Continuous veno-venous haemofiltration attenuates myocardial mitochondrial respiratory chain complexes activity in porcine septic shock.
Increasing evidence indicates that mitochondrial dysfunction plays an important role in modulating the development of septic shock. In the present study, we investigated whether continuous veno-venous haemofiltration (CVVH) with high-volume might improve myocardial mitochondrial dysfunction in a porcine model of peritonitis-induced septic shock. Sixteen male Landrace pigs weighing 31 [+ or -] 5 kg were randomly assigned to normal control group (n=4), peritonitis group (n=6) and peritonitis plus CVVH group (n=6). All animals were anaesthetised and mechanically ventilated. After baseline examinations, the peritonitis group and the peritonitis plus CVVH group underwent induction of peritonitis. One hour later, the animals in the peritonitis plus CVVH group received treatment with high-volume CVVH. Twelve hours after treatment, the animals were sacrificed. Animals in the peritonitis group were killed 13 hours after induction of peritonitis. Peritonitis challenge induced septic shock associated with increased blood lactate and high-volume CVVH improved lactate acidosis. Compared with the peritonitis group, cardiac output, stroke volume and mean arterial pressure were better maintained in peritonitis plus CVVH group. More importantly, high-volume CVVH improved myocardial mitochondrial complex I activity (0.22 [+ or -] 0.03 vs. 0.15 [+ or -] 0.04, P=0.04). These results suggest that high-volume CVVH improves haemodynamics and heart dysfunction in septic shock and the improvement may be attributed to amelioration of myocardial mitochondrial dysfunction.
Key Words: septic shock, continuous veno-venous haemofiltration, mitochondrial dysfunction, cardiac dysfunction
Cellular function requires energy supplied by adenosine triphosphate (ATP). Most of the ATP necessary to supply organs and tissues with energy is generated by the mitochondrial oxidative phosphorylation system that consists of respiratory-chain complexes I-IV. A dysfunctional mitochondrial respiratory chain can affect all organs and tissues and cause a wide variety of disorders. Several lines of evidence support the hypothesis that cellular energy metabolism is disturbed in sepsis (1-3). This disturbance was originally ascribed to inadequate tissue perfusion leading to cellular hypoxia. Recent studies however, point to a disturbance in oxygen utilisation rather than delivery, which has been labelled "cytopathic hypoxia" (1,2). First, increasing oxygen delivery in patients with septic shock does not consistently increase oxygen consumption and decrease the level of anaerobic metabolism as measured by arterial lactate concentration (4). Second, normal levels of tissue oxygen tension and elevated arterial lactate concentrations have been reported in patients with septic shock (5). Third, a number of the mediators implicated in septic shock have been demonstrated to directly impair mitochondrial function (6). Finally, measures intended to protect myocardial mitochondria have been confirmed effective in sepsis (7,8).
Despite these new insights, the cornerstone of therapy continues to be early recognition, prompt initiation of effective antibiotic therapy and eliminating the source of infection. To date, the adjuvant treatment of sepsis remains a major therapeutic challenge. Haemofiltration, based on the humoral theory of sepsis, is a safe and well-established treatment in critically ill patients with renal failure and has also been used in the treatment of severe sepsis. Early clinical reports and experimental animal studies suggested that continuous veno-venous haemofiltration (CVVH) improved cardiac dysfunction, ameliorated haemodynamics and regulated immunity (9,10). However, it remains unknown whether treatment with haemofiltration exerts a specific effect on the cell bioenergetics metabolism.
The aim of the study was to investigate the impact of high-volume CVVH on myocardial mitochondrial respiratory chain complexes activity in peritonitis-induced septic shock. To avoid the confounding effect of hypodynamic septic shock, a protocol of fluid resuscitation was applied to maintain adequate filling pressure. We used high-volume zero-balanced CVVH because this regimen had been shown to improve survival (10,12). To determine whether the treatment with CVVH can effectively reduce inflammatory mediators that have been confirmed damage from the circulation, plasma and myocardium concentrations of nitrate/nitrite were measured during CVVH.
MATERIALS AND METHODS
The study was approved by the ethical Committee of Animal Research at the First Affiliated Hospital of Zhejiang University, Hangzhou, China. The care and handling of the animals were in agreement with National Institute of Health guidelines.
Sixteen male Landrace pigs weighing 31 [+ or -] 5 kg were fasted overnight but were allowed free access to water. The animals were randomly assigned to normal control group (n=4), peritonitis group (n=6) and peritonitis plus CVVH (n=6). All animals were premedicated with ketamine chloride (25 mg x [kg.sup.-1] intramuscularly). Anaesthesia was subsequently induced with pentobarbitone sodium (20 mg x [kg.sup.-1] intravenously) and maintained with a continuous infusion of pentobarbitone sodium (10 to 25 mg x [kg.sup.-1].[h.sup.-1]). Their tracheas were intubated and ventilation was started at a tidal volume of 10 ml/kg, a respiratory rate between 20 and 25 breaths/min and a positive end-expiratory pressure level of 5 cm[H.sub.2]O. Respiratory settings were adjusted to maintain blood gas values within the physiologic range and were kept constant thereafter. Controlled ventilation was facilitated with pancuronium bromide (0.15 mg/kg initially, with supplementation at 0.075 mg x [kg.sup.-1] x [h.sup.-1] thereafter). The right carotid artery was catheterised for monitoring of arterial blood pressure and withdrawal of arterial blood samples. A 7.0 Fr Swan-Ganz flow-directed thermodilution tip catheter was inserted in the proximal pulmonary artery via the right jugular vein for monitoring of cardiac output (CO). A midline laparotomy was performed and a 14 Fr silastic catheter was inserted into the bladder. In both peritonitis and peritonitis plus CVVH groups, approximate 0.5 g/kg weight autologous faeces were collected through the incision in the caecum for later use to induce peritonitis. The caecum incision was closed with continuous sutures. At the end of surgical preparation, one large-bore tube was placed with tip in the abdominal cavity for later use to infuse faeces. In peritonitis plus CVVH group, a 10.0 Fr double-lumen catheter was inserted into the left femoral vein and served as haemofiltration access. All catheters were placed by direct cutdown and the wounds closed surgically. Rectal temperature was monitored throughout the experiment. All animals received 2 l lactated Ringer's solution during the surgical procedure and 10 to 15 ml x [kg.sup.-1] x [h.sup.-1] during the rest of the experiment, with a rate adjusted to keep pulmonary artery occlusion pressure (PAOP) at 8 to 12 mmHg.
After the surgical preparation was finished, animals were allowed to recover for 60 min followed by the baseline measurements. Then animals were exposed to faeces peritonitis by instillation of autologous faeces (0.5 [g.sup.-1] x kg body weight) suspended in 150 ml warm isotonic saline (37[degrees]C) through the tube inserted during the surgical preparation. One hour after the infusion, animals in the peritonitis plus CVVH group received high-volume CVVH. Systemic anticoagulation was started with a bolus dose of 100 IU x [kg.sup.-1] intravenous heparin sulphate followed by an intravenous infusion of 50 IU x [kg.sup.-1] x [h.sup.-1] in both the peritonitis and peritonitis plus CVVH groups. The animals were monitored thereafter for 12 hours and then sacrificed with a bolus injection of 10 ml KCl. Tissue samples were frozen immediately in liquid nitrogen and then kept at -80[degrees]C for further examination. Measurements of haemodynamics, blood gases, haemoglobin and metabolic variables were obtained every hour. All other measurements were taken at baseline, at the start of CVVH and at the end of CVVH. Body temperature was maintained using a heating blanket.
The haemofiltration device consisted of a roller pump, air detector and pressure feedback system (BM 11/BM 14; Baxter). A 1.2 [m.sup.2] polysulphone (F60) was used. Haemofiltration was performed from femoral vein to femoral vein by use of a double-lumen catheter. Zero-balance haemofiltration was achieved using a balance installed in the device. This was fully automated, resulting in constant ultrafiltration rates of approximate 100 ml x [kg.sup.-1] x [h.sup.-1]. Blood flow was 150 to 200 ml x [min.sup.-1]. A bicarbonate buffer solution ([Na.sup.+]: 138 mM, [K.sup.+]: 3 mM, [Ca.sup.2+]: 1.25 mM, [Mg.sup.2+]: 0.5 mM and bicarbonate: 32 mM) was warmed and then infused after the filter.
Measurement of haemodynamics and blood gases
Mean arterial pressure (MAP, mmHg), central venous pressure (CVP, mmHg), mean pulmonary artery pressure (MPAP, mmHg) and PAOP (mmHg) were recorded with quartz pressure transducers. Heart rate (beats/min) was measured from the electrocardiogram. Heart rate, MAP, MPAP and CVP were displayed continuously on a multimodular monitor. CO (l/min) was measured by the thermodilution technique. All pressures and CO were determined at end-expiration. Arterial and mixed venous blood samples were simultaneously drawn for immediate determination of blood gases, haemoglobin, oxygen saturation and blood lactate. The values were adjusted to body temperature. Systemic oxygen consumption and systemic oxygen delivery (V[O.sub.2]) were calculated according to standard formulas. Oxygen extraction ratio was derived from the ratio of oxygen consumption/oxygen delivery.
Determination of myocardial mitochondrial respiratory chain complexes activity
Mitochondrial respiratory chain complexes activity was assessed using well-described spectrophotometric method (13). Tissue samples were homogenised on ice with a hand-held glass homogeniser, then underwent three episodes of rapid freeze-thawing to ensure cell lysis. Complexes activity was measured at 30[degrees]C in an Uvikon XS spectrophotometer (Secomam, Domont, France) and expressed as a ratio to citrate synthase activity as this mitochondrial matrix enzyme is resistant to oxidant attack. Complex I was measured as the rotenone-sensitive decrease in NADH at 340 nm, complex II/III activity as the succinate-dependent antimycin A-sensitive reduction of cytochrome c at 550 nm and complex IV activity as the disappearance of reduced cytochrome c at 550 nm.
Assessment of plasma and myocardium nitrite/nitrate
Myocardium homogenates (1 in 5 weight/volume) were prepared from 50 mg tissue and centrifuged. Sample aliquots of plasma and tissue homogenates were measured by the griess reaction, as previously described (14). Myocardial nitrite / nitrate was standardised to soluble protein content and expressed as nmol/mg protein.
All data were expressed as mean [+ or -] SD. Overall comparisons over time and severity were made using two-way ANOVA using SPSS11.5 software. If significant, each time point difference between group animals was compared with one-way ANOVA with Bonferroni correction. P <0.05 was considered to be statistically significant.
There were no differences in body weight or other baseline parameters among the groups.
In the peritonitis group, fluid resuscitation provoked a typical hyperdynamic septic shock followed by hypodynamic shock. Looking at the graph (Figure 1A) it would appear that in the first six hours, CO was similar between the two treatment groups, but from six to 12 hours post-faecal implantation, the progressive reduction of CO observed in the peritonitis group was ameliorated in the animals receiving CVVH. This improvement of cardiac output was not associated with differences in ventricular filling pressures, as reflected by comparable PAOP in both groups (Figure 1F). With the improved CO and stroke volume (SV), systolic MAP was significantly higher in animals receiving CVVH versus the peritonitis group (Figure 1). The divergence of this physiologic parameter was apparent only after six hours of the experimental protocol. In addition, treatment with CVVH reduced elevated temperature after peritonitis challenge (Figure 2B). No significant differences were found in oxygen delivery, oxygen consumption and oxygen extraction rate (Table 1).
Plasma lactate levels increased progressively to more than three times in the peritonitis group and were significantly higher than that in the peritonitis plus CVVH group. Plasma arterial pH decreased during the experiment and was significantly improved in animals receiving CVVH (Figure 3).
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Compared with normal control, the activity of respiratory-chain complex I in myocardium was 37% lower in peritonitis animals. However, the activity of complex I was better maintained in animals receiving CVVH. No significant differences were found for complex II, III and IV (Figure 4).
The plasma concentration of nitrite/nitrate, a marker of nitric oxide production, was determined at baseline, at the start of haemofiltration and at 12 h after CVVH. At the start of haemofiltration, one hour after peritonitis challenge, plasma nitrite/ nitrate concentrations did not differ between groups. However, plasma nitrite/nitrate increased in peritonitis group, but was nearly normal in animals receiving CVVH at 13 h after peritonitis induction (Figure 5). As for concentrations of nitrite/nitrate in myocardial homogenate, there were no differences between groups (normal control group, 5.3 [+ or -] 1.2 nmol/mg protein; peritonitis group, 6.7 [+ or -] 1.4 nmol/mg protein; peritonitis plus CVVH group, 5.9 [+ or -] 1.1 nmol/mg protein; P=0.244).
The major finding of this study is that high-volume CVVH improves myocardial mitochondrial respiratory-chain complexes activity, such as higher activity of respiratory chain complex I in peritonitis-induced septic shock.
Altered activity of one or more of the respiratory-chain complexes has been reported in critical illness, particularly in sepsis (15). Depending on the species, the model and the severity and duration of the insult, data have been conflicting (15). Mitochondrial dysfunction and the associated bioenergetics failure have been regarded as factors contributing to multiple organ dysfunction, the most common cause of death in sepsis. Brealey and colleagues (3) showed mitochondrial respiratory-chain dysfunction (30% reduction in complex I activity) and decreased ATP concentrations in skeletal-muscle biopsy samples from patients with sepsis in intensive care as compared with patients after elective hip replacement. More severe abnormalities were associated with a higher risk of organ failure and adverse outcome of septic shock. Furthermore, recovery from organ failure was associated with improvement of mitochondrial function in septic patients (16).
These studies suggested a novel therapeutic target--besides simple optimisation of cardiac output, systemic oxygen delivery and regional blood flow--to prevent lethal organ failure in intensive care units. Indeed, maintenance or restoration of mitochondrial function and cellular bioenergetics (i.e. prevention or reversal of cytopathic hypoxia) might improve outcome for critically ill patients. In this study we found that complex I activity decreased by 37% in the peritonitis group 13 hours after peritonitis challenge. However, the activity of complex I was around normal in animals receiving CVVH. Our findings suggest that high-volume CVVH could be such an adjuvant therapy.
As an effective adjuvant treatment method, CVVH has been widely used in clinical patients. Although a lot of data exists demonstrating the presence of various inflammatory mediators (cytokines, prostanoids and complement factors) in the ultrafiltrate of patients with sepsis (17,18), there is substantial disagreement whether the beneficial clinical effects observed during treatment with haemofiltration can be attributed to removal of specific inflammatory mediators. To date, no specific inflammatory mediators solely responsible for endotoxin-induced organ injury have been identified. Moreover, as haemofiltration is a nonspecific blood purification technique, anti-inflammatory and beneficial mediators may be removed as well. Because of these methodological difficulties, we did not intend to investigate the hypothesis that removal of specific inflammatory mediators is beneficial in experimental sepsis.
Previous studies have confirmed that nitric oxide (NO) is one of the major factors affect the activity of mitochondrial respiratory chain complexes. Inhibition of complex I by either NO or its metabolite, peroxynitrite, is via a reversible yet longer-acting nitrosylation of thiol groups in the complex, or by irreversible nitration (19-21). In addition, NO is known to rapidly and reversibly inhibit complex IV activity by competing with oxygen at cytochrome oxidase (22). We measured plasma and tissue concentrations of nitrite/nitrate to assess whether the improvement of myocardial mitochondrial dysfunction was attributed to reducing the concentrations of nitrite/nitrate. Similar to previous reports (8), we found that NO produced in large amounts after induction of peritonitis. Treatment with CVVH greatly reduced the concentrations of plasma NO. The possible explanation for the observed reduction of NO concentrations might be that early treatment with CVVH attenuated the entire inflammatory response, including decreases in tumour necrosis factor (TNF)-[alpha] and interleukin (IL)-1 concentrations, which, in turn, might have reduced the production of NO. The decrease of plasma nitrite/nitrate levels in animals receiving CVVH argues against the involvement of NO in the decrease in pulmonary and systemic vascular resistance seen during CVVH. As in other experiments using the endotoxic shock model, we also found that haemofiltration mainly improved cardiac function (11,23), explaining the decrease in SVR during CVVH. In contrast to our expectation, there was no significant difference in myocardium levels of NO among the three groups. The possible explanation is that tissue NO concentrations change depending on the duration of the insult (24). Accordingly, the improvement of cardiac mitochondrial dysfunction by high-volume CVVH may be due to lessening plasma NO but not tissue NO.
Of course, other factors may be involved in the dysfunction of mitochondria in septic shock. Sepsis evokes a significant increase in mitochondrial free radical generation (25). More over, administration of free radical scavengers (i.e. Peg-SOD) has been shown to prevent LPS-induced mitochondrial dysfunction, arguing that the free radicals either directly (by reacting with and damaging electron transport chain components) or indirectly (e.g. by activating signaling pathways) are critically important in mediating LPS-induced alterations in mitochondrial function (26). Whether CVVH treatment can reduce the generation of free radical in septic shock needs further research.
Because 90% oxygen consumption is occurred in mitochondria, we investigated whether the amelioration of mitochondrial dysfunction by CVVH was associated with increased oxygen consumption. Interestingly, there was no significant increase in V[O.sub.2] in the peritonitis plus CVVH group compared with the peritonitis group. The possible explanation is that oxygen consumption is a global measurement and the study has only measured mitochondrial activity in one system. Alternatively, sepsis may cause excessive oxygen to compensate for pathological ATP consumption and produce oxygen free radical as a result of multiple insults from sepsis (27). Accordingly, another potential explanation is that improvement of mitochondrial dysfunction by CVVH is represented by the reduction of ineffective V[O.sub.2] (28) but not net increase of V[O.sub.2].
Although we did not further investigate the mechanisms involved in the mitochondrial dysfunction improvement, there are several possible reasons. First, NO inhibits mitochondrial complex I activity in sepsis (29,30), whereas CVVH treatment reduces plasma levels of NO as presented in the study. Second, based on the property of haemofiltration, CVVH could keep body temperature at baseline and correct acid-base disturbances. Although lower temperatures can decrease cardiac function and impair microcirculation (31), higher temperatures might also result in multiple organ failure (10,32). Finally, CVVH could nonspecifically clear amounts of molecules that increase in sepsis and maintain the internal environment. Indeed, ultrafiltrate from sepsis patients can induce myocardial dysfunction in laboratory animals (33).
As a model of experimental septic shock, there are several limitations. First, we did not give antibiotics or vasopressors, aiming to avoid any more variables. Second, the experiment course was shorter in contrast with clinical sepsis because of technological difficulties. Finally, the animals were initially healthy, which is different from the clinical situation where patients usually have several comorbidities and cardiorespiratory compromise.
As for the study design, there are also several flaws. On the one hand, we did not measure the removal of nitrite/nitrate by CVVH. On the other hand, measurement of mitochondrial activity and tissue nitrite/nitrate at a different time after peritonitis challenge should give more interesting results, given that mitochondrial changes are probably time-dependent. Finally, there are several unexplained findings from this study which need further research.
We would like to thank the Anaesthesia Department at the First Affiliated Hospital, Medical College of Zhejiang Univisity and Mr Hu Wen-Jun for their assistance in performing this study. This study was supported by the Health Bureau of Zhejiang (2003A039), China.
Accepted for publication on June 14, 2007.
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C.-M. LI *, J.-H. CHEN [[dagger]], P. ZHANG [[double dagger]], Q. HE [[double dagger]], J. YUAN [[section]], R. J. CHEN **, X.-J. CHENG *, H.-Z. TAN *, Y. YANG *
Animal Laboratory, First Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China
* Ph.D, Student, Kidney Disease Center.
[[dagger]] M.D., Professor, Kidney Disease Center.
[[double dagger]] M.D., Associated Professor, Kidney Disease Center.
[[section]] R.N., Registered Nurse, Kidney Disease Center.
** M.D., Technician, Kidney Disease Center.
Address for reprints: Dr J.-H. Chen, Kidney Disease Center, First Affiliated Hospital, Medical College of Zhejiang University, Qingchun Road 79, Hangzhou 310003, China.
TABLE 1 Changes in oxygen utilisation over time in the three groups Baseline Group 0 h 1 D[O.sub.2], Control 611 [+ or -] 137 612 [+ or -] 96 ml/min Peritonitis 513 [+ or -] 108 544 [+ or -] 110 CVVH 536 [+ or -] 110 547 [+ or -] 105 V[O.sub.2], Control 145 [+ or -] 43 160 [+ or -] 24 ml/min Peritonitis 127 [+ or -] 31 136 [+ or -] 32 CVVH 31 [+ or -] 36 133 [+ or -] 29 OER, % Control 23.5 [+ or -] 4.9 26.5 [+ or -] 5.8 Peritonitis 24.7 [+ or -] 2.6 25.2 [+ or -] 3.7 CVVH 24.2 [+ or -] 3.2 23.8 [+ or -] 2.1 Baseline Group 3 5 D[O.sub.2], Control 635 [+ or -] 143 589 [+ or -] 117 ml/min Peritonitis 697 [+ or -] 170 795 [+ or -] 155 CVVH 705 [+ or -] 210 795 [+ or -] 203 V[O.sub.2], Control 168 [+ or -] 59 183 [+ or -] 44 ml/min Peritonitis 182 [+ or -] 51 252 [+ or -] 64 CVVH 187 [+ or -] 69 208 [+ or -] 63 OER, % Control 25.8 [+ or -] 4.6 29.8 [+ or -] 2.5 Peritonitis 25.5 [+ or -] 3.1 31.2 [+ or -] 3.2 CVVH 25.3 [+ or -] 3.8 25.5 [+ or -] 3.3 Time Group 7 9 D[O.sub.2], Control 542 [+ or -] 86 614 [+ or -] 120 ml/min Peritonitis 778 [+ or -] 325 599 [+ or -] 293 CVVH 760 [+ or -] 140 698 [+ or -] 114 V[O.sub.2], Control 155 [+ or -] 38 145 [+ or -] 36 ml/min Peritonitis 207 [+ or -] 83 178 [+ or -] 73 CVVH 208 [+ or -] 47 200 [+ or -] 41 OER, % Control 27.5 [+ or -] 5.1 24.3 [+ or -] 3.1 Peritonitis 26.5 [+ or -] 4.0 30.8 [+ or -] 4.8 CVVH 28 [+ or -] 5.9 29.2 [+ or -] 4.6 Time Group 11 13 D[O.sub.2], Control 591 [+ or -] 128 633 [+ or -] 83 ml/min Peritonitis 469 [+ or -] 223 310 [+ or -] 135 CVVH 638 [+ or -] 176 599 [+ or -] 181 * V[O.sub.2], Control 165 [+ or -] 57 155 [+ or -] 37 ml/min Peritonitis 121 [+ or -] 53 98 [+ or -] 22 CVVH 176 [+ or -] 54 157 [+ or -] 56 OER, % Control 28.0 [+ or -] 5.2 24.0 [+ or -] 3.6 Peritonitis 26.0 [+ or -] 2.4 31.6 [+ or -] 7.1 CVVH 27.3 [+ or -] 1.4 27.4 [+ or -] 5.6 Data are shown as mean [+ or -] SD. * P < 0.05 vs. peritonitis. D[O.sub.2] = oxygen delivery; V[O.sub.2] = oxygen consumption; OER = oxygen extraction ratio.
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|Author:||Li, C.M.; Chen, J.H.; Zhang, P.; He, Q.; Yuan, J.; Chen, R.J.; Cheng, X.J.; Tan, H.Z.; Yang, Y.|
|Publication:||Anaesthesia and Intensive Care|
|Article Type:||Clinical report|
|Date:||Dec 1, 2007|
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