1 Clinic of Anaesthesiology and 2 Department of Surgery, 3 Institute for Epidemiology and Biometry, Klinikum Grosshadern, Ludwig-Maximilians-University, D-81377 Munich, Germany
* Corresponding author. E-mail: mthiel{at}med.uni-muenchen.de
Accepted for publication March 1, 2004.
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Abstract |
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Methods. Patients (n=68) were assigned randomly to three groups: (i) resection with the Pringle manoeuvre; (ii) with ischaemic preconditioning before the Pringle manoeuvre for resection; (iii) without pedicle clamping.
Results. Following the Pringle manoeuvre the mean arterial pressure increased transiently, but significantly decreased after unclamping as a result of peripheral vasodilation. Ischaemic preconditioning improved cardiovascular stability by lowering the need for catecholamines after liver reperfusion without affecting the blood sparing benefits of the Pringle manoeuvre. In addition, ischaemic preconditioning protected against reperfusion-induced tissue injury.
Conclusions. Ischaemic preconditioning provides both better intraoperative haemodynamic stability and anti-ischaemic effects thereby allowing us to take full advantage of blood loss reduction by the Pringle manoeuvre.
Keywords: arterial pressure ; liver, ischaemia reperfusion ; surgery, liver resection ; surgery, portal triad clamping (Pringle manoeuvre)
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Introduction |
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In the present study, we analysed the intraoperative haemodynamic course in patients who underwent elective liver resection under three defined surgical techniques: portal triad clamping (Pringle manoeuvre) for resection; ischaemic preconditioning before portal triad clamping and resection; or hepatectomy without portal triad clamping. Data were electronically recorded by a PDMS that allowed continuous measurement and documentation of cardiovascular changes, fluid loss, transfusions, infusions, and administration of catecholamines. Our aims were to determine the cardiovascular effects of the Pringle manoeuvre and how these effects are modified by ischaemic preconditioning.
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Methods |
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Anaesthesia and surgery
All patients received midazolam (3.757.5 mg) orally 2 h before surgery. Before general anaesthesia a thoracic epidural catheter (T1012) was placed to provide perioperative analgesia. Following i.v. injection of either thiopental (35 mg kg1) or propofol (23 mg kg1), fentanyl (2 µg kg1), and atracurium (0.5 mg kg) the trachea was intubated and the lungs mechanically ventilated (Dräger CATO, Dräger Werke, Germany) at a ventilatory frequency of 78 min1 and a tidal volume of 10 ml kg1 with an air/oxygen mixture of 50%. Anaesthesia was maintained with 56% end-tidal desflurane, bolus doses of atracurium for neuromuscular block and intermittent injection of bupivacaine 0.5% through the epidural catheter. An SC8000 monitor (Siemens AG, Germany) was used to monitor continuously the electrocardiogram (with ST-segment-analysis), peripheral oxygen saturation, oesophageal temperature, direct arterial pressure, and central venous pressure. In a subset of patients who had given consent, invasive cardiac monitoring (Swan-Ganz-Catheter) was used to calculate the cardiac index (CI), stroke volume index (SVI), and system vascular resistance index (SVRI).
After laparotomy the liver was mobilized and the hilar structures were prepared. The Pringle manoeuvre was performed by placing a clamp on the hepatic artery and portal vein. The Pringle manoeuvre was maintained until the liver resection was finished (PR group). In the IPC group, the Pringle manoeuvre was preceded by a brief period of ischaemia (10 min) and 10 min of reperfusion. Neither in the PR nor the IPC group was additional clamping performed during the resection.
To meet intraoperative fluid demand and to compensate for blood loss, crystalloids (sodium chloride 0.9%, BRAUN, Melsungen, Germany) and colloidal solutions (hydroxyethylstarch 10% 10 ml kg1, BRAUN, Melsungen, Germany) were infused, respectively. The blood loss was calculated from the volume collected by the continuous autotransfusion system (CATS, Fresenius, Bad Homburg, Germany). Thereafter, erythrocytes were washed and immediately re-transfused after irradiation (30 Gy). Allogeneic packed red blood cell concentrates were transfused if transfusion of autologous blood was not sufficient to return the haemoglobin concentration to 7 g dl1 or higher if electromyocardial signs of ischaemia were present.
A diuresis of more than 100 ml h1 was maintained throughout by fluid administration, low-dose dopamine infusion (23 µg kg1 min1) and, if necessary a 5 mg i.v. bolus of furosemide. Crystalloid and colloid solutions were infused to maintain the central venous pressure (CVP) at 914 mm Hg. When the mean arterial pressure (MAP) fell below 65 mm Hg despite adequate fluid infusion, vasopressors were administered. Norepinephrine was administered after establishing epidural block and (i) when dopamine concentration had to be further increased (>5 µg kg1 min1) or (ii) when the MAP decreased below 65 mm Hg after unclamping and reperfusion of the liver. All surgical procedures and anaesthesia were performed by the same team of three experienced visceral surgeons and anaesthesiologists, ensuring execution of the study protocol in a standardized way. Surgery and anaesthesia were performed by different doctors equally assigned to the three study groups. A blinded allocation of surgeons/ anaesthesists was not feasible.
Patient data management system (PDMS)
For continuous acquisition and storage of data, the monitoring equipment and the ventilator were connected to a patient data management system-PDMS (PICIS®, Barcelona, Spain) that was installed in the operating room. Data (e.g. heat rate, invasive arterial pressure, central venous pressure) were collected continuously, averaged every 10 s, and thereafter automatically saved as per minute values. Volumes and amounts of drugs infused were calculated semi-automatically by entering start and end of infusion time, infusion rate, and concentration of drug solutions (e.g. catecholamines). Bolus doses of drugs (e.g. relaxants), the amount of blood loss, urine output, cardiac and other derived indices and all surgical events (e.g. vascular clamping) were entered manually. Six different time intervals (T1T6) were defined for the analysis of the variables of interest: pre-resection (T1), portal triad clamping (T2) to start, and unclamping (T3) to end ischaemic preconditioning, early (T4) and late (T5) time points during resection with or without the Pringle manoeuvre, and (T6) after the end of the liver resection (Fig. 1). The time intervals reflect the mean values of continuously registered data over a period of 10 (T1, T4, T5, T6) or 7 min (T2, T3). All time intervals do not cover the first and last minutes of clamping and declamping to avoid artifacts in the assessment of the cardiovascular state.
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Results |
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For surgical reasons, the initial allocation had to be changed in a few patients: three NPR patients and one IPC patient were cross allocated to the PR group. The final number of patients eligible for analyses was 19, 14, and 15 patients in the PR, IPC, and NPR groups, respectively.
Patient details are shown in Table 1. No significant differences between the study groups were observed either for the time of surgical preparation (before resection: from skin-incision to start of resection) or post-resection period (after resection: from the end of resection to skin-closure) or for the total duration of surgery (from skin-incision to closure). The mean duration of resection was not different between PR (35 min) and IPC groups (32 min) but was significantly shorter than in the NPR group (53 min).
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Most importantly, the Pringle manoeuvre significantly reduced the cumulative blood loss during (T5) and after liver resection (T6) by up to approximately 65% (Table 2). The amounts of blood lost during liver transection were 350, 400, and 1020 ml in the PR, IPC, and NPR groups, respectively. The number of patients who received intraoperatively heterologous blood (transfused patients/all patients) was only one out of 19 (PR) or zero out of 14 (IPC) but six out of 15 in the NPR group. As blood loss was significantly higher in the NPR group than in the groups with vascular control (Table 2), MAP and CVP values continuously decreased throughout surgery (Fig. 2A and B) and hence NPR patients required more dopamine and norepinephrine especially during resection (P<0.05, T5 vs T4). As a result, there was also a significantly greater need for intravascular volume therapy with greater amounts of crystalloids and colloids used in patients of the NPR group (Table 2).
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Discussion |
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Ischaemia-reperfusion associated haemodynamic effects
The reduction in transfusion needs by the Pringle manoeuvre, however, has to be weighed against the adverse effects of vascular clamping, for example warm ischaemia-reperfusion and haemodynamic changes. When the blood vessels of the portal triad were clamped for ischaemic preconditioning, the CVP decreased because of a reduction in venous return from the splanchnic organs, including the liver and the intestine. In general, one would expect that an acute decrease in CVP would also cause a decrease in MAP, but this was not the case. In contrast, the MAP increased by 6% above pre-clamping values as a result of an increase in systemic vascular resistance of 20% causing cardiac output to decrease by 10%. All these changes were reversed by the release of the vascular clamps. Although these changes could be studied only in a small number of patients with invasive haemodynamic monitoring using a pulmonary artery catheter, the effects observed are similar to previously published data. Delva and co-workers19 postulated a role for sympatho-adrenergic stimulation and the endogenous release of epinephrine and norepinephrine. Subsequently block of these neuro-humoral pathways by direct injection of lidocaine into the hepatic pedicle before vascular occlusion was shown to reduce systemic levels of these catecholamines and abolish the increase of the MAP after portal triad clamping.20 All our patients received epidural anaesthesia, but presumably this was ineffective in blocking such sympathetic reflex mechanisms.
When the portal triad was clamped for periods longer than 10 min, that is for institution of the Pringle manoeuvre, the clamping-induced cardiovascular effects were the same, but removal of the vascular clamps was associated with haemodynamic changes typical of reperfusion. Post-reperfusion arterial hypotension is thought to result from the release of vasoactive substances such as prostaglandins (e.g. 6ketoPGF1-alpha/thromboxane)21 or adenosine.22 Arterial hypotension may further exacerbate reperfusion injuries, because it will reduce blood flow to the liver10 and thereby adversely affect the hepatic microcirculation. Reduced sinusoidal perfusion can exacerbate11 the negative metabolic, and pro-inflammatory6 23 24 consequences of ischaemia-reperfusion, which enhances the development of organ dysfunction. Although vasopressors are used in such situations to ensure arterial pressure-dependent perfusion of other vital organ systems, a cross over study (dopamine vs norepinephrine and vice versa) in 14 patients undergoing visceral surgery showed that norepinephrine (60 ng kg1 min1) significantly reduced blood flow of the hepatic artery and the portal vein, whereas dopamine (7 µg kg1 min1) induced a significant increase in portal vein blood-flow without affecting the flow in the hepatic artery.25 Similar results were obtained in another group of patients in which norepinephrine (60 ng kg1 min1) given for 5 min only decreased hepatic artery blood flow, while with dopamine minor changes were observed in the portal vein.25
Thus, correction of reperfusion induced arterial hypotension by the use of noradrenaline may further compromise liver tissue perfusion.
Ischaemic preconditioning attenuates haemodynamic side effects of the Pringle manoeuvre and reduces the need for vasopressor therapy
Against this background of ischaemia-reperfusion related haemodynamic problems and the knowledge that ischaemic preconditioning is able to attenuate ischaemia-reperfusion induced tissue damage, we asked whether ischaemic preconditioning might also prevent post-reperfusional arterial hypotension. In contrast to our concern that the haemodynamic instability could be worsened by an additional short ischaemic period, ischaemic preconditioning did not further aggravate the Pringle manoeuvre-induced haemodynamic changes. Indeed, ischaemic preconditioning substantially decreased the need for vasopressor therapy during the reperfusion phase with a reduction of the norepinephrine infusion rate by as much as 250-fold. This reduced need for norepinephrine in the IPC group as compared with the PR group was not a result of any differences in blood loss, or transfusion, or infusion requirements, because the blood saving effect of the PR manoeuvre was well preserved by previous ischaemic preconditioning. Given the improvements of postoperative liver function and the better intraoperative haemodynamic stability produced by ischaemic pre-treatment, one is tempted to speculate that ischaemic preconditioning may also protect by stabilization at the macrocirculatory level besides its suggested beneficial effects in the microcirculation and on cellular metabolism.
Taken together, the results presented here indicate that the Pringle manoeuvre for liver resection reduces blood loss during liver surgery. This positive effect, however, is at the expense of post-reperfusion arterial hypotension as a result of vasodilation. Pre-treatment of the liver by ischaemic preconditioning attenuates these responses without influencing the blood saving effects of the Pringle manoeuvre and protects the liver from warm ischaemia-reperfusion injury.
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Acknowledgments |
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References |
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2 Stephenson KR, Steinberg SM, Hughes KS, et al. Perioperative blood transfusions are associated with decreased time to recurrence and decreased survival after resection of colorectal liver metastases. Ann Surg 1988; 208: 67987[ISI][Medline]
3 Rudiger HA, Kang KJ, Sindram D, Riehle HM, Clavien PA. Comparison of ischemic preconditioning and intermittent and continuous inflow occlusion in the murine liver. Ann Surg 2002; 235: 4007[CrossRef][ISI][Medline]
4 Torzilli G, Makuuchi M, Inoue K. The vascular control in liver resection: revisitation of a controversial issue. Hepatogastroenterology 2002; 49: 2831[ISI][Medline]
5 Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003; 284: G15G26
6 Peralta C, Bartrons R, Riera L, et al. Hepatic preconditioning preserves energy metabolism during sustained ischemia. Am J Physiol Gastrointest Liver Physiol 2000; 279: G163G171
7 Grace PA. Ischaemia-reperfusion injury. Br J Surg 1994; 81: 63747[ISI][Medline]
8 Serracino-Inglott F, Habib NA, Mathie RT. Hepatic ischemia-reperfusion injury. Am J Surg 2001; 181: 16066[CrossRef][ISI][Medline]
9 Glanemann M, Vollmar B, Nussler AK, Schaefer T, Neuhaus P, Menger MD. Ischemic preconditioning protects from hepatic ischemia/reperfusion-injury by preservation of microcirculation and mitochondrial redox-state. J Hepatol 2003; 38: 5966[Medline]
10 Pannen BH. New insights into the regulation of hepatic blood flow after ischemia and reperfusion. Anesth Analg 2002; 94: 144857
11 Vollmar B, Glasz J, Leiderer R, Post S, Menger MD. Hepatic microcirculatory perfusion failure is a determinant of liver dysfunction in warm ischemia-reperfusion. Am J Pathol 1994; 145: 142131[Abstract]
12 Clavien PA, Yadav S, Sindram D, Bentley RC. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans [see comments]. Ann Surg 2000; 232: 15562[CrossRef][ISI][Medline]
13 Pagliaro P, Gattullo D, Rastaldo R, Losano G. Ischemic preconditioning: from the first to the second window of protection. Life Sci 2001; 69: 115[CrossRef][ISI][Medline]
14 Clavien PA, Selzner M, Rudger HA, et al. A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning. Ann Surg 2003; 238: 84350[ISI][Medline]
15 Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Ann Intern Med 2001; 134: 65762
16 Pringle JH. Notes on the arrest of hepatic hemorrhage due to trauma. Ann Surg 1908; 48: 5419
17 Arnoletti JP, Brodsky J. Reduction of transfusion requirements during major hepatic resection for metastatic disease. Surgery 1999; 125: 16671[CrossRef][ISI][Medline]
18 Bismuth H, Majno PE. Hepatobiliary surgery. J Hepatol 2000; 32 (Suppl 1): 20824[Medline]
19 Delva E, Camus Y, Paugam C, Parc R, Huguet C, Lienhart A. Hemodynamic effects of portal triad clamping in humans. Anesth Analg 1987; 66: 8648[Abstract]
20 Lentschener C, Franco D, Bouaziz H, et al. Haemodynamic changes associated with portal triad clamping are suppressed by prior hepatic pedicle infiltration with lidocaine in humans. Br J Anaesth 1999; 82: 6917
21 Aggarwal S, Kang Y, Freeman J, DeWolf AM, Begliomini B. Is there a post-reperfusion syndrome? Transplant Proc 1989; 21: 34979[ISI][Medline]
22 Chouker A, Martignoni A, Schauer R., Dugas M, Rau HG, Thiel M. Zentralvenöse und portalvenöse Purinspiegel während ischämischer Präkonditionierung der Leber. Z Gastroenterol 2001; 6: 484
23 Jaeschke H, Farhood A, Smith CW. Neutrophils contribute to ischemia/reperfusion injury in rat liver in vivo. FASEB J 1990; 4: 33559
24 Martinez-Mier G, Toledo-Pereyra LH, McDuffie JE, Warner RL, Ward PA. Neutrophil depletion and chemokine response after liver ischemia and reperfusion. J Invest Surg 2001; 14: 99107[CrossRef][ISI][Medline]
25 Fischer S, Conzen PF, Nuscheler M, Schauer R, Peter K. Influence of norepinephrine and dopamine on splanchnic blood flow and oxygen delivery during abdominal surgery: a randomized, single-blind, comparative study. ASA Meeting Abstracts 2002; A153
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