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    Levo semendan Levo semendan Document Transcript

    • Scandinavian Cardiovascular Journal, 2011; 45: 307–315 ORIGINAL ARTICLE Levosimendan decreases intracranial pressure after hypothermic circulatory arrest in a porcine model HANNA JENSEN1,2, RIMPILÄINEN EIJA1,2, MÄKELÄ TUOMAS1,2, MÄKELÄ JUSSI1,2, YANNOPOULOS FREDRIK1,2, ALESTALO KIRSI1,2, POKELA MATTI1,2, KIVILUOMA KAI1,3, TUOMINEN HANNU1,4,Scand Cardiovasc J Downloaded from informahealthcare.com by McGill University on 05/20/12 ANTTILA VESA1,2 & JUVONEN TATU1,2 1Clinical Research Center, 2Department of Surgery, 3Department of Anesthesiology and 4Department of Pathology, Oulu University Hospital, University of Oulu, Finland Abstract Objectives. Hypothermic circulatory arrest (HCA) provides an optimal operating field in aortic arch surgery, but it is asso- ciated with neurological complications. Levosimendan is an inotropic agent with clinical indications for open-heart surgery. Through peripheral vasodilatation, cardiac contractility enhancement and anti-inflammatory function it has a potential to For personal use only. improve cerebral protection after HCA. Design. Eighteen piglets were randomly assigned to a levosimendan group (n ϭ 9) and a placebo group (n ϭ 9) and underwent a 60-minute period of hypothermic circulatory arrest at 18°C. A levosimendan or placebo infusion (0.2 μg/kg/min) was commenced at the onset of anesthesia and continued for 24 hours. Animals were followed for one week and their neurological recovery was assessed daily. Finally the animals were electively sacrificed and their brain was harvested for histopathological examination. Results. Levosimendan decreased intracranial pressure during the experiment. There were no differences between the groups in terms of hemodynamic or metabolic data, brain metab- olism, neurological recovery or histopathology of the cerebral tissue. In the levosimendan group, cardiac enzymes were slightly more elevated. Conclusions. Levosimendan decreased intracranial pressure during the experiment, but in terms of cerebral metabolism, neurological recovery and histopathology of the brain tissue levosimendan did not improve brain protection in this experimental setting. Key words: hypothermic circulatory arrest, cerebral protection, levosimendan Hypothermic circulatory arrest (HCA) provides an peripheral arterial and venous dilatation (8). These optimal operating field in aortic arch surgery, but it two drug-induced actions lead to a reduction of is associated with an increase in neurological compli- peripheral vascular resistance and cardiac workload, cations due to global cerebral ischemia and reperfu- and thus result in a significant increase of cardiac sion injury. Numerous studies with various strategies, output (9). pharmacological interventions and approaches have In addition to its hemodynamic properties, attempted to find means to improve the neurological some studies have shown levosimendan to be anti- outcome of patients after surgery with HCA (1–3). inflammatory. The beneficial effects of levosimendan Levosimendan is a promising alternative inotro- on circulating pro-inflammatory cytokines (IL-6) pic agent with possible clinical indication for open- and soluble apoptosis mediators (TNF-α) have been heart surgery (4,5). It enhances cardiac contractility shown in a randomized, placebo-controlled study by improving the response of the myofilaments to (10). It is also plausible to assume that the cardio- intracellular calcium (6) and opens the adenosine vascular effects of levosimendan can decrease periph- triphosphate (ATP) dependent potassium channels eral tissue hypoperfusion, leading to down-regulation in the vascular smooth muscle cells (7), causing of systemic cytokine production (11). Correspondence: Hanna Alaoja Jensen, Clinical Research Center, Oulu University Hospital, P.O. Box 5000, 90014 Oulu University, Finland. Tel: ϩ358 40 7732183. Fax: ϩ358 8 315 2577. E-mail: hanna.alaoja.jensen@gmail.com (Received 14 February 2011; accepted 19 April 2011) ISSN 1401-7431 print/ISSN 1651-2006 online © 2011 Informa Healthcare DOI: 10.3109/14017431.2011.583356
    • 308 H. Jensen et al. We hypothesized that levosimendan’s beneficial Study drug administration hemodynamic effects create an advantageous envi- A continuous intravenous levosimendan or placebo ronment for the preservation of cerebral tissue. Fur- infusion (0.2 μg/kg/min) was commenced as soon as thermore, the immunological component of the the animal was under anesthesia and continued for reperfusion injury following deep HCA is thought to 24 h, excluding the time period of circulatory arrest play a major role in the development of post-operative (60 minutes). The drug and placebo were of same cerebral damage. In several studies, reduced accumu- consistence and color and the conductors of the lation of leukocytes has been associated with a reduced experiment were blinded to the protocol. histological inflammatory response and ischemic brain injury (12,13). The aim of this study was to investigate whether levosimendan could improve Hemodynamic monitoring cerebral protection after deep HCA; possible mecha- nisms being the advantageous hemodynamic condi- An arterial line for arterial pressure monitoring and tions for the cerebral tissue and reduced effect of blood sampling was placed on the left femoral artery. systemic inflammatory response in the brain. A pulmonary artery thermodilution catheter (Criti-Scand Cardiovasc J Downloaded from informahealthcare.com by McGill University on 05/20/12 Cath, 7 French [Ohmeda GmbH & Co, Erlangen, Germany]) for blood sampling, monitoring the pul- Material and methods monary pressure, measuring the cardiac output, pul- Experimental setting monary capillary wedge pressure as well as central venous pressure and recording of the temperature of Eighteen 6–7 week-old piglets were randomly blood was introduced through the left femoral vein. assigned to undergo CPB and a 60-minute HCA at A 10 French catheter was placed in the urinary blad- 18°C with a 24-hour (0.2 μg/kg/min) infusion of der to monitor urine output. Baseline measurements levosimendan (n ϭ 9) or placebo (n ϭ 9) commenced were recorded. at the onset of anesthesia. Cerebral metabolism and A right anterolateral thoracotomy was performed For personal use only. intracranial pressure were monitored during and in the fourth intercostal space to expose the right after surgery. Surviving animals were followed for atrium for CPB cannulation. The right thoracic ves- one week post-operatively and their neurological sels were ligated and cut and the pericardium was recovery was assessed daily. At the end of the exper- opened. After systemic heparinization (500 IU/kg), iment, the animals were electively sacrificed and their the ascending aorta was cannulated with a 16 French brain was harvested for histopathological examina- arterial cannula, and the right atrial appendage was tion. All animals received humane care in accordance cannulated with a single 24 French atrial cannula. A with the “Principles of Laboratory Animal Care” for- 12 French intracardiac sump cannula was positioned mulated by the National Society for Medical Research into the apex of the heart for decompression of the and the “Guide for the Care and Use of Laboratory heart during CPB. Animals” prepared by the Institute of Laboratory Animal Resources, National Research Council (pub- lished by the National Academy Press, revised in Cranial procedures 1996). The study was approved by the Research Animal Care and Use Committee of Finland. Two small windows (about 5 mm in diameter) were drilled over the parietal cortex. In one of them, a temperature probe (Thermocouple Temperature Anesthesia protocol Catheter-Micro-Probe, Ref C8.B [GMS]) was Piglets were sedated with intramuscular ketamine inserted to monitor intracerebral temperature hydrochloride (350 mg) and midazolam (45 mg). throughout the experiment. Into the same window, Using thiopental for further sedation as required, the a pressure-monitoring catheter (Codman Micro- piglets were intubated with a 6 mm cuffed endotra- Sensor ICP Transducer, Codman ICP Express Mon- cheal tube and ventilated with 50% oxygen and a rate itor [Codman & Shurtleff, Inc, Raynham, MA]) was of 12–15 breaths per minute, to achieve an end-tidal placed into the cerebral tissue. carbon dioxide concentration in the expired air In the second window, a microdialysis catheter (EtCO2) of 4.5–5.0%. After induction with fentanyl (CMA 70 [CMA/Microdialysis, Stockholm, Sweden]) (50 μg/kg), anesthesia was maintained by a continu- was placed into the brain cortex for a depth of ous infusion of fentanyl (25 μg/kg/h), midazolam 15 mm below the dura mater. The catheter was con- (0.25 mg/kg/h) and pancuronium (0.2 mg/kg/h), as nected to a 2.5 ml syringe placed into a microinfu- well as inhalation anesthesia of 0.5% isoflurane sion pump (CMA 106 [CMA/Microdialysis]) and throughout the entire experiment, excluding the perfused with Ringer solution at a rate of 0.3 μl/min period of HCA. (Perfusion Fluid CNS [CMA/Microdialysis]). Sample
    • Levosimendan decreases intracranial pressure after HCA 309 collection from microdialysis catheters was per- were measured at baseline, at the end of cooling, as formed at set time points peri-operatively (baseline, well as 30 min, 2 h, 4 h, and 8 h after the start of 30 min cooling, 30 min HCA, 60 min HCA, 30 min rewarming. At these time points, samples for cardiac rewarm, 1 h rewarm, 1 h 30 min rewarm, 2 h rewarm, troponin I and Creatine Kinase Isoenzyme MB 2 h 30 min rewarm, 3 h rewarm, 4 h rewarm, 5 h (CK-MB) were also collected. rewarm, 6 h rewarm, 7 h rewarm, 8 h rewarm). The concentrations of cerebral tissue glucose, lactate, pyruvate, glutamate, and glycerol were measured Blood transfusions immediately after collection with a microdialysis Fresh whole blood from a donor pig, drawn on the analyzer (CMA 600 [CMA/Microdialysis]). operative day, was transfused into the prime as required to maintain the hematocrit of all animals Cardiopulmonary bypass above 25% after the operation. After baseline recordings, a membrane oxygenator (D905 Eos [Dideco, Mirandola, Italy]) was primed Follow-upScand Cardiovasc J Downloaded from informahealthcare.com by McGill University on 05/20/12 with 1 l of Ringer acetate and heparin (5000 IU). Daily neurological assessment, elective sacrifice and Non-pulsatile CPB was initiated at a flow rate of the harvesting of brains after seven days, as well as a 90–110 ml/kg/min, and the flow was adjusted to histopathological analysis of the cerebral tissue were maintain an arterial pressure of 50 to 70 mmHg. performed as described in detail in our previous A 30-minute cooling period was carried out to studies (13). attain a brain temperature of 18°C. Cooling was managed according to the pH-stat method of CPB for 25 minutes. For the last five minutes preceding Statistical analysis the circulatory arrest, the cooling strategy was switched to α-stat principles. A heat exchanger was Statistical analysis was performed using SPSS (SPSS, For personal use only. used for core cooling. version 15.0, SPSS Inc, Chicago, IL) and SAS (ver- After 30 minutes of cooling, a 60-minute period sion 9.1.3, SAS Institute Inc., Cary, NC) statistical of HCA at 18°C was initiated and potassium chlo- software. Continuous and ordinal variables are ride (40 mmol) was injected towards the heart via expressed as the median and 25th and 75th percen- CPB arterial cannula. Cardiac cooling with topical tiles. SAS procedure Mixed was used for repeated ice slush was maintained throughout HCA. The measurements. Since the measurement intervals intracerebral temperature was controlled and main- were uneven, spatial exponential covariance struc- tained at 18°C with ice packs placed over the head. ture was defined in repeated statement. Complete At the beginning of rewarming furosemide independence was assumed across animals (by ran- (40 mg), methylprednisolone (80 mg), mannitol dom statement). Reported p-values are as follows: (150 g), calcium bioglyconate (2.25 mmol Ca2ϩ) and p-between groups (pg), indicates a level of difference lidocaine (40 mg) were administered into the pump. between the groups, p-time∗group (pt∗g), indicates During 45 minutes of rewarming, the piglets were behavior between the groups over time. Either Stu- warmed to 35°C with a 100 ml/kg/min flow rate, so dent’s t-test or Mann-Whitney U-test was used to that the warming gradient was 10°C or less at all assess the distribution of variables between the study times. Warming was carried out according to the groups. Two-tailed significance levels are reported. α-stat strategy. The heart was defibrillated if neces- P Ͻ 0.05 was considered statistically significant. sary at 30°C. The sump cannula was removed after 30 minutes of rewarming. Sufficient ventilation was restored 10 minutes before weaning from CPB, Results which itself occurred at 45 minutes after the start of Comparison of study groups rewarming. Noradrenalin was postoperatively used as The mean weight of the pigs was 23.2 kg (21.6–27.7) required. The animals of both groups were extubated in the levosimendan (LV)-group and 28.7 kg 8 h after the start of rewarming. (19.5–31.6) in the control group (p ϭ 0.585). Each group contained nine animals. All animals survived the surgery. In the LV-group, five animals lived for Biochemical data the entire observation period (seven days) and four Arterial blood gases, pH, electrolytes, serum ionized animals died on the first postoperative day. In the calcium, glucose and hemoglobin levels (i-STAT control group six animals lived for seven days, one Analyzer; i-STAT Corporation, East Windsor, NJ) died on the second postoperative day and two died
    • Scand Cardiovasc J Downloaded from informahealthcare.com by McGill University on 05/20/12 For personal use only. 310Table I. Experimental data. 30 min 2 hours 4 hours 8 hours P-value p-time∗ H. Jensen et al. Baseline End of Cooling after the start of rewarming between groups groupCardiac index (l/min/m2) 0.68 0.14 Levosimendan 3.98 (3.67–4.53) 2.33 (2.19–2.60) 2.26 (1.75–2.92) 3.03 (2.56–3.13) 2.80 (2.01–3.30) 2.56 (2.28–3.63) Control 3.52 (3.22–4.33) 2.76 (2.31–3.45) 2.60 (2.29–3.02) 2.64 (2.21–2.99) 2.43 (1.83–2.98) 2.56 (2.10–3.23)Mean arterial pressure (mmHg) 0.75 Ͼ 0.9 Levosimendan 87 (75–98) 61 (58–70) 62 (51–70) 79 (72–83) 96 (79–104) 90 (84–95) Control 83 (73–92) 63 (58–71) 61 (58–72) 73 (70–88) 89 (78–99) 85 (72–99)Heart rate (bpm) 0.33 0.13 Levosimendan 103 (94.5–118) – 138 (107–158) 124 (108–144.5) 136 (119–158) 162 (139–188) Control 106 (86.5–116.5) – 143 (86.5–173) 107 (98–124.5) 115 (103.5–135) 150 (112–162)Fluid balance (ml/kg) 0.07 0.43 Levosimendan 2.2 (0–8.6) 43.5 (23.5–54.8) 56.2 (33.6–62.4)∗ 38.1 (17.2–54.3) ∗ 26.3 (8.6–51.0) 36.5 (10.9–50.9) Control 1.5 (–1.1–5.3) 17.4 (10.0–49.2) 22.5 (14.7–44.4) 15.7 (1.6–26.8) 3.1 (–4.9–9.4) 18.6 (–0.6–39.9)Vascular resistance (dyn/s/cm–5) Ͼ 0.9 0.85 Levosimendan 2233 (1729–2555) 2829 (2275–3351) 3091 (1841–3851) 3024 (2382–3316) 3956 (2793–4566) 3079 (2314–4159) Control 2341 (1885–2773) 2437 (1714–3203) 2574 (2114–3364) 2387 (2079–3661) 3962 (2387–5135) 3716 (2402–4157)Hematocrit (%) 0.87 0.44 Levosimendan 25.0 (18.8–25.0) 26.0 (24.5–27.0) 25.0 (22.3–26.0) 26.0 (24.0–28.5) 28.0 (25.0–31.0) 27.0 (24.5–30.0) Control 21.0 (19.3–22.0) 25.0 (23.0–26.0) 24.5 (22.5–26.0) 27.0 (25.0–32.0) 31.0 (26.0–32.0) 30.0 (26.5–34.5)Intracerebral temperature (°C) 0.49 0.29 Levosimendan 37.4 (36.9–37.8) 17.9 (17.6–18.4) 29.8 (26.9–33.0) 33.3 (31.9–34.4) 36.1 (34.1–36.4) 37.4 (37.1–37.8) Control 37.3 (36.9–37.6) 18.0 (17.6–18.1) 33.0 (27.6–35.4) 32.4 (31.0–33.5) 35.7 (34.7–36.0) 37.8 (37.5–38.2)Rectal temperature (°C) 0.51 0.84 Lecvosimendan 37.5 (37.3–37.9) 17.3 (16.1–18.3) 27.0 (23.4–28.8) 32.9 (31.2–33.6) 35.7 (34.1–36.5) 37.0 (36.7–37.6) Control 37.7 (37.0–37.9) 17.8 (17.0–18.7) 25.5 (22.7–30.0) 33.0 (31.4–33.7) 36.0 (34.6–36.4) 37.9 (37.7–38.6)Blood temperature (°C) 0.27 0.30 Levosimendan 37.3 (37.1–37.9) 12.6 (11.6–15.2) 33.3 (32.2–34.7)∗ 33.1 (32.1–34.4) 36.2 (34.6–36.8) 37.7 (37.2–38.1) Control 37.5 (37.0–37.8) 13.1 (11.1–15.5) 35.2 (34.0–37.2) 33.2 (32.2–34.1) 36.1 (34.7–36.6) 38.3 (38–0–38.9)Cerebral perfusion pressure (mmHg) 0.15 0.42 Levosimendan 76 (68–94) 54 (53–59) 53 (47–63) 69 (59–76) 91 (77–100) 80 (74–83) Control 76 (64–85) 59 (48–64) 55 (51–64) 61 (57–69) 70 (63–80) 70 (53–83)Values are shown as medians and 25th and 75th percentiles; p-between groups: level of difference between groups. p-time∗group: behaviour between groups over time. ∗p-value Ͻ 0.05 at singletime point. Cardiac index: at end cool and 30 min rewarm points the determining value is pump flow. In other time points the cardiac output is used in determining the cardiac index.
    • Scand Cardiovasc J Downloaded from informahealthcare.com by McGill University on 05/20/12 For personal use only.Table II. Metabolic data. 30 min 2 hours 4 hours 8 hours P-value p-time∗ Baseline End of Cooling after the start of rewarming between groups grouppH 0.81 0.45 Levosimendan 7.53 (7.44–7.59) 7.14 (7.09–7.17) 7.36 (7.24–7.41) 7.34 (7.26–7.35) 7.43 (7.41–7.49) 7.43 (7.42–7.53) Control 7.48 (7.43–7.51) 7.15 (7.12–7.16) 7.33 (7.29–7.47) 7.36 (7.28–7.41) 7.44 (7.38–7.47) 7.45 (7.41–7.47)PaCO2 (kPa) 0.74 0.62 Levosimendan 4.7 (3.9–5.6) 14.1 (12.2–15.2) 5.4 (4.7–6.2) 5.8 (5.3–6.8) 5.7 (5.0–5.9) 5.0 (4.8–5.9) Control 4.8 (4.7–5.2) 12.7 (12.1–13.5) 5.1 (3.9–6.2) 5.7 (5.3–6.8) 5.5 (4.9–6.4) 5.1 (4.9–5.5)PaO2 (kPa) 0.037 0.s23 Levosimendan 34.6 (33.7–40.2) 106 (106–106) 75.8 (71.3–78.8)∗ 36.6 (31.7–40.1) 36.6 (33.6–46.1) 34.4 (31.3–37.9) Control 34.6 (27.3–38.4) 106 (106–106) 69.8 (59.2–74.1) 32.4 (19.1–36.9) 36.9 (32.5–39.5) 30.9 (27.4–39.0)SvO2 (%) Ͼ0.9 Ͼ0.9 Levosimendan 81 (68–85) 100 (100–100) 86 (74–90) 76 (74–80) 69 (54–77) 64 (57–78) Control 78 (69–81) 100 (100–100) 82 (78–86) 79 (74–81) 75 (58–79) 67 (45–76)Calsium ionized (mmol/l) 0.63 0.87 Levosimendan 1.35 (1.17–1.41) 1.52 (1.45–1.54) 1.50 (1.43–1.58) 1.19 (1.17–1.28) 1.33 (1.23–1.37) 1.19 (1.13–1.31) Control 1.31 (1.29–1.39) 1.49 (1.47–1.54) 1.54 (1.46–1.59) 1.18 (1.10–1.28) 1.32 ( 1.13–1.37) 1.21 (0.97–1.31)Venous glucose (mmol/l) 0.21 0.032 Levosimendan 4.3 (3.6–5.0) 4.3 (4.0–4.8) 9.0 (5.3–10.4)∗ 7.2 (4.7–8.0) 5.3 (4.7–5.8) 5.1 (4.4–6.1) Control 5.1 (3.2–5.7) 4.9 (4.5–5.7) 10.9 (9.2–13.7) 7.2 (5.9–9.2) 4.9 (4.2–5.2) 4.3 (4.1–4.7)Values are shown as medians and 25th and 75th percentiles; p-between groups: level of difference between groups. p-time ∗group: behaviour between groups over time. ∗p-value Ͻ 0.05 at singletime point. PaCO2: arterial CO2 partial pressure. PaO2: arterial oxygen partial pressure. SvO2: mixed venous oxygen saturation. Levosimendan decreases intracranial pressure after HCA 311
    • 312 H. Jensen et al. on the first postoperative day. Thus there was no sta- were no statistically significant differences in fluid tistically significant difference in survival (p ϭ 0.730). balance between the groups (Table I). There were no differences between the groups concerning osmolal- ity during the entire experiment (pg ϭ 0.84). Temperatures Three pigs in the LV-group and three pigs in the The cooling and rewarming times did not differ control group required a short infusion of noradren- between the study groups and lasted for a median of alin after the operation. The dosage needed to main- 30 min and 45 min, respectively. During hypother- tain mean arterial pressure above 60 mmHg was mic circulatory arrest, the brain temperatures were 7.9 μg/kg (2.6–24.8) in the LV-group and 4.7 μg/kg similar in both groups throughout the arrest, with a (4.5–11.5) in the control group (p ϭ 0.530). median of 18.0°C in the LV-group and 18.1°C in the control group (pg ϭ 0.27). Intracerebral, rectal and Metabolic data blood temperatures throughout the experiment are summarized in Table I. There were no significant differences between the groups concerning oxygen delivery (pg ϭ 0.66), oxy-Scand Cardiovasc J Downloaded from informahealthcare.com by McGill University on 05/20/12 gen consumption (pg ϭ 0.9) or oxygen extraction Hemodynamic data (pg Ͼ 0.9). The venous blood glucose was temporar- The heart rate tended to be higher in the LV-group, ily lower in the LV-group at 30 min after the start of but statistical significance could only be observed at rewarming, which also coincided with more dilution 4 h after hypothermic circulatory arrest (p ϭ 0.05). in terms of fluid balance in the LV-group (Tables I There were no significant differences between the and II). groups concerning cardiac index, mean arterial pres- sure, central venous pressure, cerebral perfusion Intracerebral monitoring pressure and vascular resistance during the entire For personal use only. experiment (Table I). The groups did not differ Intracranial pressure is displayed in Figure 1. There in terms of pulmonary capillary wedge pressure were no statistically significant differences in the (pg ϭ 0.42) or pulmonary artery pressures (pg ϭ 0.68). microdialysis data, namely cerebral glucose Both groups were sufficiently ventilated and oxygen- (pg ϭ 0.61), lactate (pg ϭ 0.46), pyruvate (pg ϭ 0.59), ated throughout the experiment. glutamate (pg ϭ 0.46) or glycerol (pg ϭ 0.94) during No differences were observed in hematocrit levels the entire experiment. The lactate-glucose ratio between the groups. The animals of the LV-group (pg ϭ 0.16) as well as the lactate-pyruvate ratio required more fluids during the first 2 h of rewarm- (pg ϭ 0.21) was similar in both groups throughout ing, but towards the end of the experiment there the experiment. Figure 1. Intracranial pressure. Median and interquartile range.
    • Levosimendan decreases intracranial pressure after HCA 313 Cardiac enzymes Troponin I and CkMB – levels were elevated in all animals and are displayed in Figures 2 and 3. Neurological recovery We observed no differences in neurological recovery between the groups. The sum of behavioral scores from the animals that survived for seven days was 47 (44–53.5) in the LV group and 46.5 (39.75–51.5) in the control group (p ϭ 0.575). HistopathologyScand Cardiovasc J Downloaded from informahealthcare.com by McGill University on 05/20/12 There were no significant differences whatsoever Figure 3. Cardiac enzymes; Creatine Kinase Isoenzyme MB. Median and interquartile range. between the groups concerning histopathology find- ings. Total histopathological score of all animals was 9.5 (5.0–11.0) in the LV-group and 4.0 (3.5–6.5) in considerations, the number of animals was small and the control group (p ϭ 0.119). When only animals limitations of the study include the risk of a statisti- that survived the entire seven-day follow-up period cal Type II error. were taken into account, the total score was 8.0 (3.0– Levosimendan was initially targeted to patients 13.5) in the LV-group and 4.0 (2.8–5.8) in the con- suffering from acute decompensated heart failure trol group (p ϭ 0.267). (ADHF). In the SURVIVE trial levosimendan dem- onstrated beneficial short-term effects in patients For personal use only. suffering from ADHF, but did not significantly Discussion reduce all-cause mortality at 180 days compared to In our study with a chronic porcine model, a 24-hour dobutamine (14). In addition to the on-going heart infusion of levosimendan without a loading dose did failure discussion, other uses of levosimendan are not improve cerebral protection in association with actively investigated. So far results have been pub- HCA. It lowered the intracranial pressure during the lished of levosimendan in association with cardio- experiment, but no differences in edema were genic shock (15), myocardial infarction (16) and observed in the histopathology one week after the different settings of cardiac surgery (17). operation. In terms of microdialysis data, neuro- Lack of difference in heart rate and cardiac index logical recovery and histopathology there was no in our study were not altogether surprising, as the improvement of brain protection compared to the loading dose was omitted. In our pilot studies the placebo infusion. Due to the laborious regime of loading dose induced a clear identifiable tachycardic a chronic large animal model as well as ethical reaction in the animals receiving levosimendan and thus to ensure complete blinding of the study we opted to use a continuous infusion without a loading dose. Due to the vasodilatory effects of levosimen- dan, the animals of the LV-group required more fluid during the first 2 h of rewarming. The more positive fluid balance probably provides an explanation for lesser blood glucose in the LV-group at 30 min after the start of rewarming and clarifies the slightly slower trend of rewarming in terms of blood temperature in the LV-group, as well as the consequently higher par- tial pressure of arterial oxygen at 30 min of rewarm- ing (Tables I and II). It could be speculated whether these slight differences at the initial stages of rewarm- ing, stemming from the vasodilatory effects of levo- simendan, could have temporarily improved cerebral protection reflected in the lower intracranial pressure Figure 2. Cardiac enzymes; Cardiac Troponin I. Median and of the LV-group after the operation. Levosimendan interquartile range. did not decrease the need for other inotropes in our
    • 314 H. Jensen et al. study, a similar number of animals required nora- 4. Lilleberg J, Nieminen MS, Akkila J, Heikkilä L, Kuitunen A, drenalin after the operation in both groups. Lehtonen L, et al. Effects of a new calcium sensitizer, levosi- mendan, on haemodynamics, coronary blood flow and myo- Cardiac enzymes tended to be more elevated in cardial substrate utilization early after coronary artery bypass the LV-group. While it is plausible that a 60-minute grafting. Eur Heart J. 1998;19:660–8. hypothermic circulatory arrest introduces such a 5. Raja SG, Rayen BS. Levosimendan in cardiac surgery: Current strain to the myocardium that calcium-sensitization best available evidence. Ann Thorac Surg. 2006;81:1536–46. can cease to be beneficial and even becomes adverse, 6. Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier LS, Just H. Influence of the novel inotropic agent levosimendan other possible explanations may exist. In earlier stud- on isometric tension and calcium cycling in failing human ies of levosimendan’s effects on ischemic myocar- myocardium. Circulation. 1998;98:2141–7. dium, the results have been encouraging in clinical 7. Pataricza J, Krassoi I, Hohn J, Kun A, Papp JG. Functional trials with human patients (18) as well as in experi- role of potassium channels in the vasodilating mechanism of mental models with rabbits (19) and dogs (20). levosimendan in porcine isolated coronary artery. Cardiovasc Drugs Ther. 2003;17:115–21. Similar studies with pigs, however, have frequently 8. Yokoshiki H, Sperelakis N. Vasodilating mechanisms of led to more disappointing results in terms of levosimendan. Cardiovasc Drugs Ther. 2003;17:111–3. myocardial infarction size (21), arrhythmias (22) 9. Follath F, Cleland JG, Just H, Papp JG, Scholz H, PeuhkurinenScand Cardiovasc J Downloaded from informahealthcare.com by McGill University on 05/20/12 and contractile function (23). The possibility of a K, et al. Efficacy and safety of intravenous levosimendan detrimental effect of levosimendan on the porcine compared with dobutamine in severe low-output heart failure (the LIDO study): A randomised double-blind trial. myocardium has to be considered. Lancet. 2002;360:196–202. We conclude that in this experimental setting levo- 10. Parissis JT, Adamopoulos S, Antoniades C, Kostakis G, Rigas simendan decreased intracranial pressure during the A, Kyrzopoulos S, et al. Effects of levosimendan on circulat- experiment, but it did not demonstrate persistent neu- ing pro-inflammatory cytokines and soluble apoptosis medi- roprotective effects in an operation requiring the use ators in patients with decompensated advanced heart failure. Am J Cardiol. 2004;93:1309–12. of deep hypothermic circulatory arrest. 11. Valen G, Yan ZQ, Hansson GK. Nuclear factor kappa-B and the heart. J Am Coll Cardiol. 2001;38:307–14. 12. Feuerstein GZ, Wang X, Barone FC. The role of cytokines For personal use only. Acknowledgements in the neuropathology of stroke and neurotrauma. Neuroim- munomodulation. 1998;5:143–59. This study was supported by grants from the Oulu 13. Rimpiläinen J, Pokela M, Kiviluoma K, Anttila V, Vainionpää University Hospital, the Finnish Foundation for Car- V, Hirvonen J, et al. Leukocyte filtration improves brain pro- diovascular Research and the Sigrid Juselius Founda- tection after a prolonged period of hypothermic circulatory arrest: A study in a chronic porcine model. J Thorac Cardio- tion. The authors would like to express their deepest vasc Surg. 2000;120:1131–41. gratitude to anesthesiologist Vilho Vainionpää, MD, 14. Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, PhD, biostatistician Pasi Ohtonen, MSc, and Seija Kleber FX, Pocock SJ, et al. Levosimendan vs dobutamine Seljänperä, RN, for their expert guidance and assis- for patients with acute decompensated heart failure: The tance in this study. We are also grateful to Jouko Levi- SURVIVE Randomized Trial. JAMA. 2007;297:1883–91. 15. Russ MA, Prondzinsky R, Christoph A, Schlitt A, Buerke U, joki, of Orion Pharma, who provided the study drug. Söffker G, et al. Hemodynamic improvement following This paper was presented at the Annual Meeting of levosimendan treatment in patients with acute myocardial The Scandinavian Society for Cardiothoracic Surgery infarction and cardiogenic shock. Crit Care Med. 2007;35: in Geilo, Norway, February 2008. 2732–9. 16. Christoph A, Prondzinsky R, Russ M, Janusch M, Schlitt A, Lemm H, et al. Early and sustained haemodynamic Declaration of interest: The authors report no improvement with levosimendan compared to intraaortic balloon counterpulsation (IABP) in cardiogenic shock com- conflicts of interest. The authors alone are respon- plicating acute myocardial infarction. Acute Card Care. sible for the content and writing of the paper. 2008;10:49–57. 17. Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart References failure (the LIDO study): A randomised double-blind trial. 1. Bachet J, Guilmet D. Brain protection during surgery of the Lancet. 2002;360:196–202. aortic arch. J Card Surg. 2002;17:115–24. 18. Moiseyev VS, Põder P, Andrejevs N, Ruda MY, Golikov AP, 2. Di Eusanio M, Di Eusanio G. Cerebral protection during Lazebnik LB, et al. Safety and efficacy of a novel calcium surgery of the thoracic aorta: A review. Ital Heart J. 2004; sensitizer, levosimendan, in patients with left ventricular fail- 5:883–91. ure due to an acute myocardial infarction. A randomized, 3. Hagl C, Khaladj N, Karck M, Kallenbach K, Leyh R, placebo-controlled, double-blind study (RUSSLAN). Eur Winterhalter M, et al. Hypothermic circulatory arrest during Heart J. 2002;23:1422–32. ascending and aortic arch surgery: The theoretical impact of 19. Rump AF, Acar D, Rosen R, Klaus W. Functional and anti- different cerebral perfusion techniques and other methods ischaemic effects of the phosphodiesterase inhibitor levosi- of cerebral protection. Eur J Cardiothorac Surg. 2003;24: mendan in isolated rabbit hearts. Pharmacol Toxicol. 1994; 371–8. 74:244–8.
    • Levosimendan decreases intracranial pressure after HCA 315 20. Kersten JR, Montgomery MW, Pagel PS, Warltier DC. 22. Du TE, Hofmann D, McCarthy J, Pineda C. Effect of Levosimendan, a new positive inotropic drug, decreases levosimendan on myocardial contractility, coronary and myocardial infarct size via activation of K(ATP) channels. peripheral blood flow, and arrhythmias during coronary Anesth Analg. 2000;90:5–11. artery ligation and reperfusion in the in vivo pig model. 21. Busk M, Maeng M, Kristensen J, Berg JS, Mortensen UM, Heart. 2001;86:81–7. Nielsen TT, et al. Effects of levosimendan on myocardial 23. Tassani P, Schad H, Heimisch W, Bernhard-Abt A, Ettner U, infarct size and hemodynamics in a closed-chest porcine Mendler N, et al. Effect of the calcium sensitizer levosimendan ischemia-reperfusion model. Cardiovasc Drugs Ther. 2006; on the performance of ischaemic myocardium in anaesthetised 20:335–42. pigs. Cardiovasc Drugs Ther. 2002;16:435–41.Scand Cardiovasc J Downloaded from informahealthcare.com by McGill University on 05/20/12 For personal use only.