insufflating the mixed vapour of a perfluorochemical and air into the sheep’s rhinopharynx tract at a flow of 40–60 L/min.14 When the core temperature decreased to approximately 34.5 ◦C, nasal cooling was stopped and the saline infusion replaced with a Hartmann’s solution at a rate of 2 mL/kg/h. The target temper- ature was maintained at 34–35 ◦C by applying or removing ice packs. After 6 h of maintenance, all ice packs were removed and the sheep was re-warmed to baseline temperature in 4–5 h using an electrothermal blanket. During the protocol, ventilator settings were adjusted according to the temperature-corrected blood gas values to maintain a PaO2 ≥12 kPa (≥90 mmHg) and PaCO2 of 5.0–5.5 kPa (38–41 mmHg). Arterial and mixed venous blood sam- ples were analysed with automated analysers (ABL725 and OSM3, Radiometer Medical A/S, Denmark). The rate of fluid infusion was adjusted to maintain a positive fluid balance. All variables were recorded every 60 min during the maintenance phase and at each degree (36–40 ◦C) during re-warming. The sublingual microcircu- lation was investigated at four time-points: baseline (T1), 1 h after starting MTH (T2), at the end of the MTH phase (T3), and at the end of re-warming (T4). 2.6. Statistical analysis Data were checked for normality using the Shapiro–Wilk test. Data consistent with a Gaussian distribution are presented as mean ± SD and other data as median values with quartiles (ranges). Repeated measures analysis of variance (ANOVA) for time compar- ison was used, with Bonferroni correction for Post hoc analysis. Cluster analysis was used to categorise the relationship between CI and O2EI into different groups, according to the main time-points of the study, i.e., baseline, hypothermia, and re-warming. Statis- tical tests were two-tailed and differences were considered to be statistically significant at p < 0.05. The statistical analyses were per- formed with software SPSS Statistics 17.0 (SPSS Inc., Chicago, IL, USA). 3. Results The cooling phase lasted 61 ± 13 min, and the re-warming phase 267 ± 37 min. Core temperature decreased from 39.5 ± 0.5 ◦C at baseline to 34.6 ± 0.3 ◦C, and remained stable during the main- tenance phase. Urine output was 37 ± 11 mL/h in the cooling phase, 109 ± 32 mL/h in the maintenance phase, and 58 ± 27 mL/h in the rewarming phase. There was a positive fluid balance of 1112 ± 215 mL in the cooling phase, 1213 ± 274 mL in the main- tenance phase and 1174 ± 256 mL in the rewarming phase. There were no significant changes in MAP, MPAP, PAOP or CVP during the study period (Table 2). Despite an increase in HR, CI and DO2 decreased during MTH (Fig. 1), whereas vascular resistances increased (Table 2). LVSWI and RVSWI also decreased significantly during cooling (Fig. 1). The relationship between LVSWI and PAOP showed a downward shift during hypothermia compared to nor- mothermia (Fig. 2). All these variables returned to baseline levels at the end of the re-warming phase. VO2I and O2EI decreased dur- ing MTH, but increased above baseline levels during rewarming (Table 2). The relationship between CI and O2EI did not change during the study period (Fig. 3 Microcirculatory analysis showed a significant reduction in sPPV, sPVD and MFI during MTH when compared to baseline nor- mothermic values, which recovered during the rewarming phase (Table 2, Fig. 4). htPPV and htMFI increased significantly during MTH and returned to baseline values after rewarming. The blood lactate concentration increased slightly but significantly during the study period and returned to baseline values after rewarming (Table 2). 4. Discussion From the results of this study, MTH may result in: (a) a decrease in cardiac function, as shown by a reduction in ventricular stroke work in the absence of hypovolaemia; (b) a decrease in oxygen consumption and extraction; (c) a limited but consistent increase in blood lactate levels despite maintenance of positive fluid balance; (d) an impairment in peripheral microcirculatory density and flow occurring in the absence of hypotension. Harmful effects of MTH on the myocardium, including reduced contractility and CO or mild diastolic dysfunction without impair- ment in systolic function, have been reported in animal10,15 and human studies.16 In pigs on partial ventricular bypass and cooled from 38 ◦C to 34 ◦C, Greene et al. reported a marked depression of left ventricular contractility and a significant impairment in dias- tolic relaxation.9 In another pig model, cooling to 25 ◦C for 1 h resulted in reduced systolic but not diastolic ventricular function.17 This myocardial depression was associated with an increase in troponin T levels at rewarming, suggesting myocardial damage, although there was no evidence of inadequate global oxygenation. Author's personal copy X. He et al. / Resuscitation 83 (2012) 760– 766 763 Table 2 Haemodynamic, metabolic and microcirculatory variables during the study. Parameters T1 (baseline) T2 (1 h after starting MTH) T3 (end of MTH) T4 (end of re-warming phase) ANOVA Heart rate (beats/min) 121 ± 10 147 ± 31* 150 ± 14* 132 ± 13 0.032 Cardiac index (L/min/m2) 6.2 ± 0.7 5.3 ± 0.8* 5.0 ± 0.4* 6.6 ± 0.9 0.001 Stroke index (mL/beat/m2) 51.6 ± 5.5 36.7 ± 6.2* 33.5 ± 5.1* 49.6 ± 6.1 <0.001 MAP (mmHg) 107.1 ± 10.1 95.6 ± 18.0 100.7 ± 10.5 96.0 ± 10.9 NS MPAP (mmHg) 15.9 ± 2.3 20.0 ± 5.9 16.0 ±