Thoracic epidural anesthesia: Effects on splanchnic circulation and implications in Anesthesia and Intensive care

Table 1 Animal studies evaluating macrohemodynamics and liver microhemodynamics

Subjects	Ref.	Year	Title	Type of study	Scenario	No. subjects	Sensory blockade	Surrogate measure of splanchnic flow	Findings
Monkeys	Sivarajan et al[2]	1976	Systemic and regional blood flow during epidural anesthesia without epinephrine in the rhesus monkey	Prospective randomized	Anesthetized animals, epidural catheter placed L1-L2	9 (4 low epidural aneshtesia - level T10 vs 5 high epidural anesthesia - level T1)	higher level T10 or T1	Radioactive microspheres and direct invasive monitoring of cardiac output	Low epidural - no difference in blood flow to major organs, while T1 epidural ↓ blood flow to liver, pancreas and gut (hepatic artery, portal vein)
Dogs	Meissner et al[4]	1999	Limited upper thoracic epidural block and splanchnic perfusion in dogs	Prospective observational	Induction of upper thoracic epidural in awake and anesthetized dogs and measurements of splanchinc perfusion	13 (6 anesthetized, 7 no)	T1-T5	Coloured microspheres injected in the aorta and then collected from tissue samples after autopsy	High TEA had no effect on sympathetic activity and splanchnic blood flow, nor in the awake nor anesthetized state. Propofol anaestehsia increased liver perfusion
Rabbits	Ai et al[6]	2001	Epidural anesthesia retards intestinal acidosis and reduces portal vein endotoxin concentrations during progressive hypoxia in rabbits	Prospective randomized	Progressive hypoxia in anesthetized animals	18 (9 TEA/Lidocaine vs 9 TEA/NaCl 0.9%)	insertion point T12-L1 and 3-4 cm advancement	Portal blood flow, portal oxygen extraction ratio, portal pH, portal Lactate, intramucosal pH (pHi) of the ileum, portal endotoxin	pHi and pHart significantly higher and portal Endotoxin and Lactate significantly lower in TEA/Lido group. No diifferences in portal blood flow
Pigs	Vagts et al[5]	2003	The effects of thoracic epidural anesthesia on hepatic perfusion and oxygenation in healthy pigs during general anesthesia and surgical stress	Prospective randomized	Anesthetized and acutely instrumented pigs, assigned to 3 groups: control vs TEA plus basic fluid (BF) vs TEA plus VL	19 (3 CTRL; 8 TEA alone; 8 TEA + VL)	T5 to T12	Hepatic blood flow using ultrasonic transit-time perivascular flowprobes around the hepatic artery and portal vein; multiwire surface electrode placed onto the liver to measure tissue surface PO2; PDR-icg	Despite a decrease in MAP, TEA had no effect on total hepatic blood flow, liver DO2 and VO2. Liver tissue PO2 did not decrease. Lactate uptake and PDR-icg remained unchanged. Volume loading did not show any benefit with regard to hepatic perfusion, oxygenation, and function
Rats	Shäper et al[3]	2010	TEA attenuates endotoxin induced impairment of gastro intestinal organ perfusion	Prospective randomized	Sepsis model through infusion of LPS, evaluation of regional flow at 30', 60', 120'	18 (9 TEA vs 9 sham)	T4-T11 (methilen blue spread)	Fluorecent microspheres withdrawal technique, then evaluation of microspheres in brain, heart, ileopsoas muscle, liver pancreas gut segments; determination plasma cathecolamines	TEA ↑ blood flow to GIT organs under LPS effect
		Studies evaluating liver micro hemodynamics
Rats	Freise et al[17]	2009	Hepatic effects of TEA in experimental severe acute pancreatitis	Prospective randomized blinded image analysis	Animal model of acute pancreatitis induced by taurocholate injection or sham lesion	28 (7 sham + sham, 7 sham + TEA, 7 pancreat + sham, 7 pancreat + TEA) an additional 22 animals were assigned to the three group to asses hepatic apoptosis	catheter tip placed T6	Intravital microscopy of liver left lobe, cell adehesion to sinusoid wall (rollers and stickers), apoptosis of cells by Fas-L pathway	TEA ↑ diameter of sinusoids in pancreatitis, TEA ↓ the number of parenchymal apoptotic cells in pancreatitis (Fas-L pathway), TEA does not have much influence in sham groups
Rats	Freise et al[18]	2009	TEA reduces sepsis related hepatic hyperperfusion and reduces leucocyte adehesion in septic rats	Prospective randomized blinded image analysis	Sepsis model induced with cecal ligation and perforation	24 (8 sham + sham, 8 sepsis + sham, 8 sepsis + TEA); another 21 animals were assessed for liver failure and hemodynamics	catheter tip placed T6	Intravital microscopy of liver left lobe, cell adehesion to sinusoid and venules, serum transaminase activity, TNFα activity	TEA ↓ sinusoid dilation in sepsis by probably restoring hepatic arterial buffer response. TEA ↓ temporary adhesion to sinusoid wall but did not affect permanent adhesion. TEA did not affect transaminase or TNF activity. No differences in hemodynamics

↑: Increase; ↓: Decrease; VL: Volume loading; TEA: Thoracic epidural anesthesia; CTRL: Control; MAP: Mean arterial pressure; PDRICG: Plasma disappearance rate of Indocyanine Green; LPS: Lipopolysaccharide; GIT: Gastrointestinal tract; HR: Heart rate; PEEP: Positive end expiratory pressure; HES: Hydroxethyl starch; PCO₂: Carbon dioxide partial pressure; LEA: Lumbar epidural anesthesia; ERCP: Endoscopic retrograde cholangiopancreatography.

Table 2 Animal studies evaluating intestinal and pancreatic microhemodynamics

Subjects	Ref.	Year	Title	Type of study	Scenario	No. subjects	Sensory blockade	Surrogate measure of splanchnic flow	Findings
Rabbits	Hogan et al[7]	1993	Effects of epidural and systemic lidocaine on sympathetic activity and mesenteric circulation in rabbits	Prospective randomized	Anesthetized animals receiving thoraco-lumbar epidural block with different anesthetic concentrations	32 (7 lidocaine 6 mg/kg im vs 5 lidocaine 15 mg/kg im vs 5 TEA lido 0.5% vs 8 TEA lido 1.0% vs 7 TEA lido 1.5%)	T2-L5	Mesenteric vein diameter, sympathetic efferent nerve activity (SENA) of post ganglionic splanchnic nerve	TEA ↑ splanchnic venous capacitance and ↓ SENA
Rabbits	Hogan et al[8]	1995	Region of epidural blockade determines sympathetic and mesenteric capacitance effects in rabbits	Prospective randomized	Anesthetized and non anesthetized animals receiving either a thoracic or lumbar block with special epidural catheters limiting anesthetic spread	26 (6 lidocaine 1% TEA vs 6 lido 1% LEA, vs 8 thoracolumbar anesthesia in spontaneous ventilation with lido 1% vs 6 thoracolumbar anesthesia with lido 1% in fully awake animals)	T11-L7 (LEA group), T4-L1 (TEA group), T1-L4 (thoracolumbar anesthesia)	Mesenteric vein diameter, sympathetic efferent nerve activity (SENA) of post ganglionic splanchnic nerve	↑ SENA and ↓ mesenteric vein diameter after lumbar epidural anesthesia while ↓ SENA and ↑ mesenteric vein diameter after thoracic epidural anesthesia
Rats	Sielenkämper et al[10]	2000	Thoracic epidural anesthesia increases mucosal perfusion in ileum of rats	Prospective randomized	Anesthetized and mechanically ventilated rats that underwent laparotomy to obtain access to the ileum	19: 11 bupivacaine 0.4% (TEA); 8 normal saline (CTRL)	Catheter tip placed T7-T9	Intravital microscopy on the ileum mucosa	TEA ↑ gut mucosal blood flow and ↓ the extent of intermittent flow in the villus microcirculation
Rats	Adolphs et al[12]	2003	Thoracic epidural anesthesia attenuates hemorrhage-induced impairment of intestinal perfusion in rats	Prospective randomized	Hemorragic shock model (PAM 30 mmHg for 60 min) induced by withdrawal of blood and subsequent retransfusion for resuscitation	32 (4 groups of 8); epidural lidocaine 2% (TEA) or normal saline (CTRL), muscolaris or mucosa evaluated	catheter tip placed T11-T12	Intravital microscopy with fluorescein (FCD = functional capillary density and erythrocyte velocity in the mucosa and muscularis of distal ileum)	TEA ↑ intestinal microvascular perfusion and ↓ hypotension-induced impairment of capillary perfusion in the muscularis, ↓ systemic acidemia during hypotension and ↓ leukocyte rolling after resuscitation
Rats	Adolphs et al[11]	2004	Effects of thoracic epidural anaesthesia on intestinal microvascular perfusion in a rodent model of normotensive endotoxaemia	Prospective randomized	Normotensive endotoxaemia model through LPS infusion in anesthetized animals	32 (8 no TEA vs 24 TEA) +/- E.coli LPS infusion +/- epidural lidocaine 2% or saline infusion, muscolaris or mucosa evaluated	catheter tip placed T11-T12	Intravital microscopy with fluorescein (densities of perfused and non-perfused capillaries and erythrocyte velocity in both the mucosa and the muscularis of the terminal ileum)	TEA ↓ MAP and HR, ↑ muscularis and ↓ mucosal microvascular perfusion
Dogs	Schwarte et al[15]	2004	Effects of thoracic epidural anaesthesia on microvascular gastric mucosal oxygenation in physiological and compromised circulatory conditions in dogs	Prospective randomized	Chronically instrumented and anaesthetized dogs. Animals were studied under physiological and compromised circulatory conditions (PEEP 10 cm H(2)O), both with and without fluid resuscitation	12 (6 lidocaine vs 6 saline)	catheter tip placed T10, thoracolumbar - paresis of the ocular nictitating membrane, sensory block up to the neck region, and motor block of the limbs	Gastric mucosal oxygenation by measuring microvascular haemoglobin oxygen saturation (µHbO2) using reflectance spectrophotometry	Under physiological conditions, TEA preserved gastricmucosal oxygenation but aggravated its reduction during impaired circulatory conditions, thereby preserving the correlation between gastric mucosal and systemic oxygenation. Fluid resuscitation completely restored these variables
Rabbits	Kosugi et al[9]	2005	Epidural analgesia prevents endotoxin-induced gut mucosal injury in rabbits	Prospective randomized	Normotensive endotoxaemia model through LPS infusion in anesthetized animals	PROTOCOL 1: 28 = 14 saline (C = CONTROL) vs 14 lidocaine (E = EPIDURAL); PROTOCOL 2: 20, into groups C or E (10 each group)	catheter placed via T11-T12 interspace	PROTOCOL 1: Measurements of systemic and splanchnic variables using catheter inserted through the mesenteric vein and perivascular probe attached around the portal vein. Intramucosal pH using tonometer catheter surgically inserted into the terminal ileum. Mucosal edema and microstructure of the terminal ileum using tissue sampling to determine wet-to-dry weight ratio and histological analysis (histopathological injury scores of gut mucosa). PROTOCOL 2: gut permeability using fluorescence spectrometry	The application of epidural analgesia in endotoxemic hosts attenuates the progression of intramucosal acidosis, the increase of intestinal permeability, and the structural alterations of intestinal villi, possibly throught the restoration of microcirculation, despite a significant decrease of perfusion pressure and arterial oxygen content
Rats	Freise et al[13]	2006	Thoracic epidural analgesia augments ileal mucosal capillary perfusion and improves survival in severe acute pancreatitis in rats	Prospective randomized	Animal model of acute pancreatitis (AP) induced by taurocholate injection or sham lesion	28 (4 groups of 7): sham + saline TEA (Sham) vs AP + saline TEA (PANC) vs AP + TEA (EPI) vs AP + delayed TEA (delayed EPI). Outcome protocol: (n = 30): 15 AP vs 15 TEA	catheter tip placed T6	Intravital microscopy of the ileal mucosa	TEA ↓ intercapillary area (↑ local perfusion) ↓ IL-6 and serum lactate and ↓ 66% mortality
Rats	Daudel et al[14]	2007	Continuous thoracic epidural anesthesia improves gut mucosal microcirculation in rats with sepsis	Prospective randomized, blinded image analysis	Sepsis model induced with cecal ligation and perforation (CLP)	27 (10 CLP/TEA vs 9 CLP/Control vs 8 sham laparotomy)	catheter tip placed T6	Intravital videomicroscopy performed on villi of ileum mucosa	Smaller intercapillary area hence ↑ villus perfusion in CLP/TEA vs CLP/Control. Diameter of terminal arterioles and red blood cell velocity didn't differ
Pigs	Bachmann et al[16]	2013	Effects of thoracic epidural anesthesia on survival and microcirculation in severe acute pancreatitis: a randomized experimental trial	Prospective randomized	Animal model of SAP induced by intraductal injection of glycodesoxycholic acid in the main pancreatic duct followed by closure	34: 17 bupivacaine via TEA after induction of SAP (TEA) vs 17 no TEA (control)	catheter introduced T7-T8 and advanced 2 cm (documented by epidurogram)	Continuous measurement of the tissue oxygen tension (tpO2) using a flexible polarographic measuring probe placed in the pancreatic head and pancreatic microcirculation using Laser-Doppler imager during a period of 6 h after induction SAP. Histopathologic tissue damage (histopathologic severity score of acute pancreatis) by postmortem examination of the animals sacrificed after 7 d of observation	TEA improved survival as well as pancreatic microcirculation and tissue oxygenation resulting in reduced histopathologic tissue-damage

↑: Increase; ↓: Decrease. TEA: Thoracic epidural anesthesia; LEA: Lumbar epidural anesthesia; SAP: Severe acute pancreatitis.

Table 3 Human studies

Ref.	Year	Title	Type of study	Scenario	No. subjects	Sensory blockade	Surrogate measure of splanchnic flow	Findings
Lundberg et al[19]	1990	Intestinal hemodynamics during laparotomy: effects of thoracic epidural anesthesia and dopamine in humans	Prospective observational	Patients undergoing abdominal aorto-bifemoral reconstruction	9	Catheter inserted T7-T8 or T8-T9 and advanced 2-3 cm	Superior mesenteric artery blood flow (SMABF) via electromagnetic flow probe, mesenteric arteriovenous oxygen difference mesenteric venous lactate	↓ SMABF and ↓ MAP only restored by dopamine infusion
Tanaka et al[23]	1997	The effect of dopamine on hepatic blood flow in patients undergoing epidural anesthesia	Prospective controlled	Patients ASA 1-2 undergoing elective gynecological surgery. Normotension maintained either with HES infusion or HES + dopamine	28 (7 no TEA vs 14 TEA + HES vs 7 TEA + HES + dopamine)	Upper T5	Hepatic blood flow using Plasma Disappearance Rate of indocyanine green (PDR-icg)	↓ PDR-icg in TEA + HES group, = PDR-icg in TEA + HES + dopamine group
Väisänen et al[25]	1998	Epidural analgesia with bupivacaine does not improve splanchnic tissue perfusion after aortic reconstruction surgery	Prospective randomized controlled	Patients undergoing elective aortic reconstruction surgery	20 (10 TEA vs 10 controls)	Catheter inserted T12-L1 and advanced 5 cm	Gastric and sigmoid mucosal PCO2, pHi. Splanchnic blood flow direct invasive measure by cannulation of hepatic vein and dye diluition method (indocyanine green)	No differences
Spackman et al[26]	2000	Effect of epidural blockade on indicators of splanchnic perfusion and gut function in critically ill patients with peritonitis: a randomised comparison of epidural bupivacaine with systemic morphine	Double-blinded, prospective, randomised, controlled	Critically ill patients admitted in ICU with peritonitis (and systemic sepsis) and adynamic small bowel following abdominal surgery	21 (10 intravenous morphine vs 11 epidural bupivacaine)	Low thoracic or high lumbar epidural catheter insertion	Gastric tonometry: gastric intramucosal pH (pHig) and the intramucosal-arterial PCO2 gradient (Pg-PaCO2)	Significant improvements in gastric mucosal perfusion (a rise in Pg-PaCO2 and a fall in pHig in the morphine group and a significant difference between groups in the Pg-PaCO2 trends) and in the ultrasound appearance of the small bowel in the epidural group
Gould et al[20]	2002	Effect of thoracic epidural anaesthesia on colonic blood flow	Prospective observational	Patients undergoing elective anterior resection for rectal cancer	15	Cahteter inserted T9-T10	Doppler flowmetry for inferior mesenteric artery flow and Laser Doppler flowmetry for serosal red cell flux	↓ inferior mesenteric artery flow and ↓ serosal red cell flux significantly correlated to ↓ MAP reverted only by vasoconstrictors usage
Michelet et al[22]	2007	Effect of thoracic epidural analgesia on gastric blood flow after oesophagectomy	Prospective controlled	Patients undergoing elective radical oesophagectomy, postoperative evaluation	27 (18 TEA vs 9 controls)	C8-T11	Gastric mucosal blood flow (GMBF) measured using laser Doppler flowmetry at 1 and 18 h post surgery	↑GMBF in TEA group without correlation with MAP or CI
Kortgen et al[27]	2009	Thoracic but not lumbar epidural anaesthesia increases liver blood flow after major abdominal surgery	Prospective	Patients undergoing major abdominal surgery	34 (17 TEA vs 17 LEA)	Thoracic catheters between T5-T6 and T9-T10, lumbar catheters between L1-L2 and L4-L5	Blood lactate levels, central venous oxygen saturation (ScvO2), PDR-icg	TEA but not LEA ↑ PDR-icg
Meierhenrich et al[21]	2009	The effects of thoracic epidural anesthesia on hepatic blood flow in patients under general anesthesia	Prospective controlled	Patients undergoing major pancreatic surgery	30 (15 TEA vs 5 TEA + Norepinephrine vs 10 no TEA)	T4-T11	Hepatic blood flow index and hepatic stroke volume index in the right and middle hepatic vein by use of multiplane TEE	↓ Hepatic venous blood flow. The combination of thoracic TEA with continuous infusion of NE seems to induce a further decrease in hepatic blood flow. CO was not affected by TEA
Trepenaitis et al[24]	2010	The influence of thoracic epidural anesthesia on liver hemodynamics in patients under general anesthesia	Prospective randomized	Patients undergoing upper abdominal surgery for carcinoma of the stomach, papilla of Vater, and pancreas	50 (40 TEA vs 10 controls)	T5-T12	Hepatic blood flow using Plasma Disappearance Rate of indocyanine green (PDR-icg)	↓ PDR-icg in TEA group, even if ephedrine was administered to correct hypotension. ↑ PDR-icg in patients receiving general anetshesia. CO was unaffected

↑: Increase; ↓: Decrease. HES: Hydroxyethyl starch; NE: Norepinephrine; TEA: Thoracic epidural anesthesia; TEE: Transesophageal echocardiography.

Table 4 Delphi List for animal studies evaluating macrohemodynamics and liver microhemodynamics

	Hogan et al[7]	Hogan et al [8]	Sielenkä­mper et al [10]	Adolphs et al [12]	Adolphs et al [11]	Schwarte et al [15]	Kosugi et al [9]	Freiseet al[13]	Daudelet al[14]	Bachmann et al [16]
Treatment allocation
(1) Was a method of randomization performed?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was the treatment allocation concealed?	No	No	Yes	Yes	Yes	Yes	No	Yes	No	No
Were the groups similar at baseline regarding the most important progNostic indicators?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Were the eligibility criteria specified?	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Was the outcome assessor blinded?	No	No	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes
Was the care providor blinded?	No	No	No	No	No	No	No	No	No	No
Was the patient blinded?	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Were point estimates and measures of variability presented for the primary outcome measures?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Did the analysis include an intention-to- treat analysis?	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A

Table 5 Delphi list for animal studies evaluating gut and pancreatic microhemodynamics

	Lundberg et al[19]	Tanaka et al [23]	Väisänen et al [25]	Spackman et al [26]	Gouldet al[20]	Micheletet al[22]	Kortgen et al [27]	Meierhenrich et al [21]	Trepenaitis et al [24]
Treatment allocation
Was a method of randomization performed?	No	No	No	Yes	N/A	No	No	No	No
Was the treatment allocation concealed?	No	No	No	Yes	N/A	No	No	No	No
Were the groups similar at baseline regarding the most important progNostic indicators?	N/A	Yes	Don't know	Yes	N/A	Yes	No	Yes	Yes
Were the eligibility criteria specified?	No	Yes	No	Yes	Yes	Yes	No	Yes	Yes
Was the outcome assessor blinded?	No	No	No	Yes	N/A	Don't know	Don't know	Yes	No
Was the care providor blinded?	No	No	No	No	N/A	No	No	No	No
Was the patient blinded?	No	Don't know	No	Yes	N/A	No	No	No	No
Were point estimates and measures of vari ability presented for the primary outcome measures?	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Did the analysis include an intention-to-treat analysis?	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A

Table 6 Delphi List for human studies

	Sivarajanet al[2]	Meissner et al [4]	Ai et al [6]	Vagtset al[5]	Shäperet al[3]	Freiseet al[17]	Freiseet al[18]
Treatment allocation
Was a method of randomization performed?	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Was the treatment allocation concealed?	No	No	No	Yes	No	Yes	Yes
Were the groups similar at baseline regarding the most important progNostic indicators?	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Were the eligibility criteria specified?	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Was the outcome assessor blinded?	No	No	don't kNow	No	Yes	Yes	Yes
Was the care providor blinded?	No	No	No	No	No	Yes	Yes
Was the patient blinded?	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Were point estimates and measures of variability presented for the primary outcome measures?	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Did the analysis include an intention-to-treat analysis?	N/A	N/A	N/A	N/A	N/A	N/A	N/A

Table 7 Ongoing clinical trials

Title	Start year	Scenario	No. subjects	Current primary outcome measures	Current secondary outcome measures	Findings
Effect of Epidural Anesthesia on Pancreatic Perfusion and Clinical Outcome in Patients With Severe Acute Pancreatitis	July 2005	Acute pancreatitis with Ranson Criteria over 2, and/or CRP over 100, and or pancreatic necrosis on CT scan	35 (epidural anesthesia with carbostesin and fentanyl vs PCA with fentanyl)	Number of patients with adverse events related to epidural anesthesia, pancreatic perfusion measured by computerized tomography	Clinical outcome, Lenght of stay, admission to intensive care unit, need for surgery	n/d
Epidural Analgesia for Pancreatitis (Epipan Study)	April 2014	Patients admitted to the ICU for acute pancreatitis	148 (PCEA with Ropivacaine and sufentanyl vs conventional analgesia - acetaminophen, nefopam, tramadol, opidoids)	Ventilator-free days	Duration of invasive and/or non invasive mechanical ventilation, incidence of various complications, biological inflammatory response, cost analysis, incidence of intolerance to enteral feeding, effectiveness of pain management, duration of EA	n/d
Study of Effectiveness of Thoracic Epidural Analgesia for the Prevention of Acute Pancreatitis After ERCP Procedures	January 2008	Patients undergoing therapeutic ERCP for the first time without clinical signs of acute pancreatitis	491 (standard premedication + TEA vs standard premedication)	prevention of post-ERCP pancreatitis	Not provided	n/d
The Effects of Local Infiltration Versus Epidural Following Liver Resection 2 (LIVER 2)	December 2012	Patients undergoing open hepatic resection for benign or malignant conditions	100 (EA vs wound catheter)	Length of stay	Pain Scores, Molecular response to surgery, Central Venous Pressure, estimated Blood Loss, Operative field asessment, Pringle time, Quality of Life (EQ-5D), Morphine consumption, IV Fluid volume, Complications, Post-operative blood tests	n/d