Regulation of hepatic blood flow: the hepatic arterial buffer response revisited.

The interest in the liver dates back to ancient times when it was considered to be the seat of life processes. The liver is indeed essential to life, not only due to its complex functions in biosynthesis, metabolism and clearance, but also its dramatic role as the blood volume reservoir. Among parenchymal organs, blood flow to the liver is unique due to the dual supply from the portal vein and the hepatic artery. Knowledge of the mutual communication of both the hepatic artery and the portal vein is essential to understand hepatic physiology and pathophysiology. To distinguish the individual importance of each of these inflows in normal and abnormal states is still a challenging task and the subject of ongoing research. A central mechanism that controls and allows constancy of hepatic blood flow is the hepatic arterial buffer response. The current paper reviews the relevance of this intimate hepatic blood flow regulatory system in health and disease. We exclusively focus on the endogenous interrelationship between the hepatic arterial and portal venous inflow circuits in liver resection and transplantation, as well as inflammatory and chronic liver diseases. We do not consider the hepatic microvascular anatomy, as this has been the subject of another recent review.

[1]  M. Menger,et al.  Hepatic arteriolo‐portal venular shunting guarantees maintenance of nutritional microvascular supply in hepatic arterial buffer response of rat livers , 2001, The Journal of physiology.

[2]  J. Revelly,et al.  Role of nitric oxide in porcine liver circulation under normal and endotoxemic conditions. , 1995, Journal of applied physiology.

[3]  W W Lautt,et al.  Hepatic arterial pressure-flow autoregulation is adenosine mediated. , 1987, The American journal of physiology.

[4]  M. Menger,et al.  Nitric oxide reduces organ injury and enhances regeneration of reduced‐size livers by increasing hepatic arterial flow , 2008, The British journal of surgery.

[5]  R. Mathie Hepatic blood flow during cardiopulmonary bypass , 1993, Critical care medicine.

[6]  L. Nyhus,et al.  Hepatic arterial and portal venous pressure-flow relationships in isolated, perfused liver. , 1962, The American journal of physiology.

[7]  G. Burnstock,et al.  Characterization of P2X‐ and P2Y‐purinoceptors in the rabbit hepatic arterial vasculature , 1991, British journal of pharmacology.

[8]  J. Spitzer,et al.  Effects of endotoxin on regional blood flow in the unanesthetized guinea pig. , 1978, The Journal of surgical research.

[9]  P. Neuhaus,et al.  Ischemic Preconditioning Impairs Liver Regeneration in Extended Reduced-Size Livers , 2005, Annals of surgery.

[10]  R. Mathie,et al.  The role of adenosine in the hyperaemic response of the hepatic artery to portal vein occlusion (the ‘buffer response’) , 1990, British journal of pharmacology.

[11]  C. Vigouroux,et al.  Portal and hepatic arterial blood flow measurements of human transplanted liver by implanted Doppler probes: interest for early complications and nutrition. , 1990, Surgery.

[12]  Charles M. Miller,et al.  “Splenic artery steal syndrome” is a misnomer: The cause is portal hyperperfusion, not arterial siphon , 2008, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[13]  Brigitte Vollmar,et al.  The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. , 2009, Physiological reviews.

[14]  J. Ellis,et al.  Hepatic artery resistance before and after standard meal in subjects with diseased and healthy livers. , 1995, Radiology.

[15]  T. Kiuchi,et al.  Small-for-size graft in liver transplantation. , 2003, Nagoya journal of medical science.

[16]  F. Weber,et al.  Late hepatic artery thrombosis in liver allograft recipients is associated with intrahepatic biliary necrosis. , 1996, Transplantation.

[17]  T. Komatsu,et al.  Hepatic venous hemoglobin oxygen saturation predicts liver dysfunction after hepatectomy. , 1992, Anesthesiology.

[18]  R. Groszmann,et al.  Compensatory mechanisms in response to an elevated hepatic oxygen consumption in chronically ethanol-fed rats. , 1985, The American journal of physiology.

[19]  M. Menger,et al.  An intravital fluorescence microscopic study of hepatic microvascular and cellular derangements in developing cirrhosis in rats , 1998, Hepatology.

[20]  J. Takala,et al.  EFFECTS OF LOW ABDOMINAL BLOOD FLOW AND DOBUTAMINE ON BLOOD FLOW DISTRIBUTION AND ON THE HEPATIC ARTERIAL BUFFER RESPONSE IN ANAESTHETIZED PIGS , 2006, Shock.

[21]  A Marcos,et al.  THE INTERRELATIONSHIP BETWEEN PORTAL AND ARTERIAL BLOOD FLOW AFTER ADULT TO ADULT LIVING DONOR LIVER TRANSPLANTATION , 2000, Transplantation.

[22]  T. Thomas,et al.  Hepatic stellate cells: role in microcirculation and pathophysiology of portal hypertension , 2002, Gut.

[23]  R. Stratta,et al.  Vascular complications after orthotopic liver transplantation. , 1991, American journal of surgery.

[24]  P. Neuhaus,et al.  Does concommitant splenectomy raise the mortality of liver transplant recipients? , 1994, Transplant International.

[25]  D. Morel,et al.  Effects of abdominal CO 2 insufflation and changes of position on hepatic blood flow in anesthetized pigs , 1998 .

[26]  P. Asfar,et al.  Low-dose terlipressin during long-term hyperdynamic porcine endotoxemia: Effects on hepatosplanchnic perfusion, oxygen exchange, and metabolism* , 2005, Critical care medicine.

[27]  Y. Kimura,et al.  Portal Blood Flow Regulates Volume Recovery of the Rat Liver after Partial Hepatectomy: Molecular Evaluation , 2006, European Surgical Research.

[28]  S. Dulchavsky,et al.  Effect of increased intra-abdominal pressure on hepatic arterial, portal venous, and hepatic microcirculatory blood flow. , 1992, The Journal of trauma.

[29]  M. Büchler,et al.  Splanchnic microcirculatory changes during CO2 laparoscopy. , 1997, Journal of the American College of Surgeons.

[30]  O. Boillot,et al.  Portomesenteric disconnection for small-for-size grafts in liver transplantation: Preclinical studies in pigs. , 2003, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[31]  B. Pannen New insights into the regulation of hepatic blood flow after ischemia and reperfusion. , 2002 .

[32]  O. Smiseth,et al.  The NO donor sodium nitroprusside reverses the negative effects on hepatic arterial flow induced by endotoxin and the NO synthase inhibitor L-NAME. , 1996, European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes.

[33]  N. Heaton,et al.  The ‘small for size’ liver syndrome , 2005, Current opinion in critical care.

[34]  K. Godfrey,et al.  Hepatic Artery Hemodynamics Suggest Operation of a Buffer Response in the Human Fetus , 2008, Reproductive Sciences.

[35]  P. Angeli,et al.  Hepatic arterial resistance in cirrhosis with and without portal vein thrombosis: relationships with portal hemodynamics. , 1995, Gastroenterology.

[36]  M. Menger,et al.  Significance of hepatic arterial responsiveness for adequate tissue oxygenation upon portal vein occlusion in cirrhotic livers , 2000, International Journal of Colorectal Disease.

[37]  K. Hirohashi,et al.  Changes in portal venous pressure in the early phase after living donor liver transplantation: pathogenesis and clinical implications1,2 , 2003, Transplantation.

[38]  J. Reichen Etiology and pathophysiology of portal hypertension. , 1988, Zeitschrift fur Gastroenterologie.

[39]  Charles M. Miller,et al.  Adenosine restores the hepatic artery buffer response and improves survival in a porcine model of small‐for‐size syndrome , 2009, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[40]  J. Emond,et al.  Split‐Liver Transplantation: A Review , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[41]  J. Fangmann,et al.  Splenohepatic arterial steal syndrome in liver transplantation: clinical features and management , 2002, Transplant international : official journal of the European Society for Organ Transplantation.

[42]  J M Rubin,et al.  Porta hepatis: duplex Doppler US with angiographic correlation. , 1987, Radiology.

[43]  Rappaport Am,et al.  Hepatic blood flow: morphologic aspects and physiologic regulation. , 1980 .

[44]  Y. Bandai,et al.  Safe intraabdominal pressure of carbon dioxide pneumoperitoneum during laparoscopic surgery. , 1993, Surgery.

[45]  C. Ethier,et al.  Hepatic artery buffer response following left portal vein ligation: its role in liver tissue homeostasis. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[46]  Y. Kuroda,et al.  Evidence that portal vein decompression improves survival of canine quarter orthotopic liver transplantation. , 1995, Transplantation.

[47]  Angelo Gatta,et al.  Change in portal flow after liver transplantation: Effect on hepatic arterial resistance indices and role of spleen size , 2002, Hepatology.

[48]  M. Miyazaki,et al.  Hepatic venous hemoglobin oxygen saturation predicts regenerative status of remnant liver after partial hepatectomy in rats , 1998, Hepatology.

[49]  W W Lautt,et al.  Quantitation of the hepatic arterial buffer response to graded changes in portal blood flow. , 1990, Gastroenterology.

[50]  M. Bauer,et al.  Differential regulation of hepatic arterial and portal venous vascular resistance by nitric oxide and carbon monoxide in rats. , 1998, Life sciences.

[51]  K. Messmer,et al.  [The pressure relationship of hepatic circulation]. , 1966, Pflugers Archiv fur die gesamte Physiologie des Menschen und der Tiere.

[52]  J. Revelly,et al.  Alternations in liver hemodynamics in an intact porcine model of endotoxin shock. , 1995, The American journal of physiology.

[53]  J. Villeneuve,et al.  Intrahepatic Circulation in Liver Disease1 , 1986, Seminars in liver disease.

[54]  Brigitte Vollmar,et al.  H2S contributes to the hepatic arterial buffer response and mediates vasorelaxation of the hepatic artery via activation of K(ATP) channels. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[55]  Y. Maehara,et al.  Effect of intraportal infusion to improve small for size graft injury in living donor adult liver transplantation , 2005, Transplant International.

[56]  M. Kutner,et al.  Hemodynamics during liver transplantation: The interactions between cardiac output and portal venous and hepatic arterial flows , 1992, Hepatology.

[57]  R. Uflacker,et al.  Transcatheter Splenic Artery Occlusion for Treatment of Splenic Artery Steal Syndrome After Orthotopic Liver Transplantation , 2002, CardioVascular and Interventional Radiology.

[58]  J M Schoen,et al.  Shear stress-induced nitric oxide release triggers the liver regeneration cascade. , 2001, Nitric oxide : biology and chemistry.

[59]  J. Müller,et al.  Does pneumoperitoneum with different gases, body positions, and intraperitoneal pressures influence renal and hepatic blood flow? , 1997, Surgery.

[60]  S. Fan,et al.  Portal hyperperfusion injury as the cause of primary nonfunction in a small‐for‐size liver graft‐successful treatment with splenic artery ligation , 2003, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[61]  J. Kalk,et al.  Hepatic arterial pulsatility index in cirrhosis: correlation with portal pressure. , 1999, Journal of hepatology.

[62]  Peter Smeets,et al.  Effects of Hemi‐Portocaval Shunts For Inflow Modulation on the Outcome of Small‐for‐Size Grafts in Living Donor Liver Transplantation , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[63]  F. Smulders,et al.  Laparoscopic insufflation of the abdomen reduces portal venous flow , 1998, Surgical Endoscopy.

[64]  B. Vollmar,et al.  Hyperperfusion Syndrome in Small-for-Size Livers , 2005, European Surgical Research.

[65]  W. Lautt,et al.  Hepatic venous compliance and role of liver as a blood reservoir. , 1976, The American journal of physiology.

[66]  C V Greenway,et al.  Hepatic vascular bed. , 1971, Physiological reviews.

[67]  S. Sherlock,et al.  Intrasplenic pressure as index of portal venous pressure. , 1954, Lancet.

[68]  A. Sanyal,et al.  Right lobe living donor liver transplantation. , 1999, Transplantation.

[69]  N. Ohkohchi,et al.  Excessive portal flow causes graft failure in extremely small-for-size liver transplantation in pigs. , 2005, World journal of gastroenterology.

[70]  D. Balfour,et al.  Hepatic vein pressure studies for evaluation of intrahepatic portal hypertension. , 1954, Archives of Surgery.

[71]  Lautt Ww,et al.  Relationship between hepatic blood flow and overall metabolism: the hepatic arterial buffer response. , 1983 .

[72]  W W Lautt,et al.  The use of 8-phenyltheophylline as a competitive antagonist of adenosine and an inhibitor of the intrinsic regulatory mechanism of the hepatic artery. , 1985, Canadian journal of physiology and pharmacology.

[73]  M. Menger,et al.  Kupffer Cells Are Mandatory for Adequate Liver Regeneration by Mediating Hyperperfusion via Modulation of Vasoactive Proteins , 2008, Microcirculation.

[74]  B. Delafosse,et al.  Small-for-size partial liver graft in an adult recipient; a new transplant technique , 2002, The Lancet.

[75]  M Ishikawa,et al.  Hemodynamic changes in blood flow through the denervated liver in pigs. , 1995, Journal of investigative surgery : the official journal of the Academy of Surgical Research.

[76]  F. Gorunescu,et al.  Hepatic arterial blood flow in large hepatocellular carcinoma with or without portal vein thrombosis: assessment by transcutaneous duplex Doppler sonography , 2002, European journal of gastroenterology & hepatology.

[77]  W W Lautt,et al.  Conceptual review of the hepatic vascular bed , 1987, Hepatology.

[78]  C. Putensen,et al.  The effects of mechanical ventilation on the gut and abdomen , 2006, Current opinion in critical care.

[79]  P. Johnson,et al.  Local control of hepatic arterial and portal venous flow in the dog. , 1966, The American journal of physiology.

[80]  Yoshinobu Sato,et al.  Splenectomy for reduction of excessive portal hypertension after adult living-related donor liver transplantation. , 2002, Hepato-gastroenterology.

[81]  W. Lautt Control of hepatic arterial blood flow: independence from liver metabolic activity. , 1980, The American journal of physiology.

[82]  H. B. Torrance,et al.  The control of the hepatic arterial circulation , 1961, Journal of the Royal College of Surgeons of Edinburgh.

[83]  F. Romani,et al.  Splenic artery steal syndrome after orthotopic liver transplantation: diagnosis and treatment. , 1993, Transplantation proceedings.

[84]  W. Fleig,et al.  Hepatic arterial flow volume and reserve in patients with cirrhosis: use of intra-arterial Doppler and adenosine infusion. , 1999, Gastroenterology.

[85]  F. Jakab,et al.  The interaction between hepatic arterial and portal venous blood flows; simultaneous measurement by transit time ultrasonic volume flowmetry. , 1995, Hepato-gastroenterology.

[86]  D. Tamandl,et al.  Nitric Oxide Administration Restores the Hepatic Artery Buffer Response During Porcine Endotoxemia , 2008, Journal of investigative surgery : the official journal of the Academy of Surgical Research.

[87]  Yoshinobu Sato,et al.  Role of shear stress and immune responses in liver regeneration after a partial hepatectomy , 2006, Surgery Today.

[88]  A. Lauterio,et al.  Should we still offer split‐liver transplantation for two adult recipients? A retrospective study of our experience , 2008, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[89]  R. Latimer,et al.  Endotoxin‐induced organ injury , 1993, Critical care medicine.

[90]  M. Menger,et al.  Impact of intrinsic blood flow regulation in cirrhosis: maintenance of hepatic arterial buffer response. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[91]  S. Todo,et al.  Transient portacaval shunt for a small‐for‐size graft in living donor liver transplantation , 2007, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[92]  W G SCHENK,et al.  Direct Measurement of Hepatic Blood Flow in Surgical Patients: With Related Observations on Hepatic Flow Dynamics in Experimental Animals , 1962, Annals of surgery.

[93]  Koichi Tanaka,et al.  "Small-for-size graft" and "small-for-size syndrome" in living donor liver transplantation. , 2004, Yonsei medical journal.

[94]  A. Toyonaga,et al.  Hepatic artery hemodynamic responsiveness to altered portal blood flow in normal and cirrhotic livers. , 1996, Radiology.

[95]  Yoshihiro Sakamoto,et al.  Intraoperative direct measurement of hepatic arterial buffer response in patients with or without cirrhosis , 2005, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[96]  G. Michalopoulos Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. , 2010, The American journal of pathology.

[97]  W. Fleig,et al.  Functional significance of hepatic arterial flow reserve in patients with cirrhosis , 2003, Hepatology.

[98]  C. Herfarth,et al.  Arterial steal: an unusual cause for hepatic hypoperfusion after liver transplantation , 1991, Transplant international : official journal of the European Society for Organ Transplantation.

[99]  R. Mathie,et al.  The action of ATP on the hepatic arterial and portal venous vascular networks of the rabbit liver: the role of adenosine. , 1997, European journal of pharmacology.

[100]  W. Lautt,et al.  Adenosine as putative regulator of hepatic arterial flow (the buffer response). , 1985, The American journal of physiology.

[101]  J. Spitzer,et al.  Cardiac output and redistribution of organ blood flow in hypermetabolic sepsis. , 1984, The American journal of physiology.

[102]  S. Fan,et al.  Graft Injury in Relation to Graft Size in Right Lobe Live Donor Liver Transplantation: A Study of Hepatic Sinusoidal Injury in Correlation With Portal Hemodynamics and Intragraft Gene Expression , 2003, Annals of surgery.

[103]  R. Mathie,et al.  The role of ATP and adenosine in the control of hepatic blood flow in the rabbit liver in vivo , 2003, Comparative hepatology.

[104]  Peter Smeets,et al.  Modulation of Portal Graft Inflow: A Necessity in Adult Living-Donor Liver Transplantation? , 2003, Annals of surgery.

[105]  M. C. Rogers,et al.  Effect of Abdominal Distension on Central and Regional Hemodynamics in Neonatal Lambs , 1985, Pediatric Research.

[106]  G. Mentha,et al.  Sequential changes in the splanchnic circulation during continuous endotoxin infusion in sedated sheep: evidence for a selective increase of hepatic artery blood flow and loss of the hepatic arterial buffer response. , 1993, Acta physiologica Scandinavica.

[107]  H. Herbst,et al.  The endothelin/nitric oxide balance determines small-for-size liver injury after reduced-size rat liver transplantation , 2005, Virchows Archiv.

[108]  R. Mathie,et al.  The transhepatic action of ATP on the hepatic arterial and portal venous vascular beds of the rabbit: the role of nitric oxide , 1994, British journal of pharmacology.

[109]  W. Lautt,et al.  Regulatory processes interacting to maintain hepatic blood flow constancy: Vascular compliance, hepatic arterial buffer response, hepatorenal reflex, liver regeneration, escape from vasoconstriction , 2007, Hepatology research : the official journal of the Japan Society of Hepatology.

[110]  Rui Wang,et al.  H2S-induced vasorelaxation and underlying cellular and molecular mechanisms , 2002 .

[111]  T. Brzozowski,et al.  Role of afferent nerves and sensory peptides in the mediation of hepatic artery buffer response. , 2003, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[112]  M. Menger,et al.  Loss of Physiologic Hepatic Blood Flow Control (“Hepatic Arterial Buffer Response”) During CO2-Pneumoperitoneum in the Rat , 2001, Anesthesia and analgesia.

[113]  M. de Castro,et al.  Inducible nitric oxide synthase pathway in the central nervous system and vasopressin release during experimental septic shock* , 2002, Critical care medicine.

[114]  X. Rogiers,et al.  Split-Liver Transplantation: An Underused Resource in Liver Transplantation , 2008, Transplantation.

[115]  A. Demetris,et al.  Pathophysiologic Observations and Histopathologic Recognition of the Portal Hyperperfusion or Small-for-Size Syndrome , 2006, The American journal of surgical pathology.

[116]  W. W. Lautt The hepatic artery: subservient to hepatic metabolism or guardian of normal hepatic clearance rates of humoral substances. , 1977, General pharmacology.

[117]  R. Troisi,et al.  Clinical relevance of adapting portal vein flow in living donor liver transplantation in adult patients , 2003, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[118]  U. Settmacher,et al.  Diagnosis and treatment of arterial steal syndromes in liver transplant recipients , 2003, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[119]  K. Mystakidou,et al.  Hemodynamic interaction between portal vien and hepatic artery flow in small‐for‐size split liver transplantation , 2002 .

[120]  R. Busuttil,et al.  Split liver transplantation. , 1999, Annals of surgery.

[121]  N. Tanaka,et al.  Preoperative proximal splenic artery embolization: a safe and efficacious portal decompression technique that improves the outcome of live donor liver transplantation , 2007, Transplant international : official journal of the European Society for Organ Transplantation.

[122]  C. Fondevila,et al.  Portal hyperperfusion: Mechanism of injury and stimulus for regeneration in porcine small‐for‐size transplantation , 2010, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[123]  Brigitte Vollmar,et al.  Splenectomy improves survival by increasing arterial blood supply in a rat model of reduced‐size liver , 2010, Transplant international : official journal of the European Society for Organ Transplantation.

[124]  P. Neuhaus,et al.  Evolving experience with prevention and treatment of splenic artery syndrome after orthotopic liver transplantation , 2010, Transplant international : official journal of the European Society for Organ Transplantation.

[125]  T. Huynh,et al.  Hepatic vascular response to elevated intraperitoneal pressure in the rat. , 2002, The Journal of surgical research.

[126]  G. Burnstock,et al.  Nitric oxide is the mediator of ATP‐induced dilatation of the rabbit hepatic arterial vascular bed , 1991, British journal of pharmacology.

[127]  W. Lautt,et al.  Hepatic venous resistance site in the dog: localization and validation of intrahepatic pressure measurements. , 1987, Canadian journal of physiology and pharmacology.

[128]  W. Lautt Hepatic vasculature: a conceptual review. , 1977, Gastroenterology.

[129]  M. Lafortune,et al.  Hepatic artery: effect of a meal in healthy persons and transplant recipients. , 1993, Radiology.

[130]  W. Lautt,et al.  Maintenance of hepatic arterial blood flow during hemorrhage is mediated by adenosine. , 1989, Canadian journal of physiology and pharmacology.

[131]  R. Groszmann,et al.  Vascular endothelial dysfunction in cirrhosis. , 2007, Journal of hepatology.

[132]  M. Costuleanu,et al.  Hepatic artery hemodynamics in acute viral hepatitis. , 1999, Romanian journal of physiology : physiological sciences.

[133]  T. Tønnessen,et al.  Importance of nitric oxide in hepatic arterial blood flow and total hepatic blood volume regulation in pigs. , 1997, Acta Physiologica Scandinavica.

[134]  P. Clavien,et al.  Small‐for‐Size Syndrome After Partial Liver Transplantation: Definition, Mechanisms of Disease and Clinical Implications , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[135]  Klaus Haag,et al.  Hepatic arterial buffer response in patients with advanced cirrhosis , 2002, Hepatology.

[136]  K M Hanson,et al.  Dilator responses of the canine hepatic vasculature. , 1973, Angiologica.

[137]  C. Lang,et al.  Regional blood flow during continuous low-dose endotoxin infusion. , 1986, Circulatory shock.