Understanding intestinal circulation – Many barriers, many unknowns

Trends in Anaesthesia and Critical Care xxx (2013) 1e8

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Trends in Anaesthesia and Critical Care journal homepage: www.elsevier.com/locate/tacc

REVIEW

Understanding intestinal circulation e Many barriers, many unknowns Santosh Patel a, b, * a b

Pennine Acute NHS Trust, Rochdale, UK School of Biomedicine, Faculty of Medical and Human Sciences, University of Manchester, UK

s u m m a r y Keywords: Intestinal circulation Microcirculation Critical illness Surgery Anaesthesia

Intestinal macro and microcirculation play an important role in homeostasis. Intestinal microcirculation is regulated by multiple regional and systemic factors which have dynamic interactions. Intestinal circulation is compromised in critical illness such as haemorrhage and sepsis. Consequently, intestinal hypoperfusion may complicate into multi-organ dysfunction syndrome. Intestinal circulation is also vulnerable during the perioperative period of some high risk surgery. In humans, the effects of anaesthetic agents and techniques on intestinal microcirculation remain unknown. Some recent research studies have focused on anaesthesia interactions with intestinal circulation during haemorrhage, sepsis and intestinal ischaemia/reperfusion injury. However, experimental studies of intestinal circulation are difficult to conduct and have produced controversial results. Therapeutic options to optimize intestinal circulation are also limited by many barriers such as the disparity between the circulation of other splanchnic organs and systemic haemodynamics. Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction

the ileocolic, right colic, and middle colic arteries. The SMA also supplies the small intestine via multiple intestinal arteries. The left colon and sigmoid colon are supplied by the inferior mesenteric artery (IMA) via the left colic and sigmoidal arteries. The rectum receives its blood supply from branches from the IMA (via superior rectal) and the internal iliac artery (final branches middle and inferior rectal artery). Branches of the SMA and IMA interconnect via arcades with straight branches which pierce the intestinal wall. Despite intense collateral circulation, the middle of the small intestine and some areas of the colon (‘watershed areas’) are susceptible to ischaemia. The microcirculation is arranged as complex parallel circuits in the serosa and submucosa. From the submucosal complex, arterioles branch towards crypts and to the tip of the villi where they form the capillary plexus. Each villus has one arteriole. In each villus, venules drain from the mucosal tip towards the submucosa. The superior mesenteric vein and splenic veins form the portal vein. The inferior mesenteric vein drains into the splenic vein. Normal SMA and IMA blood flow is approximately 700 and 500 ml/min respectively (20e 25% of cardiac output). The mucosa and submucosa receive 75% of the blood supply. Unique microcirculation arrangements permit transmural redistribution of blood flow. The small bowel mucosa is susceptible to hypoxia and hypoperfusion because of the counter current flow arrangement of the arteriole and venulae in a villus and also the possibility of plasma skimming.1 Autoregulation of the intestinal circulation is not as profound as that of the kidney or the brain. Intrinsic metabolic and myogenic

The intestinal circulation (IC) is important for the absorption of nutrients, formation and excretion of faeces, and preservation of the peristalsis. Protection of the gut mucosal barrier function is pivotal during the perioperative period as well as during certain critical conditions such as haemorrhage and sepsis. In crises, 60e 70% of blood volume can be shifted from the splanchnic to the systemic circulation. In addition, intestinal blood flow (IBF) is particularly at risk during intestinal, aortic and open cardiac surgery and following abdominal trauma. Intestinal hypoperfusion is common during the perioperative period. Persistent intestinal hypoperfusion causes a delay in gastrointestinal (GI) functional recovery and may lead to multi-organ dysfunction. However, optimization, manipulation and monitoring of the intestinal circulation remain impractical. This review summarizes the basic sciences and behaviour of the intestinal circulation during anaesthesia, high risk surgery and critical illness. Therapeutic strategies and their effects on intestinal circulation are discussed. 2. Basic sciences Arterial blood supply to the colon from the caecum to the splenic flexure is through the superior mesenteric artery (SMA) via * Pennine Acute NHS Trust, Rochdale, UK. E-mail address: [email protected]. 2210-8440/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tacc.2013.08.002

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mechanisms for autoregulation have been demonstrated. Metabolic regulation predominates and overrides in critical conditions (e.g. low flow) to maintain intestinal oxygen uptake by capillary recruitment. Autoregulation is better preserved in the mucosa in diseases.2 Extrinsic regulatory factors include the sympathetic nervous system, local gastrointestinal hormones (vascular intestinal peptide, glucagon, cholecystokinin, etc.), circulatory vasoactive substances e.g. angiotensin II (AII), vasopressin and systemic haemodynamic parameters such as mean arterial pressure (MAP), volume status and cardiac output (CO). In addition, adenosine, nitric oxide (NO), prostaglandins (PGs) and some other mediators can also play a part in the control of intestinal microcirculation. 3. Problems of intestinal circulation studies Studies related to intestinal circulation are difficult to perform. Intestinal circulation is not easily accessible and is controlled by complex multiple local, regional and systemic factors. There are several reasons for the disparity in results among studies assessing intestinal circulation. These are summarized below (1) Very few human studies particularly for anaesthetic agents or techniques. (2) Experimental studies are conducted in various species e.g. pigs, rats, mice, dogs. Pig’s intestinal circulation is closer to human intestinal circulation. (3) Small sample size in both human and experimental studies (4) Sensitivity of animals differs for a specific insult or therapeutic manoeuvre e.g. endotoxin used to cause endotoxic shock, fluid challenge, etc. (5) Studies are often conducted in strict and single physiological or pathological condition. (6) Study duration is usually short e.g. a few hours of shock. They also differ in timing in the pathological process e.g. early vs. late septic shock (7) Isolated and de-innervated loop preparations e.g. to study mesenteric vascular smooth muscle responses (8) Often there is an indirect conclusion about intestinal circulation and oxygenation. For example, a conclusion about the intestinal effects from gastric tonometry or mucosal oxygenation studies. (9) Anatomical sites of intestine studied e.g. serosa vs. muscularis vs. mucosa, or jejunum vs. ileum vs. colon (10) The end point of adequacy of macro or microcirculation e.g. quantitative effect, oxygenation or metabolic results (11) A wide variety of measurement and evaluation techniques are used e.g. direct vs. indirect measurement of flow, indirect metabolic parameters, etc.

4. Effects of anaesthetic agents and technique 4.1. Inhalational agents Inhalational anaesthetic agents (AA) may change IBF by cardiovascular effects (cardiac output, systemic vascular resistance, mean arterial blood pressure), redistribution of blood flow involving the intestines or a direct effect on mesenteric vascular smooth muscle. Effects on circulatory catecholamines, central sympathetic discharge and splanchnic nerve activity may alter the mesenteric vascular resistance (MVR). Other factors such as the mode of ventilation, blood gases (i.e. PaCO2 and PaO2) and their effects on reflex cardiovascular responses (e.g. baroreflex) may modify the effects of inhalational anaesthetics in the intestinal and portal circulation.

In patients undergoing colon resection and anastomosis,3 equipotent doses of desflurane and isoflurane had no significant differences in systemic haemodynamics and oxygenation. Pre- and post-anatamotic colon PO2 did not change in the desflurane group. Isoflurane increased PO2 near the resection and anastomotic site. Isoflurane probably better preserved reactive hyperaemia following local tissue injury or manipulation. Desflurane is a potent mesenteric vasodilator. Variable effects on IBF have been reported. It decreased the IBF and oxygen delivery.4 However, it does not interfere with the intestinal mucosal autoregulation and oxygen uptake and metabolism. In an experimental study, desflurane maintained jejunal mucosal perfusion even with a lower MAP of 40 mmHg.5 In contrast, in a human study,6 use of 1 MAC desflurane increased the jejunal blood flow in comparison to 1 MAC isoflurane without significant changes in systemic haemodynamics. Therefore, local mechanisms controlling IBF play a role during inhalational anaesthesia. Desflurane has been reported to blunt the effects of an infrarenal aortic clamp on portal circulation.7 1 MAC halothane during spontaneous ventilation decreased small and large IBF by 27% (P < 0.01) and 14% (P < 0.01) respectively with no change in vascular resistances.8 Portal blood flow (PBF) also reduced significantly without changes in portal vascular resistance. In contrast, equipotent concentration of sevoflurane did not affect IBF, PBF and respective regional vascular resistances in comparison to controls. Authors suggested greater changes in IBF and PBF with halothane anaesthesia may reflect a greater reduction (28%) in the cardiac index. At deeper levels of anaesthesia, gastrointestinal organs may receive a different fraction of cardiac output. Conzen et al.9 used sevoflurane and isoflurane to reduce MAP 70 mmHg (1.66 vol% sevoflurane and 0.96 vol% isoflurane) and 50 mmHg (1.7 MAC e 3.95 vol% sevoflurane and 2.43 vol% isoflurane). There were no significant changes in small or large IBF compared with control at either level of MAP. However, at a MAP of 50 mmHg, systemic vascular resistance was lower and cardiac output and gastric flow were significantly higher in the isoflurane group compared to the sevoflurane group. Use of inhalational anaesthetics may blunt the stress induced increase in mesenteric vascular resistance and associated reduction in intestinal blood flow.10 Liver blood flow (LBF) and oxygenation may be affected secondary to intestinal effects. However, the final effects of inhalational AA on LBF are also influenced by whether the hepatic artery buffer response remains intact (a mechanism whereby the hepatic artery flow changes reciprocally with changes in PBF) and direct effects on hepatic vascular smooth muscle. For example, in a human study11 jejunal blood flow was higher with 1 MAC desflurane in comparison with 1 MAC isoflurane. However, total liver blood flow was not changed significantly due to preserved hepatic buffer response with both AAs. In another study,12 at higher MAC (1.75 and 2 MAC) desflurane and isoflurane caused a dose dependant reduction in MAP and stroke volume. PBF was reduced. Total LBF was not changed with desflurane while it was increased in the case of isoflurane with an associated decrease in hepatic artery vascular resistance. Most splanchnic blood volume resides in mesenteric venous sites. The effects of inhalational AAs on mesenteric venous resistance and compliance are also of interest. Other unanswered questions in humans are the effects on intestinal autoregulation, intestinal oxygen delivery and consumption. In summary, with current evidence from animal studies, there is no specific choice among modern inhalational AAs with regards to intestinal circulation. Experimental research suggests, if systemic haemodynamics are maintained, most likely intestinal circulation may not be jeopardized by inhalational AAs. However, at lower

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arterial blood pressure and when IBF is compromised, inhalational AA induced changes may have adverse effects. In humans, the effects of inhalational AAs on intestinal microcirculation and oxygenation are not known. 4.2. Intravenous anaesthetic agents There are only a few experimental studies investigating the effects of IV AA on the intestinal circulation. Propofol decreased MVR in a dose dependant manner. It increased IBF despite a decrease in MAP.13 An increase in IBF is greater in the small intestine than the colon. Propofol in varying doses did not change the portal oxygen delivery to the liver. However, propofol-induced direct mesenteric arteriolar and venodilatory effects may pool blood into the mesenteric area from the systemic circulation. Consequently, venous return may decrease leading to an exaggeration of systemic hypotension and a decrease in IBF particularly in the elderly and hypovolaemic patients. Direct effects on mesenteric vascular smooth muscles are reported to be mediated via endothelium independent (via calcium channels) or dependant mechanisms (altering NO, PGs production).14,15 Brookes et al.16 studied the effects of propofol/fentanyl, thiopentone and ketamine on the mesenteric microcirculation following haemorrhage and resuscitation. Propofol caused a generalized contraction in intestinal microcirculation following haemorrhage which was worsened with a decrease in systemic arterial pressure. Ketamine maintained the capillary circulation and prevented leak following haemorrhage and re-infusion. Ketamine has also been found to be protective against intestinal endotoxic or IR intestinal injury by multiple effects. 4.3. Analgesics/sedatives No significant information is available. 4.4. Anaesthetic/analgesic agents and intestinal ischaemia/ reperfusion injury Anaesthetic or analgesic agents may protect the intestines against ischaemia/reperfusion injury.17e24 However, their clinical use for the prevention of intestinal ischaemia/reperfusion injury has not yet been established. These are summarized in Table 1.

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was strongly correlated with a reduction in MAP. In this study, blood flow was not related to CO and did not respond to fluid alone but required a vasopressor to restore MAP, IMA flow and colon serosal blood flow. Authors suggested maintaining MAP with a vasopressor during the perioperative period in the presence of epidural block. In both these studies a 0.5% bupivacaine bolus was used during the intraoperative study period. In another human study,28 TEA reduced SMA blood flow by 25% and MAP by nearly 50% despite maintaining preload (measured by CVP and PCWP). Reduced SMA blood flow led to increase in mesenteric arteriovenous oxygen difference (AVDO2) and mesenteric venous lactate level. However, systemic AVDO2 and lactate remain normal. Low dose dopamine improved SMA blood flow and MAP during TEA and returned mesenteric AVDO2 to normal. In both the studies of anaesthetised patients, precise level of block was not known.27,28 In an experimental study in pigs,29 epidural block (T5-T12) caused systemic hypotension whilst CO remained normal. SMA blood flow did not change. SMA vascular resistance was reduced by 1/3rd and intestinal oxygen supply-uptake remained normal. Fluid loading improved in MAP but did not change the SMA flow. Recently, there has been interest in the intestinal circulatory effects of an epidural during critical conditions such as sepsis and haemorrhage. An epidural blunted the decrease in functional capillary density (FCD) in the muscularis layer associated with haemorrhagic hypotension and prevented leucocyte infiltration in capillaries following resuscitation.30 The effects of an epidural on intestinal microcirculation in the presence of sepsis are controversial. Adolphs et al.31 reported a worsening of intestinal mucosal blood flow because an epidural impeded the redistribution of blood flow from the muscularis to the mucosa in the presence of sepsis. In contrast, Daudel et al.32 demonstrated improved capillary recruitment and an increased number of continuously perfused capillaries. In this study the epidural did not worsen the systemic haemodynamics which were caused by sepsis. In summary, the effects of epidural analgesia (with routinely used lower concentrations of local anaesthetic) on intestinal macro and microcirculation and oxygenation have not been studied. There is very limited experimental knowledge about the protective or harmful effects of an epidural in the presence of critical conditions such as haemorrhage or sepsis. 5. Critical conditions

4.5. Epidural

5.1. Haemorrhage

There are only two human studies measuring macrointestinal blood flow directly during thoracic epidural anaesthesia.25 The level of block and associated systemic haemodynamic changes predominantly determine the intestinal effects of epidural anaesthesia/analgesia. Theoretically, if a block is limited to mesenteric sympathetic activity (T8-L1), arteriolar dilatation and venodilation would increase both the macro and microcirculation. If epidural anaesthesia/analgesia does not block mesenteric sympathetic activity and is associated with systemic hypotension it may lead to a reflex increase in splanchnic sympathetic activity and a decrease in IBF. In addition, epidural anaesthesia/analgesia has a potential to cause redistribution of intestinal blood flow to other organs or away from the ischaemic or anastomotic site to the normal intestine (longitudinal steal) or transmural from the mucosa to the muscularis region (horizontal steal). Johannson26 observed an increase in intestinal microcirculatory blood flow despite a decrease in systolic BP in patients undergoing colon resection. Authors attributed this effect to decreased mesenteric vascular resistance. In contrast, Gould et al.27 found a reduction in IMA flow by 20% and colon serosal flow by 35% which

During haemorrhage, mesenteric sympathetic stimulation causes a shift of mesenteric blood volume into the systemic circulation. MVR may double or triple to SVR due to AII and vasopressin.33 Sinaasappel et al.34 demonstrated the functional shunting of oxygen within intestinal microcirculation during haemorrhagic shock. The reduction in microcirculatory flow (MCF) depends on the degree of haemorrhage. In severe cases, MCF may be reduced by up to 70%. Intestines, particularly the mucosal tips, are at risk of ischaemic acidosis and necrosis. However, autoregulation of the mucosa is better preserved in haemorrhagic shock in comparison with septic shock. Restoration of IBF and oxygenation, with fluids and blood resuscitation, usually lag behind the improvement in systemic haemodynamic parameters.35 Following haemorrhagic shock resuscitation, reduced intestinal functional capillary density (FCD) and PO2 at 24 h predicts poor outcome.36 5.2. Sepsis The etiology, stage of sepsis (early or late), intestine-specific inflammatory response, volume status, and systemic hypotension

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Table 1 Experimental studies investigating the effects of anaesthetic or analgesic agents during ischaemia/reperfusion injury. Drug (year)/reference

Animals

Ischaemia/reperfusion setting

Preconditioning/postconditioning

Beneficial effects

Mechanisms

Remifentanyl (2013)17

Mice

Remifentanyl 1 mg/kg 5 min before laparotomy to clamp SMA.

8 fold less intestinal villi injury in ileum. Reduced serum IL-6 levels.

Isoflurane (2012)18

Mice

30 min of SMA clamping followed by 60 min period of reperfusion. 30 min of SMA clamping followed by 5 h of reperfusion and study.

Once reperfused, 4 h of 1 MAC isoflurane administration.

Reduced intestinal injury and while improving vascular permeability in ileum. Reduced liver and renal injury.

Ketamine (2010)19

Rats

30 min occlusion of SMA and SMV followed by 60 min of perfusion.

Ketamine pretreatment 50 mg/kg.

Intestinal mucosal injury reduced.

Ketamine (2010)20

Rats

30 min of SMA and PV clamping followed by 60 min of perfusion.

Ketamine pretreatment was administered by intraperitoneal injections at doses of 100, 50, 12.5, or 6.25 mg/kg.

Dose dependant reduction in inflammatory and thrombotic damage. Also reduced myenteric ganglion cell morphological alterations.

Ketamine (2008)21

Rats

Selective clamping of the vascular supply of an ileum segment for 45 min followed by either 60 min or 24 h reperfusion.

Animals anaesthetized with ketamine 100 mg/kg.

In comparison with phenobarbitone anaesthesia intestinal damage significantly reduced. Ketamine also abolished intestinal transit delay induced by I/R.

Propofol (2008)22

Rats

SMA occlusion for 30 min followed by 3 h of reperfusion.

30 min before ischaemia propofol 50 mg/kg intraperitoneal.

Reduced intestinal apoptosis and injury.

Propofol (2007)23

Rats

Occluding the SMA with a microvessel clip for 60 min followed by 180 min reperfusion.

3 treatment groups propofol 50 mg/kg intraperitoneally: 1 30 min before ischaemia 2 30 min before reperfusion 3 30 min after reperfusion.

Propofol treatments, especially pre-treatment, significantly reduced histological damage and levels of MDA, NO, ET-1 and LD, while restoring SOD activity.

Morphine (2004)24

Rats

SMA occlusion for 30 min followed by reperfusion.

30 min before ischaemia morphine given either via epidural (0.02 mg) or intraperitoneal (0.2 mg).

Higher transit indexes were achieved with morphine. No difference in epidural or intraperitoneal morphine group.

Reduced oxidative stress (reduced malondialdehyde -MDA) in ileum. Decreased inflammation and apoptosis via induction of intestinal epithelial TGF-b1. Reduced p-selectin levels and prevents decrease in A-III levels. Other finding intact myenteric plexus necessary for protective effects. Anti-inflammatory by inhibition of neutrophil infiltration. Inhibits platelet aggregation and microvascular aggregation. NMDA receptor antagonism leading to inhibition of glutamate toxicity. Anti-inflammatory actions e.g. reduction in interleukin 6 and TNF alpha and neutrophil infiltration. Attenuates up-regulation of sphingomyelinase mRNA expression and increase in lipid oxidation. Propofol may increase haemoxygenase levels which have antioxidant properties. Inhibition of iNOSeNOe peroxynitrite pathway. ET-1 level might have been low due to improvement in microcirculation. Direct effects such as opioid receptor agonist or effects on motilin or nitric oxide release. Indirect effects such as immune modulation or alleviating pain and reducing sympathetic discharge.

are important clinical factors which determine the magnitude of intestinal circulatory disturbances. Whether sepsis disturbs the microcirculatory autoregulation or not is controversial. In an experimental model of bacterial shock in pigs,37 jejunal mucosal blood flow was preserved despite a 45% reduction in the SMA flow. With fluid resuscitation, SMA blood flow reached above the baseline keeping in parallel with changes in the cardiac index. Colon blood flow was reduced by 47% and did not return to baseline with fluid resuscitation.

In the early stages of endotoxic shock IBF is decreased due to raised MVR. Endotoxin-induced direct mesenteric arteriolar contraction interferes with the MCF despite normal macrocirculation and cardiac output. The hyperdynamic phase following fluid resuscitation is associated with an increase in IBF. Redistribution of blood flow from the muscularis to mucosa38 or the mucosa to muscularis39 has been reported. Different blood flow redistribution patterns among studies of sepsis may be because of direct or indirect microcirculatory blood flow measurement.

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In advanced septic shock the MCF may be reduced by 50% due to additional microvascular changes such as endothelial swelling and microvascular thrombosis. Reduced capillary blood flow and functional capillary density have been demonstrated. Shunting due to counter current flow and direct cytotoxic effects of toxins on mucosal cells may cause mucosal acidosis despite normal mucosal flow.40 Intestinal capillary leak occurs due to local microvascular pressure changes or the direct effect of toxins on the capillary membrane. There is a risk of bacterial and inflammatory mediator translocation and local oedema formation. Increased intestinal metabolic demands leading to increased oxygen consumption is initially met by increased oxygen extraction. However, like other tissues, oxygen utilization is impaired. 5.3. Increased intra-abdominal pressure Most experimental studies have demonstrated that increased intra-abdominal pressure (IAP) causes a decrease in the mesenteric blood flow. Mucosal perfusion is affected at lower pressures but with higher pressures (>20 mmhg) mesenteric artery flow is also reduced.41 Persistent raised IAP causes intestinal hypoperfusion despite normal systemic BP. Decreased cardiac output, mechanical ventilation and hypovolaemia further exaggerate the effects. As the IAP increases, perfusion in the outer layers is worsened more in comparison to mucosal perfusion. Bacterial translocation, intestinal oedema, impaired intestinal motility and the breakdown of anastomosis are serious consequences of moderate to severe raised IAP.42 Diebel et al.43 investigated the effect of IAP on gastrointestinal blood flow in anaesthetized pigs. The IAP was progressively raised to 10, 20, 30, and 40 mmHg whilst keeping MAP normal by intravenous infusion of lactated Ringer’s solution. IAP greater than 20 mmHg progressively decreased the mesenteric and mucosal blood flow. The intestinal mucosal blood flow measured diminished to 61% of the baseline at an IAP of 20 mmHg and 28% of the baseline at an IAP of 40 mmHg. The oxygen partial pressure in the jejunum may also fall progressively as IAP increases whilst in the subcutaneous tissue it may remain unchanged.44 The exact mechanisms of the diminished mesenteric perfusion are not well defined but may involve a direct effect of increased IAP on mesenteric arterial resistance or humoral factors or a combination of the two. 5.4. Intraluminal pressure Small bowel mucosal perfusion is affected earlier with raised intraluminal pressure above 10 to 20 cm of H2O or distention. Initially venous outflow is affected. With higher pressure arteriolar and mucosal capillary blood flow is also reduced. Large intestine may tolerate higher intraluminal pressure without compromising microcirculation. With closed abdomen effects of intraluminal pressure are more pronounced particularity if abdominal pressure is also raised. Release of inraluminal pressure causes hyperamia. 5.5. Haemodilution During haemodilution, complex systemic and regional haemodynamic changes occur such as the redistribution of cardiac output and tissue blood flow, capillary recruitment, microvascular shunting and changes in erythrocyte rheology. Acute reduction of haemoglobin concentration to 5.9  0.3 g/dl in anaesthetized humans by acute normovolaemic haemodilution (ANH) sufficiently diminished splanchnic and preportal oxygen delivery (DO2) such that oxygen consumption (VO2) became impaired.45 There was evidence of an increased regional lactate level. However, despite a significant reduction in systemic DO2, systemic oxygenation apparently remained adequate as VO2 did

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not decrease. There is increased susceptibility of intestinal hypoxia during ANH. Schwarte et al.46 found that reduced intestinal microvascular oxygenation was associated with a redistribution of O2 delivery away from the intestines and also shunting of the residual O2 within the intestines itself. With mild ANH mucosal oxygenation was preserved because of blood flow diversion from the serosa to the mucosa. This could be due to capillary recruitment in the highly metabolic mucosa. There was evidence of RBC deformity in intestinal capillaries during ANH. Critical haematocrit (Hct) for intestines is around 15%.47 Although the SMA blood flow is increased with haemodilution it is not sufficient to compensate for the reduced intestinal oxygen delivery. In this study,47 both intestinal microcircular PO2 and intestinal VO2 became DO2 dependant at the same time. Beyond this critical DO2 point intestinal VO2 became dependant on intestinal microcirculatory oxygenation. Functional shunting was observed as microvascular PO2 decreased significantly below mesenteric venous PO2. Authors suggested that an increase in oxygen extraction (O2ER) is more important in the preservation of intestinal VO2. Critical Hct (tolerance to anaemia) is lower for the intestines compared with the kidney but higher than the heart.48 6. Effect of therapeutic strategies 6.1. Mechanical ventilation Effects of mechanical ventilation (MV) on intestinal circulation depends on several factors including mode of ventilation, PaCO2 and level of positive end expiratory pressure (PEEP). PEEP greater than 10 Cm H2O, hypovolemia and presence of sepsis may compound the effects of MV on IBF. Enteral feeding, low dose dopexamine or dopamine and spontaneous breathing may counter PEEPinduced intestinal ischemia and hypoxia. 6.2. Nutrition Following ingestion of food, there is a sequential increase in blood flow as the chyme passes through the intestines. With enteral feeding macro and microintestinal blood flow is increased by 2e3 times. The magnitude of response is mainly determined by the chyme composition. Lipids followed by glucose are mostly responsible for an increase in blood flow. Postprandial hyperaemia occurs due to multiple mechanisms mainly due to the release of local hormones such as VIP, cholecystokinin and reflex vasodilation due to mechanical distension. Intraluminal glucose has also been found to be protective against ischaemia/reperfusion (IR) injury to bowel mucosa. In contrast, TPN decreases IBF.49 6.3. Fluid therapy Goal directed (GD) fluid therapy has been suggested for better GI function recovery. In healthy pigs,50 crystalloid therapy between 3 and 20 ml/kg/h did not affect oxygenation in the jejunum and colon. Goal directed colloid therapy has been found to improve SMA blood flow by 20% and mucosal microcirculatory blood flow by 40%. Mesentric oxygen delivery was also significantly high.51 GD crystalloid therapy did not change the IBF and oxygen delivery. The intestinal metabolic function was better preserved in GD colloid therapy whilst restricted crystalloid fluid therapy impaired it. GD colloid therapy has been found to improve healthy colon mucosal blood flow and colon oxygenation. However, although the partial pressure of oxygen improved, mucosal blood flow around the anastomotic colon was similar during GD colloid or crystalloid therapy.52 Compensatory mechanisms for mucosal blood flow at the site of tissue trauma might have exhausted.

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Resuscitation, following haemorrhagic shock, with hyperoncotic hetastarch has been found to maintain post-resuscitation intestinal microvascular function. In various animal septic models, colloids have been reported to have positive microcirculatory effects in the intestines such as improved microcirculatory flow, decreased inflammatory markers, increased perfused capillary density, blockage of capillary leakage, reduced leucocyte adherence to endothelium, inhibition of platelet and erythrocyte aggregation. However, experimental evidence has not been translated into clinical studies. To my knowledge, there are no studies evaluating effects of goal directed fluid therapy in human intestinal circulation during elective or emergency intestinal surgery. 6.4. Vasopressors/inotropes The common indications for vasopressor use in gastrointestinal surgical patients are septic shock and to counter effects of vasodilator effects of epidural block and/or anaesthetic agents. The effects of inotropes/vasopressors on intestinal circulation are complex and diverge from their other regional and systemic haemodynamic actions. Several reviews have addressed this subject.53,54 Catecholamines are commonly used agents. Their effects on intestinal circulation depend on several factors including the model of sepsis, drug used and its dose, if given without, with or after fluid resuscitation, timing of administration (early vs. late), and baseline MVR. Norepinephrine (NE) has been recommended as a first choice vasopressor in septic fluid resuscitated patients. The effects of NE on intestinal circulation and metabolic function are controversial. Some recent studies have shown that NE in short term55,56 or long term septic shock57 may not improve the intestinal microcirculatory flow despite achieving targeted MAP. Although MCF does not return to pre-shock level there was no additional deterioration after administration of NE. It is possible that the ‘autoregulatory escape’ from vasoconstrictor effects of NE may prevent intestinal hypoxia particularly in the mucosa. The ultimate effects on intestinal cellular metabolism are controversial with results demonstrating positive, negative or no effect with the use of NE. NE may be safe to use in fluid restricted patients undergoing abdominal surgery.58 In an experimental study, a dose of 0.035  0.012 and 0.12  0.05 mg/kg/min of NE was needed to increase to a targeted MAP of 65 and 75 mmHg respectively. Fluid administration was limited to 3 ml/kg/h. There were no adverse effects on the small intestine or colon blood flow and oxygenation with the use of NE with fluid restriction. However, the use of vasopressors in hypovolaemic patients may cause deleterious effects on the intestinal circulation and a cautious approach is necessary. Vasopressin is often used in refractory septic shock. In a fluid resuscitated faecal peritonitis experimental model,59 vasopressin in clinical dose (0.06 U/kg/h) decreased the mesenteric and systemic oxygen delivery by 30 and 50% respectively which was associated with a 20% reduction in oxygen consumption. A marked increased in the MVR was associated with nearly a 25% reduction in mucosal blood flow in the stomach and jejunum. However, the colon MCF was not changed. In comparison to control septic animals, vasopressin-treated animals developed higher jejunal mucosalarterial PaCO2 gap. Mesenteric haemodynamic and oxygenation changes with vasopressin suggest a dependency on oxygen supply and risk of intestinal ischaemia. The deleterious effects of vasopressin on intestinal MCF have been reported with some other studies.60 There is no ideal inotropic agent which can be recommended for all clinical circumstances. In euvolaemic septic pigs,61 dopamine (5e10 mg/kg/min), dopexamine (5e10 mg/kg/min) and dobutamine (2 mg/kg/min) increased the cardiac index by 18, 35 and 48%. There were no significant changes in MCF in the stomach, jejunum and

colon mucosa despite an increase in the SMA flow in the case of dopamine (by 33%) and dopexamine (by 13%). In septic patients, an inotrope-related increase in the systemic oxygen delivery may not reach gastrointestinal microcirculation. This may explain the failure to improve the clinical outcome in some studies of ‘supranormal’ oxygen delivery to tissues. 6.5. Drug interactions Anaesthetic agents may modulate the effects of vasopressors and inotropes on GI microcirculation. A dose dependant increase in gastric mucosal oxygen saturation was observed with NE during sevoflurane anaesthesia.62 Neither epinephrine nor NE changed the gastric mucosal oxygen saturation in the presence of propofol anaesthesia. Systemic oxygen delivery was doubled with epinephrine in the presence of either agent. Systemic cardiovascular effects, alpha vs. beta agonistic effects of a catecholamine on mesenteric vessels, regional redistribution of blood flow, AArelated autoregulation interference and AA’s direct mesenteric vascular effects are some of the explanatory mechanisms for drug interactions on GI microcirculation. 7. Specific surgical conditions 7.1. Cardiac surgery 15e20% of GI complications are attributed to mesenteric ischaemia which is mostly related to hypoperfusion, although in some cases microemboli may have been the cause. Anaesthesia, cardiopulmonary bypass (perfusion pressure, degree and type of flow, duration, cross clamp time), hypothermia, haemodilution, associated use of vasoconstrictor, reperfusion injury and low cardiac output are major determinants of intestinal perfusion and oxygenation during cardiac surgery. In experimental normothermic CPB,63 the overall SMA blood flow increased. However, the ileal mucosal blood flow decreased by 50% leading to mucosal acidosis and reduced portal venous oxygen saturation. Mesenteric oxygen delivery was reduced while gut oxygen consumption was increased. Redistribution of blood flow away from the mucosa and increased oxygen consumption resulted in mucosal ischaemia during CPB. Whether intestinal mucosal autoregulation is preserved or not during CPB is controversial. Often study protocols are variable. Some authors have shown that intestinal perfusion during CPB is pressure64 or flow65 dependant suggesting loss of autoregulation. In contrast, Nygren et al.66 demonstrated that jejunal mucosal perfusion and haematocrit, and RBC flow velocity remain unchanged during the variations in MAP caused by changes in the CPB flow rate. Administration of prostacyclin (a vasodilator) resulted in loss of mucosal autoregulation. Heterogeneity in GI circulation is common during CPB like other critical conditions such as haemorrhage and sepsis. Intestinal microvascular changes may persist for 24 h due to vascular endothelial dysfunction. Whether off pump cardiac surgery preserves intestinal circulation better than on pump cardiac surgery is not yet confirmed. 7.2. Aortic surgery Mesenteric blood flow may be compromised due to aortic atherosclerotic disease. Atherosclerosis may affect both SMA and IMA. Collateral circulation plays an important role during the perioperative period. Infrarenal aortic clamping increased the SMA blood flow in patients receiving GA, epidural and low dose dopamine infusion.67 After declamping, SMA blood flow increased significantly

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compared with the preclamp period. Mesenteric venous pH and lactate did not change significantly. Intestinal reperfusion injury may cause mucosal injury. Sigmoidal pH monitoring can predict ischaemic complications of abdominal aortic aneurysm (AAA). In endovascular repair IMA is sacrificed in all cases. Some studies have reported overall lower incidences of ischaemic colitis compared with open AAA. Watershed areas (splenic flexure and sigmoid colon) are more at risk. However, embolic mechanism for ischaemia is more likely. 7.3. Abdominal surgery Stress response itself may lead to intestinal hypoperfusion which may persist despite GD fluid optimization during the perioperative period. During the postoperative period, in fluid optimized animals, SMA and portal venous blood flow was 25% and 13% respectively lower which was associated with an increase in jejunal mucosal PaCO2. The gastric, coeliac and hepatic artery blood flow was significantly higher.68 The SMA blood flow was reduced in the early hours and caused mucosal hypercarbia. Systemic haemodynamics were stable during the study period of 10 h. Gut perfusion can be compromised during routine laparotomy despite stroke volume targeted fluid therapy and may trigger postoperative organ dysfunction if not detected and corrected. 8. Can sublingual microcirculation mimic intestinal microcirculation? Monitoring and optimization of the microcirculation during resuscitation in critical conditions such as sepsis is a new emerging concept. Whether sublingual microcirculation can represent and reflect intestinal microcirculatory changes during haemorrhage or sepsis is controversial. Verdant et al. found a similar severity and time course of microcirculatory changes (decreased FCD and erythrocyte velocity) between sublingual and jejunum during hyperdynamic septic shock.69 A correlation has also been reported between microcirculations of sublingual and splanchnic regions (e.g. stomach, intestines) during hypodynamic septic and haemorrhagic shock. However, Boerma et al70 found no correlation between sublingual and intestinal MCF in early phase of the abdominal sepsis. MCF in both the regions was not related to routinely monitored systemic hemodynamics parameters such as MAP and cardiac index. However, during later period, once blood flow was normalized in both the regions there was correlation among both the regional microcirculations. In this study authors used intestinal stomas as a model of intestinal microcirculation. 9. Conclusion Intestinal circulation is not well studied in humans during the perioperative period and critical illness. Most factual knowledge about intestinal circulation during surgery and critical illness is from experimental studies. This experimental evidence demonstrates heterogeneity between intestinal macro and microcirculation and also among intestinal and other organ/system circulations. Although pathophysiological changes compromising intestinal circulation are often predictable, therapeutic manipulation and monitoring of it is not possible during routine patient management. In humans, there is very little information about the effects of AA and techniques on the intestinal macro and microcirculation. Anaesthetic agents may interact with other therapeutic modalities applied to optimize the gastrointestinal circulation. However, anaesthesia-related alterations in human intestinal circulation in the presence of sepsis, haemorrhage and other intestinal ischaemic conditions remain mysterious.

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