Gastrointestinal perfusion in septic shock.
Article Type: Clinical report
Subject: Isolation perfusion (Physiology) (Research)
Septic shock (Research)
Authors: van Haren, F.M.P.
Sleigh, J.W.
Pickkers, P.
van der Hoeven, J.G.
Pub Date: 10/01/2007
Publication: Name: Anaesthesia and Intensive Care Publisher: Australian Society of Anaesthetists Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2007 Australian Society of Anaesthetists ISSN: 0310-057X
Issue: Date: Oct, 2007 Source Volume: 35 Source Issue: 5
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: Netherlands Geographic Code: 4EUNE Netherlands
Accession Number: 188847479
Full Text: SUMMARY

Septic shock is characterised by vasodilation, myocardial depression and impaired microcirculatory blood flow, resulting in redistribution of regional blood flow. Animal and human studies have shown that gastrointestinal mucosal blood flow is impaired in septic shock. This is consistent with abnormalities found in many other microcirculatory vascular beds Gastrointestinal mucosal microcirculatory perfusion deficits have been associated with gut injury and a decrease in gut barrier function, possibly causing augmentation of systemic inflammation and distant organ dysfunction.

A range of techniques have been developed and used to quantify these gastrointestinal perfusion abnormalities The following techniques have been used to study gastrointestinal perfusion in humans, tonometry, laser Doppler flowmetry, reflectance spectrophotometry, near-infrared spectroscopy, orthogonal polarisation spectral imaging indocyanine green clearance, hepatic vein catheterisation and measurements of plasma D-lactate. Although these methods share the ability to predict outcome in septic shock patients, it is important to emphasise that the measurement results are not interchangeable. Different techniques measure different elements of gastrointestinal perfusion. Gastric tonometry is currently the most widely used technique because of its non-invasiveness and ease of use

Despite all the recent advances, the usefulness of gastrointestinal perfusion parameters in clinical decision-making is still limited. Treatment strategies specifically aimed at improving gastrointestinal perfusion have failed to actually correct mucosal perfusion abnormalities and hence not shown to improve important clinical endpoints

Current and future treatment strategies for septic shock should be tested for their effects on gastrointestinal perfusion, to further clarify its exact role in patient management, and to prevent therapies detrimental to gastrointestinal perfusion being implemented.

Key Words: sepsis, shock, splanchnic circulation, gastrointestinal blood flow, micro circulation, mucosal blood flow, tonometry, indocyanine green, reflectance spectrophotometry, laser Doppler flowmetry, near-infrared spectroscopy, orthogonal polarisation spectral imaging, D-lactate, hepatic vein catheterisation, prognosis, treatment, resuscitation, vasopressor, vasodilator

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Intestinal mucosal hypoperfusion is thought to be important in septic shock patients, both as an indicator of inadequate resuscitation and potentially as a mechanism by which multiorgan failure may occur. Loss of gut barrier function may lead to translocation of bacteria, endotoxin and other inflammatory mediators, thereby increasing systemic inflammation and resulting in distant organ dysfunction.

Global haemodynamic measurements are routinely performed in septic shock patients and are used to guide fluid resuscitation and administration of vasoactive agents. However, these measurements do not provide reliable data on gut perfusion, either because of regional redistribution of blood flow, or because gut blood flow may paradoxically be preserved when cardiac output is decreased. Conversely, therapy used to treat shock can apparently normalise clinical or global variables, but still allow the existence of occult defective tissue oxygenation (1). Measuring variables of splanchnic perfusion is thought to be a better predictor of the presence of uncompensated shock than markers of global perfusion (2,3).

In this review the splanchnic circulation and the different techniques that are available to measure adequacy of gastrointestinal perfusion are discussed. We specifically focus on the gastrointestinal perfusion deficits found in septic shock, including relevance for the pathogenesis of multiple organ dysfunction and for prognosticating and treating septic patients.

References were obtained from PubMed and Medline databases from the earliest records to November 2006. We used the following keywords: intestinal, gastrointestinal, splanchnic, perfusion, blood flow, circulation, sepsis, septic shock, vasodilatory shock, shock and microcirculation. We also reviewed reference lists of all relevant articles. Laboratory, animal, as well as human studies were included to describe the underlying pathophysiological mechanisms implicated in gastrointestinal perfusion abnormalities in septic shock. We then focused on studies describing techniques that have been used to measure gastrointestinal perfusion in human septic shock situations. Retrospective as well as prospective studies that reported mortality were included to describe the prognostic value of measurement of gastrointestinal perfusion in septic patients. Only prospective controlled studies were included to determine the effects of treatment guided by gastrointestinal perfusion on outcome of septic patients. Finally, animal and human studies reporting the effects of various interventions on gastrointestinal perfusion are discussed, to give an overview of potential treatment strategies that need further studies.

REGULATION OF GASTROINTESTINAL PERFUSION

Splanchnic blood flow, at both macrovascular and microvascular levels of perfusion, is regulated to perform two basic gastrointestinal functions: to digest and absorb ingested nutrients and to sustain barrier function to prevent transepithelial migration of bacteria and antigens.

Three direct branches of the aorta supply the human gastrointestinal system: the coeliac artery, the superior mesenteric artery and the inferior mesenteric artery. Total blood flow in this system consumes approximately 25% of cardiac output. Following ingestion of food, blood flow increases by as much as 200% for two to three hours. The mucosal layer receives 70 to 80% of the total blood flow and is capable of rapidly recruiting closed capillaries. Blood flow to the mucosa is autoregulated by metabolic factors such as decreases in P[o.sub.2], pH, or osmolarity, increases in Pc[o.sub.2], or adenosine. Other potential vasoactive mediators of the enteric circulation are neural mediators (e.g. sympathetic and parasympathetic tone), circulating humoral mediators (e.g. vasopressin, adrenomedullin, catecholamines) and paracrine and autocrine mediators (e.g. nitric oxide, endothelin-1) (4).

GASTROINTESTINAL PERFUSION IN SEPTIC SHOCK

Septic shock is characterised by cardiac depression, vasodilation and micro circulatory defects resulting in redistribution of regional blood flow. In a broader perspective, severe dysfunction of the microcirculation in sepsis has been well described and classifieds (5).

The metabolic demand for oxygen in the splanchnic region during sepsis is increased, partly by increased hepatic metabolism (6). In hyperdynamic shock states, mucosal vascular perfusion is compromised, despite decreased total peripheral resistance and increased total splanchnic blood flow (7,8). This appears to be comparable to the situation in post-cardiac surgery patients, where there is no consistent association between local intestinal mucosal perfusion and global splanchnic blood flow (9). Most experimental sepsis models show intestinal microvascular vasoconstriction and hypoperfusion (4). The observed changes in microcirculatory blood flow in splanchnic organs are quite heterogeneous, both in early hypodynamic and in resuscitated hyperdynamic septic shock (10). In early septic shock, autoregulation of microcirculatory mucosal blood flow is largely intact and blood seems to be diverted from the muscularis towards the mucosa (11). Acute bacteraemia causes both endothelial alterations and vascular smooth muscle cell changes. Vasomotion (a normally occurring rhythmic process of dilation and contraction) is impaired in magnitude and frequency in both inflow and premucosal arterioles following E. coli infusion (12).

Different control mechanisms have been implicated in this impairment of mucosal vascular perfusion. Abnormalities in the nitric oxide system induced by inflammation can be regarded as one of the mechanisms responsible for the distributive defects observed. Local intestinal oxygen-derived free radicals also play a role in the intestinal microvascular sequelae as the administration of lazaroids--which are antioxidants that scavenge radicals and block lipid radical chain reactions--prevents vasoconstriction in both inflow and premucosal arterioles in an animal sepsis model (13). Gene expression of endothelin-1, a potent vasoconstrictor, is upregulated in sepsis models and implicated in the shift towards a more tonically constricted state. Other mediators that have been associated with the observed mucosal perfusion abnormalities in sepsis include platelet-activating factor and adrenomedullin (4).

Cellular hypoxia from these perfusion abnormalities and from possible mitochondrial dysfunction, combined with the direct cytotoxic effects of inflammatory mediators, is thought to result in increased gut permeability and impaired immunological gut barrier function. Under ischaemic conditions, enhanced paracellular permeability and epithelial destruction increases the mucosal permeability for endotoxin in human endothelial cell lines, an effect that has also been described in vivo in rats (14).

An impaired gut barrier is thought to play a role in subsequent amplification of systemic inflammation and distant organ dysfunction (15). Numerous animal experiments have shown the importance of bacterial translocation and systemic spill of mediators in the pathogenesis of multiple organ dysfunction syndrome. Haemorrhagic shock can induce the gut to become a cytokine-generating organ (16). In vitro studies have documented that mesenteric lymph, following haemorrhagic shock, activates neutrophils, is toxic to endothelial cells and increases endothelial permeability (17). In other experiments, ligation of intestinal lymphatic flow prevented lung injury after haemorrhagic shock (18). In a recent porcine study, mesenteric lymph collected following haemorrhagic shock increased neutrophil activation and endothelial cell permeability as opposed to lymph from control animals (19). These results indicate that the lymphatic route could be the primary route by which gut injury causes distant organ injury and could explain the reported absence of detectable bacteraemia in human studies of increased gut permeability (20). However, in one case series several cases of Saccharomyces boulardii fungaemia have been described in critically ill patients who received this agent enterally as a probiotic, possibly as a result of translocation (21).

Increased gut permeability has been found in Sepsis (22), pancreatitis (23), trauma (24), burns (25) and following cardiopulmonary bypass surgery (26). Some of these studies used differential absorption of various polysaccharides of differing molecular weights to estimate gut permeability. Specific pitfalls to the use of these tests in ICU patients have been described elsewhere (27). The association between splanchnic mucosal perfusion and systemic inflammation has been studied in different patient groups. In septic shock patients, the gastric to arterial Pc[o.sub.2] gap correlated well with systemic levels of tumour necrosis factor-alpha and interleukin-6, indicating that gut injury and the inflammatory response are associated (28). In patients following cardiopulmonary bypass surgery (characterised by a systemic inflammatory response) gastrointestinal permeability increased despite normal global splanchnic blood flow and oxygen delivery (29).

Intestinal mucosal injury is associated with a poor outcome in critically ill patients. In one small study, levels of serum and urine intestinal fatty acid binding protein were measured, which are sensitive and specific markers for intestinal mucosal injury. The presence of detectable intestinal fatty acid binding protein was associated with a poor prognosis (30).

TECHNIQUES TO MEASURE GASTROINTESTINAL PERFUSION

Gastrointestinal perfusion can be measured in many different ways. Some techniques are able to directly measure intestinal mucosal perfusion (e.g. laser Doppler studies of blood flow); other techniques measure endpoints of oxygen delivery (e .g. lactate measurement with intraluminal microdialysis). Some techniques have only been used in animal studies and are therefore not discussed in detail. Table 1 summarises currently available techniques and the advantages and limitations for their use in septic patients.

Tonometry

There is now more than 20 years experience with tonometry in humans. With this minimally invasive technique, intraluminal partial pressure of C[O.sub.2] is measured.

Most studies have applied tonometry in the stomach, but other sites such as the jejunum, the rectum and sigmoid colon have been examined as well. The difference between intraluminal and arterial partial pressures of C[O.sub.2] is called the C[O.sub.2] gap or the C[O.sub.2] gradient, which should be smaller than 10 mmHg. An increased gradient is indicative of gut hypoxia, especially when the gradient is greater than 20 mmHg. Ischaemic hypoxia due to hypoperfusion results in a more pronounced increase in Pc[o.sub.2] gradient than hypoxic hypoxia or anaemic hypoxia (31,32). The Pc[o.sub.2] gap is therefore largely dependent on mucosal perfusion and is considered to be a valid measure for gastrointestinal perfusion (33). The use of the Pc[o.sub.2] gap has replaced the use of mucosal pH (pHi, calculated from luminal Pc[o.sub.2] and blood bicarbonate content) because of increased sensitivity and specificity for regional ischemia (34,35). Saline tonometry has been replaced with automated air tonometry because of technical problems, including long equilibration time, variability and lack of quality in the determination of saline Pc[o.sub.2], which is discussed elsewhere in more detail (36-38).

The variability of gastric Pc[o.sub.2] in intensive care patients has been compared with systemic haemodynamic parameters. In patients with acute respiratory or circulatory failure, the coefficient of variation for gastric-arterial Pc[o.sub.2] gradient was 15%, compared with 10% for thermodilution cardiac output measurements (6). One of the limitations of tonometry is that it only provides information of the site of measurement (e.g. gastric perfusion), which is important in view of the known heterogeneity in microvascular perfusion within the gastrointestinal tract.

Laser Doppler flowmetry

Laser Doppler flowmetry provides continuous measurement of microcirculatory blood flow. The principle of this method is the Doppler shift, the frequency change that light undergoes when reflected by moving objects, e.g. red blood cells (39). The output voltage varies linearly with the product of mean red blood cell velocity and red blood cell concentration. This is referred to as red cell flux, which is proportional to blood flow at all but very high haematocrits. The tissue penetration of the laser is approximately 1 to 3 mm, allowing the study of mucosal blood flow without interference from the greater muscularis blood flow. Due to variable optical properties of different tissues, absolute blood flow cannot be measured. Laser Doppler devices indicate microcirculatory blood flow in arbitrary perfusion units. The results are usually expressed as changes relative to baseline. It has been used to measure microcirculatory blood flow in many tissues including muscle and intestine (40). As a non-invasive instrument, it can also provide information on endothelium-dependent vascular responsiveness in the skin microcirculatoon (41).

To assess intestinal mucosal perfusion in humans, custom-made laser Doppler catheters have been developed for placement in the lumen of the proximal jejunum under fluoroscopic guidance (42). Jejunal mucosal perfusion is calculated as the product of jejunal mucosal haematocrit and red blood cell velocity, both of which are measured variables. For example, this technique has been used to study the effects of different vasoconstrictors on jejunal mucosal perfusion after cardiac surgery. In a prospective randomised crossover study in ten patients, noradrenaline and phenylephrine were randomly and sequentially infused to increase mean arterial blood pressure by 30%. Neither of the vasoconstrictors exerted a significant effect on jejunal mucosal perfusion, or on gastric-to-arterial Pc[o.sub.2] gradient (43).

Positioning of the probes is essential to ensure continuous and steady contact with the surface of the measurement site. The technique gives an average of blood velocities and does not take into account the heterogeneity of blood flow in the window studied, making it less suitable for monitoring of gut perfusion in septic patients.

Reflectance spectrophotometry

The technique of reflectance spectrophotometry for assessment of gastric mucosal blood flow was first described by Sato et al in 1979 (44). This optical technology uses white light (wavelengths between 390 nm and 780 nm) to illuminate tissues. The light that returns (reflects) to the detector is analysed quantitatively. Using visible light, the recovered signal is predominantly due to haemoglobin absorption in the superficial 0.25 mm of tissue. To measure mucosal microvascular haemoglobin oxygen saturation and relative haemoglobin concentration, light from a xenon high-pressure arc lamp is transmitted to the mucosal surface using a single flexible microlightguide. This microlightguide is introduced through the operation canal of a gastroscope and attached to the mucosal surface under visual control. With newer commercially available instruments, it is also possible to obtain a stable signal without endoscopy by using a probe that is embedded in a nasogastric or rectal tube. Validation studies applying these probes in patients are awaited.

In typical gastrointestinal mucosa, the average haemoglobin saturation is approximately 70%. The microvascular haemoglobin oxygenation reflects the balance between regional oxygen delivery and oxygen uptake. Decreased values may be caused by decreased delivery, enhanced uptake, or a combination of both.

This technique has been applied to measure intestinal mucosal perfusion in ulcer disease, portal hypertension, cardiopulmonary bypass, septic shock and in response to infusion of vasoactive agents (45). For example, septic shock patients showed a decrease in average gastric mucosal haemoglobin oxygen saturation to 51%, compared with 70% in healthy controls. Infusion of dopexamine increased mucosal saturation in the septic patients by an average of 10% (46).

Because reflectance spectrophotometry measurements are easily obtained several times per second, real-time monitoring of perfusion is possible. However, and in contrast to laser Doppler flowmetry, reflectance spectrophotometry does not measure blood flow, but provides an estimate of the adequacy of oxygen delivery to the mucosa. Several factors can impact the quality of measurements, such as the presence of optically active materials in the lumen (e.g. bile, stool, blood), the effect of pressure when the probe touches the mucosa and the endoscope light. Newer systems correct for an uneven baseline and obtain measurements without touching the mucosa.

Near-infrared spectroscopy

Near-infrared spectroscopy is another non-invasive optical technique to measure tissue oxygenation. Near-infrared light penetrates more deeply into tissues than visible light, therefore enabling measurements in the muscularis propria or deeper structures. Tissue penetration is directly related to the spacing between illumination and detection fibres. At 25 mm spacing approximately 95% of the reflected optical signal is from a depth of 0 to 23 mm. Absorption and hence reflection of near-infrared light depends on the oxygenation state of haemoglobin. Each tissue type has a so-called path length through which the near-infrared light travels. The absolute concentrations of oxygenated and deoxygenated haemoglobin cannot be measured without knowledge of this path length. This problem has been overcome by the development of newer generations of near-infrared spectrometers, often referred to as spatially resolved spectroscopy, allowing additional measurement of a quantitative tissue oxygenation index, which represent the ratio of oxygenated haemoglobin to total haemoglobin.

This technique has been applied in superficial muscles as a non-invasive measure of peripheral perfusion in haemorrhagic and septic shock (40). It has also been used to measure liver tissue oxygenation transcutaneously in critically ill children, and a good correlation (r=0.72, P< 0.0001) with invasively measured central venous oxygen saturation was shown (47). However, there are several limitations to the latter observations that prevent this tool from being generally applicable in the measurement of hepatosplanchnic perfusion in septic patients. Measurements of single point liver tissue oxygenation show a large inter-individual variation (47). Also, in adults, the liver is usually not as accessible as in small children and differences in subcutaneous fat and oedema may result in significant inter-individual differences in measured liver tissue oxygenation. Furthermore, liver oxygenation may not be a good marker for splanchnic perfusion because of the dual hepatic blood supply and lack of autoregulation.

In animal studies, side-illuminating near-infrared spectroscopy nasogastric probes have been shown to rapidly reflect changes in splanchnic perfusion. In an experimental haemorrhagic shock model, bowel pH obtained with intraluminal near-infrared spectroscopy correlated well with pH measured with microelectrodes (48). Human studies of intraluminal near-infrared spectroscopy in septic shock are currently awaited.

Orthogonal polarisation spectral imaging

This recently developed and non-invasive technique uses reflected light to produce real-time images of the microcirculation (49). It allows microscopic visualisation of the microcirculation as well as of the flow of red blood cells in the microvessels. In order to improve spatial resolution and allow for better visualisation of the smallest capillaries, an improved imaging modality called sidestream dark-field imaging has been developed. With this technique, the light guide is surrounded by 530 nm light-emitting diodes. Because this wavelength is absorbed by the haemoglobin of red blood cells, these cells can be seen as dark cells flowing in the microcirculation.

Tissue perfusion is assessed and quantified by using the functional capillary density, which is the length of perfused capillaries per observation area in cm/cm(2), and by semi-quantitative measurement of blood flow velocities in capillaries. Although the technique can be used to visualise microcirculation in many organs (e.g. during surgery), it is most commonly applied sublingually. Hand-held devices are commercially available. Limitations include artefacts secondary to movement and secretions, and observer-related bias including the amount of pressure that is used to obtain the images. Nevertheless, in a recent validation study, agreement and kappa coefficients were >85% and >0.75 respectively, for inter-rater and intra-rater variability in quantification of flow abnormalities in vascular beds of the sublingual and stoma region during sepsis (50). Interpretation of the obtained images is time-consuming and software has been developed to analyse and quantify the images.

Although the oropharynx can be considered as part of the gastrointestinal system, perfusion of the tongue is regulated in a complex way, which is different from the way the splanchnic perfusion is controlled. Sublingual orthogonal polarisation spectral (OPS) imaging is therefore not a direct measure of gastrointestinal perfusion. However, OPS-derived measurements have been shown to correlate well with measurements of sublingual capnometry and gastric tonometry in septic patients', but more validating studies are needed.

Indocyanine green clearance

Global liver function and splanchnic perfusion can be quantified with measurements of indocyanine green dye clearance. After venous injection, indocyanine green is eliminated unchanged by the liver into the bile without enterohepatic recirculation. Elimination of indocyanine green is determined by hepatic blood flow, hepato-cellular uptake and excretion into the bile. After administration of a bolus of indocyanine green, the blood clearance can be calculated by taking repeated venous samples or by using intra-arterial fibreoptic spectroscopic measurements. Alternatively, the plasma disappearance rate can be assessed transcutaneously, with comparable results to venous sampling (52). The major advantage of the latter is that it is a non-invasive technique. Normal values in healthy control subjects for indocyanine green clearance and for indocyanine green plasma disappearance rate are >700 ml/min/m (2) and 18% /min respectively.

As a method to measure splanchnic perfusion, this technique has several limitations. Results are not only dependent on perfusion, but also on hepatic uptake and excretion, which makes it difficult to determine what exactly is being measured. Estimated hepatic blood flow calculated from systemic indocyanine green clearance correlates poorly with values obtained using hepatic vein catheterisation and the Fick principle, because of the variability in dye extraction (6).

Hepatic vein catheterisation

Monitoring of hepatic vein oxygen saturation is invasive and involves the insertion of a hepatic catheter. Fluoroscopic or ultrasound guidance is commonly necessary for adequate insertion. A new technique for blind insertion has been described, using galactose infusion combined with a specific biosensor (53). The use of these catheters appears to be safe. Several studies have documented that the gradient between mixed-venous and hepatic vein saturation is commonly increased in septic shock (54). However, as this measurement reflects portal and hepatic arterial flow, maintained hepatic venous oxygen saturation does not exclude gut hypoperfusion. Hepatic vein lactate measurements can be used to detect splanchnic hypoxia, with similar limitations.

Hepatic blood flow can also be determined by hepatic venous sampling during constant infusion of indocyanine-green, therefore enabling the calculation of the indocyanine-green extraction, as discussed earlier. The coefficient of variation for splanchnic blood flow in septic shock patients using hepatic vein catheterisation derived indocyanine green clearance measurements was 9% (55). In another study using the same technique, the standard error for repeated measurements was 31% (56).

Plasma D-lactate

Measurement of plasma D-lactate has been suggested to be a marker of splanchnic hypoperfusion. D-lactate is produced by bacterial fermentation in the colonic lumen and subsequently absorbed into the blood. Bacterial overgrowth and increased gut permeability are both features of gastrointestinal dysfunction during septic shock. During hypoperfusion in the gut, both L-lactate and D-lactate are produced in increased amounts. Because humans lack the enzyme D-lactate dehydrogenase, liver metabolism of D-lactate is slower than that of L-lactate. D-Lactate may therefore reflect the intestinal perfusion more closely than L -lactate.

Increased D-lactate levels were found in acute intestinal ischaemia, acute pancreatitis and severe burns (57-60). In a study in 20 septic shock patients, D-lactate levels but not L-lactate levels correlated significantly with gastric tonometry results, indicating that D-lactate is a better marker for splanchnic hypoperfusion and increased splanchnic luminal C[O.sub.2] production than L-lactate in septic patients (61).

These results need to be reproduced by subsequent studies. Further clinical validation of the usefulness of this assay is needed. This technique may not be able to rapidly reflect changes in gastrointestinal perfusion (e.g. to study specific interventions) because of the relatively long half-life of D -lactate. Current clinical use is also limited by the fact that the D-lactate assay is not available in most institutions.

Future techniques

Other techniques are being developed to measure gastrointestinal (mucosal) perfusion or oxygenation. Currently, these methods have limited use in humans and as such are not within the scope of this review. Examples include contrast-enhanced ultrasonography (62) and intestinal luminal microdialysis (63,64).

Conclusion

Different techniques have been developed to measure gastrointestinal perfusion. Realistically, most methods are actually indirect estimates of gastrointestinal perfusion. The clinical usefulness and relevance of the different techniques is dependent on the problem that is being investigated, and results of different methods can sometimes appear seemingly conflicting (e.g. normal global splanchnic blood flow does not equal adequate oxygen delivery to the cells). Also, there is no technique that is considered the 'gold standard'.

In sepsis, heterogeneity in microcirculatory flow seems to be a key characteristic. Interruption or decrease of red blood cell velocity, as well as hyperdynamic microcirculatory flow patterns (shunting) has been observed. Techniques that evaluate the adequacy of mucosal oxygenation (e.g. reflectance spectrophotometry and tonometry) are likely to better reflect the microcirculatory disturbances in sepsis than techniques that simply measure flow (e.g. laser Doppler flowmetry). OPS imaging is a useful technique to quantify microcirculatory abnormalities in sepsis, but studies are awaited to further correlate sublingual measurements with gastrointestinal mucosal perfusion.

PROGNOSTIC VALUE OF IMPAIRED GASTROINTESTINAL PERFUSION

Gastrointestinal mucosal hypoperfusion in critically ill patients is associated with a poor outcome, as illustrated in Table 2.

Several studies in different patient populations have investigated the association between gastric intramucosal pH (pHi), gastric mucosal Pc[o.sub.2] or the gastric to arterial Pc[o.sub.2] gradient and outcome (65-67). In the majority of these studies, a low pHi at admission, or failure to normalise pHi after a set time period (most often 24 hours), discriminates non-survivors from survivors. However, pHi is closely related to the systemic acid-base status, which may partly explain why pHi has been shown to be a good prognostic marker. Only one study investigated the prognostic role of the gastric to arterial Pc[o.sub.2] gap using automated air tonometry, convincingly demonstrating that the Pc[o.sub.2] gap is a marker of mortality in ventilated ICU patients (65).

In a recent study, global haemodynamic variables were compared with different regional variables in 28 septic patients. After initial resuscitation aimed at improving global pressure-related haemodynamics, hepatosplanchnic variables but not global haemodynamic variables were independent predictors of outcome. Gastric mucosal pH, mucosal to end-tidal C[O.sub.2] gap and indocyanine green blood clearance were the most important predictors of outcome (78). Indocyanine green elimination rate has been shown to correlate with survival in critically ill and septic shock patients in other studies as well (79-81). Sakka et al retrospectively studied 336 critically ill patients who were monitored with transpulmonary double indicator dilution technique. The lowest value of indocyanine green plasma disappearance rate (ICG-PDR) was significantly lower in non-survivors (n= 168) than in survivors (n= 168) (median, 6.4% /min vs. 16.5%/min). The area under the ROC curve as a measure of accuracy was 0.8 when using the lowest ICG-PDR in each patient and found to be comparable with values obtained with APACHE II and SAPS II scores. The predictive value of ICG-PDR was found to be independent from the underlying disease, as subgroup analysis showed that in sepsis, ARDS and all other patients, the IGC-PDR was always significantly higher in survivors (80).

In one small study looking at endoscopic reflectance spectrophotometry, values for gastroduodenal blood flow in mechanically ventilated septic patients were approximately 40 to 50% of values found in healthy control patients. This impairment of gastroduodenal perfusion was associated with a higher in-hospital mortality than predicted by APACHE II (83% vs. 25%) (82).

Persistent abnormalities in the sublingual micro circulation of septic patients (as visualised with orthogonal polarisation spectral imaging) are associated with organ failure and death. Sakr et al found that at the onset of shock, survivors and non-survivors had similar vascular density and percentage of perfused small vessels. However, small vessel perfusion significantly improved over time in survivors but not in non-survivors. Despite similar haemodynamic and oxygenation profiles and use of vasopressors at the end of shock, patients dying after the resolution of shock in multiple organ failure had a significantly lower percentage of perfused small vessels than survivors (57.4% vs. 79.3%) (83).

Plasma D-lactate has also been studied as a prognostic marker. A rapid decrease in plasma D -lactate levels, but not L -lactate levels, between day one and two in septic shock patients, discriminated between survivors and non-survivors (84).

In summary, these results show that measurements of gut perfusion can be used to predict outcome in septic patients.

TREATMENT OF GASTROINTESTINAL PERFUSION DEFECTS

Gut injury has been shown to be associated with infectious complications, systemic inflammation and organ failure in septic patients. In view of the above-described correlations between splanchnic perfusion and prognosis, interventions targeted at preventing or ameliorating gut injury are warranted. However, many of the studies that we report on below show disappointingly negative results; presumably in part due to small sample size and ineffective therapies that do not reach their treatment goals. They do clearly demonstrate that hyper-aggressive use of some 'traditional' method of macrovascular resuscitation (usually applied in the treatment arm of the study) often fails to improve gastrointestinal microcirculatory function. It is likely that radical new approaches to microvascular resuscitation are needed before we can expect to achieve positive survival benefits. This is further elaborated on in the discussion section.

Global and regional resuscitation

Resuscitation strategies aimed at global haemodynamic parameters often fail to improve gastrointestinal perfusion and microcirculation. Prospective randomised controlled studies that have investigated the effect of treatment strategies specifically aimed to improve gastrointestinal perfusion on clinically important outcome parameters are listed in Table 3.

Two small controlled studies in different patient populations have examined whether treatment aimed at increasing gastric intramucosal pH (pHi) improves outcome (69,85). No significant differences were found in mortality or morbidity between the treatment groups and the control groups. However, both studies were not adequately powered to detect differences in outcome. Moreover, failure of the intervention (fluids and more vasoactive agents) to improve pHi strongly predicted poor outcome in both studies.

Three larger controlled studies--that investigated the influence of splanchnic perfusion directed therapy in critically ill patients--were performed in 260, 210 and 151 patients (86-88). In all three studies, patients in the intervention groups with a low pHi received additional fluid resuscitation and vasoactive agents in an attempt to correct the abnormal pHi and to improve outcome. In one study, patients in a second intervention group additionally received therapies specifically aimed at optimising splanchnic perfusion and minimising reperfusion damage, including mannitol, hydrocortisone, antioxidants, glutamine and vasodilator therapy (88). Only the Gutierrez trial showed a beneficial effect of pHi guided treatment (86). In this study, patients admitted with a low pHi had similar survival rates in both the intervention and the control group (36% vs. 36%). However, in patients with a normal admission pHi, survival was significantly better in the intervention than in the control group (58% vs. 42%, P<0.01). These patients received additional resuscitation whenever pHi fell below a certain level. This drop in pHi indicated potential inadequate resuscitation despite normal global haemodynamics. The authors suggested that timing of the intervention could be crucial and that their therapeutic approach could be ineffective after prolonged (irreversible?) mucosal acidosis as seen in the patients admitted with a low pHi. However, treatment in the control arm of this multicentre study was not standardised. This, combined with the high mortality in the control group, suggests that the difference in mortality may have been unrelated to the treatment of low pHi. Interestingly, in general, attempts at correction of pHi in the three trials usually failed to alter this parameter (compared to baseline or to the control group) in a sustained and significant manner. This suggests that the additional treatment provided, which consisted of significantly more administration of fluid and vasoactive agents, in fact was ineffective in resuscitating or recruiting the gastrointestinal microcirculation. In the two trials that measured pHi in the control patients as well (86,87), admission pHi was significantly lower in non-survivors compared to survivors, confirming the prognostic value of tonometry. An important limitation of these studies is the use of saline tonometry derived pHi as the marker for gastrointestinal hypoperfusion (as discussed earlier, this has been replaced by the more accurate automated gas tonometry). Also, it is important to realise that the patient population studied was heterogeneous and not limited to a diagnosis of septic shock. Moreover, different resuscitation protocols were used, including infusion of crystalloids, colloids and blood products. The effect of fluid resuscitation on gastrointestinal perfusion is variable and dependent on the type of fluid used. Simply optimising cardiac output by fluid loading in septic patients, with or without subsequent reduction of vasopressor dose, is not necessarily associated with an increase in splanchnic blood flow (89,90). Different fluids have different properties (e.g. composition and tonicity), which may result in different biological effects in septic shock. Specific to gastrointestinal perfusion, hydroxyethyl starch (HES) has shown to have a more pronounced beneficial effect on splanchnic perfusion than Ringer's solution or modified fluid gelatin",". In a recent uncontrolled study in septic patients, the effect of HES fluid challenge on gastric mucosal PC[O.sub.2] was variable between patients. Improvement was more pronounced in septic patients with an abnormal baseline Pc[o.sub.2] gap, indicating the actual presence of gastrointestinal mucosal hypoperfusion (93). Theoretically and supported by animal studies, hypertonic fluid resuscitation (e.g. 7.5% hypertonic saline solution) has the potential to recruit gastrointestinal microcirculation (94). In a recent animal study, hypertonic saline decreased thermal injury induced bacterial translocation in the gut, and enhanced host response to bacterial challenge by augmenting Toll-like receptor expression of inflammatory cells (95). The effect of hypertonic fluid resuscitation on gastrointestinal perfusion, microcirculation and immunomodulation is the subject of an ongoing randomised controlled study in septic shock patients. Finally, transfusion of red blood cells to enhance systemic oxygen delivery in septic patients failed to improve gastric pHi in two studies (96,97).

In conclusion, resuscitation of septic shock patients on the basis of tonometry has not convincingly been shown to improve outcome. Patient heterogeneity, lack of statistical power, the use of saline tonometry and failure of the treatment protocols to actually improve pHi may explain this lack of efficacy. Persistently low pHi despite treatment in these studies identified patients at risk for poor outcome and illustrates the fact that the therapies studied seem generally not effective in actually resuscitating mucosal microcirculation.

Vasoactive therapy

The influence of classic vasoactive therapies on gastrointestinal perfusion in septic shock has been well described in a recent review article and will not be further elaborated on (98). In summary, increasing perfusion pressure with vasopressor therapy in septic shock patients does not significantly improve or impair splanchnic perfusion (99,100). However, from a micro circulatory perspective, vasopressors should be applied with caution (101). We have previously shown that vasopressin infusion in septic shock patients treated with high dose noradrenaline results in a significant increase in gastric-arterial Pc[o.sub.2] gap (102). Preliminary results from the Vasopressin and Septic Shock Trial show that vasopressin infusion in patients with septic shock may be beneficial in patients who require low dose noradrenaline, but demonstrate no improved outcome in patients with 'high' dose (> 15 [micro]g/min) noradrenaline dependency. Although no significant increase in overt mesenteric ischaemia was reported, this potentially may have been caused by inadvertent effects on gastrointestinal perfusion.

While pressure-guided resuscitation in septic patients has consistently been found to be effective in restoring systemic blood pressure, it does not, by definition, have an equivalent correcting effect on microcirculatory perfusion (83).

Vasodilator therapy increases the driving pressure at the entrance of the microcirculation and is potentially able to recruit microcirculatory perfusion (103). One of the problems in interpreting the results of administration of vasodilator drugs is that these drugs often have other pharmacological effects as well (e.g. reduction in leucocyte adhesion and platelet aggregation). Nitric oxide donors such as nitroglycerine improved gut microcirculation in a number of animal experiments (103) and also improved sublingual microcirculatory blood flow in an observational uncontrolled human study, as measured by orthogonal polarisation spectral imaging (104). However, as part of a complex therapeutic intervention protocol to resuscitate trauma patients and prevent ischaemia-reperfusion damage, vasodilators failed to correct a low pHi (88).

Prostacyclin and its analogue iloprost have vasodilator and cytoprotective properties. Administration of these drugs in septic patients either intravenously or aerosolised increased gastric intramucosal pH in two studies (105,106). In a prospective uncontrolled study in 20 septic shock patients, iloprost was infused and plasma disappearance rate of indocyanine green increased significantly 24 hours after start of iloprost infusion (baseline: 13.9[+ or -]1.7% vs. 18.6[+ or -]2.2%/min) and significantly decreased one hour after end of infusion (13.7[+ or -]1.7%/min) (107). Iloprost also improved cardiac index and global hepato-splanchnic perfusion in another small uncontrolled study in septic shock patients (108).

The complex interactions between the exogenous administered vasodilators and the endogenous sepsis-induced vasodilatory mechanisms (e.g. through iNOS activation) are not well understood. This makes it difficult to resolve the clinical conundrum of attempting to administer vasodilator drugs to a critically ill septic patient who is concurrently requiring vasoconstrictors to maintain adequate macrocirculatory parameters.

Enteral nutrition

Under normal conditions, blood flow to the gastrointestinal system increases during the digestion and absorption of nutrients. Regulation of this postprandial hyperaemia is complex (4). In several clinical situations, enteral feeding has been shown to prevent or ameliorate the increase in gut permeability and systemic inflammation induced by the disease state. For example, in one study, multiple injured patients who had recovered from shock within six hours were randomised in an early enteral nutrition group and a late enteral nutrition group. Intestinal permeability was measured using a lactose/mannitol (L/M) clearance assay. On post injury day four L/M ratio was significantly higher in the second group, suggesting that immediate enteral nutrition protects against an increase in intestinal permeability induced by multiple injury (109). In surgical critically ill patients, early administration of enteral nutrition decreases the number of infectious complications and the length of hospital stay (110,111). The mechanisms by which enteral nutrition is thought to decrease the pathological gut permeability include an increase in hepatosplanchnic blood flow, prevention of gut-associated lymphoid tissue atrophy and modulation of immunological phenomena (110,112).

Experimental therapies

Endothelium-derived substances such as endothelin and nitric oxide are recognised as important mediators of systemic inflammation. Selective inhibition of inducible nitric oxide synthase blunted the progressive increase in ileal to arterial Pc[o.sub.2] gap in an animal model of long-term endotoxaemia (113). The use of endothelin receptor antagonists has been studied in several animal models of septic shock. In one porcine study, bosentan completely restored the gut oxygen delivery with a reversal of intestinal mucosal acidosis as measured by ilea] tonometry (114). These findings were reproduced in another study with the use of laser Doppler flowmetry, confirming the hypothesis that endothelin plays an important role in the regulation of splanchnic microcirculatory flow in septic shock (115). In patients with severe sepsis, endothelin plasma levels are markedly increased (116). To our knowledge, there are no studies published to date that look at the effects of endothelin receptor antagonists in septic patients. Timing of these potential interventions would seem to be crucial. The selective inhibition of inducible nitric oxide synthase during the hyperdynamic, earlier phase of sepsis combined with the blockade of endothelin receptors at a later stage may represent a novel promising strategy for the therapy of septic shock (117).

Blockade of the angiotensin II type 1 receptor ameliorates splanchnic hypoperfusion in acute experimental circulatory failure. In animal models of septic shock however, administration of the angiotensin II type 1 receptor antagonist candesartan had no effect on mucosal acidosis (118). Although survival improved when used as pre-treatment, survival decreased compared to controls when candesartan was administered during endotoxaemia (119).

DISCUSSION

Septic shock is associated with splanchnic perfusion abnormalities, which can be measured with several techniques as discussed above. These perfusion abnormalities are associated with a poor outcome. The main question now is: if impairment of splanchnic mucosal perfusion in sepsis adversely affects outcome, why have trials aimed at improving gut perfusion failed to show survival benefit? Several explanations may be considered. First of all, the majority of studies have looked at intermediate physiologic effects (e.g. gastric intramucosal pH) and not at mortality as primary outcome measure. Clearly, if an intervention--which is targeted to improve mucosal microcirculatory perfusion--fails to do so it is also unlikely to find a significant difference in outcome. The effect of those treatment strategies that are actually potentially capable of effectively restoring systemic and gastrointestinal microcirculatory defects (e.g. hypertonic fluid resuscitation) on outcome in septic patients has not yet been studied.

Measurement of treatment effects on physiologic variables such as splanchnic perfusion has potential intrinsic problems. Measurement errors can produce false positive as well as false negative results. The magnitude of treatment effect has to be greater than the baseline physiologic variability of the variable studied. Knowledge of this variability is essential in interpreting the results of these measurements. In healthy subjects, splanchnic blood flow has been demonstrated to exhibit a circadian variation (120). Animal experiments suggest that splanchnic haemodynamic parameters could exhibit a more pronounced variability than systemic haemodynamics (6). Some of the physiologic variability in splanchnic blood flow is explained by abdominal pressure variation during the respiratory cycle. However, in patients with acute lung injury, lung recruitment manoeuvres and prone positioning interestingly had no significant effect on gastric mucosal perfusion (121,122).

There is also the possibility that splanchnic hypoperfusion is a marker of disease or an epiphenomenon rather than a factor in its pathogenesis. However, as outlined above, current experimental evidence supports the hypothesis that mucosal microcirculatory abnormalities play a role in the pathogenesis of systemic inflammation and multiple organ failure. From this pathophysiological understanding, it would seem likely that the main therapeutic benefit of effective mucosal resuscitation treatments would be to prevent an ongoing inflammatory insult to the patient. As a consequence, we would expect a benefit in reducing late sepsis-associated deaths (usually from multiple organ failure). However, the subset of septic patients who die from the primary infective insult (such as fulminant meningococcaemia) would not be expected to benefit from treatments that act to reduce secondary inflammatory processes.

Clinical research in this specific area is also subject to a more common dilemma present in sepsis studies. The pathogenesis and pathophysiology of sepsis is complex. Sepsis can be looked at as a self-regulating complex system, with multiple cascading non-linear interactions and feedbacks, acting in series and in parallel, to form a 'scale-free' network. As such, interfering with one variable is unlikely to change the course of the disease process (123). Many 'magic bullets' have been considered and subsequently shown to yield disappointing results in clinical trials. An approach targeted at different elements of that complex system therefore seems more rational. Examples are resuscitation strategies that at the same time modulate the immune response, such as hypertonic fluid resuscitation and the use of selective nitric oxide inhibitors as vasopressors.

CONCLUSION

Normal regulation of gastrointestinal blood flow is impaired in septic shock, resulting in mucosal hypoperfusion. Gastrointestinal mucosal hypoperfusion is an important marker, and also probably a cause, of poor prognosis in septic patients. Impaired gut barrier function could play a role in amplification of systemic inflammation, causing distant multiple organ dysfunction.

The aim of monitoring splanchnic perfusion is to detect, prevent and reverse tissue hypoperfusion. Several techniques have been developed to measure gastrointestinal perfusion. These methods share the ability to predict outcome in septic shock patients. Gastric tonometry is the most widely used technique because of its non-invasiveness and ease of use. However, as treatment strategies aimed at improving gastrointestinal perfusion have not been able to correct mucosal perfusion abnormalities and hence have not shown to improve outcome, the use of these tools in clinical decision-making is currently limited.

New treatment strategies for septic shock should be tested for their effects on gastrointestinal perfusion; to further clarify its exact role in patient management, and to prevent therapies detrimental to gastrointestinal perfusion being implemented.

Address for reprints: Dr F. M. P. van Haren, Intensive Care Department, Waikato Hospital, Private Bag 3200, Hamilton, New Zealand.

Accepted for publication on May 22, 2007.

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F. M. P. VAN HAREN *, J. W. SLEIGH ([dagger]), P. PICKKERS ([double dagger]), J. G. VAN DER HOEVEN ([double dagger]) Intensive Care Department, Waikato Hospital, Hamilton, New Zealand

* M.D., F.J.F.I.C.M., Intensive Care Consultant.

([dagger]) M.B., Ch.B., M.D., F.A.N.Z.C.A., F.J.F.I.C.M., Intensive Care Consultant.

([double dagger]) M.D., Ph.D., Intensive Care Consultant, Intensive Care Department, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
TABLE 1
Summary of techniques to measure gastrointestinal perfusion in
patients

Method                           Variable

Tonometry                        Gastric-arterial P[co.sub.2] gap,
                                 mucosal-end tidal P[co.sub.2] gap,
                                 pHi

Laser Doppler flowmetry          Mucosal haematocrit,
                                 mucosal red blood cells
                                 velocity, blood flow in
                                 arbitrary perfusion units

Reflectance                      Tissue microvascular
spectrophotometry                haemoglobin oxygen
                                 saturation, relative
                                 haemoglobin concentration

Near-infrared spectroscopy       Quantitative tissue
                                 oxygenation index (ratio
                                 oxygenated haemoglobin to
                                 total haemoglobin)

Orthogonal polarisation          Functional capillary density,
spectral imaging                 percentage of perfused small
                                 vessels, semi-quantitative
                                 blood flow

Indocyanine green clearance      Plasma disappearance rate
                                 ICG

Hepatic vein catheterisation     Lactate, venous saturation,
                                 indocyanine green extraction

Plasma D -lactate                Plasma D-lactate levels

Method                           Advantages

Tonometry                        Minimally invasive; measure of
                                 mucosal perfusion; validated;
                                 reproducible; commercially
                                 available

Laser Doppler flowmetry          Useful to evaluate endothelium-
                                 dependent vascular responses;
                                 real-time velocity measurement

Reflectance                      Estimates adequacy of oxygen
spectrophotometry                delivery; commercially available;
                                 real time monitoring possible

Near-infrared spectroscopy       Minimally invasive; measures
                                 tissue oxygenation

Orthogonal polarisation          Easy; non-invasive; reproducible;
spectral imaging                 commercially available

Indocyanine green clearance      Commercially available;
                                 measures splanchnic perfusion
                                 as well as global liver function

Hepatic vein catheterisation     Allows measurement oxygen and
                                 indocyanine-green extraction

Plasma D -lactate                Easy; correlates with gastric
                                 tonometry results

Method                           Limitations

Tonometry                        Limited by site of measurement;
                                 gastric feeding interferes with
                                 measurement; requires equilibration
                                 (no real time monitoring)

Laser Doppler flowmetry          Small sampling volume for blood
                                 flow measurement; does not reflect
                                 heterogeneity of blood flow; no
                                 measurement of absolute blood flow

Reflectance                      Not a measure of blood flow;
spectrophotometry                endoscopic introduction; blind
                                 probes need validation; luminal
                                 contents interfere with measurement

Near-infrared spectroscopy       Penetrates into muscularis layer;
                                 nasogastric probes not tested in
                                 human studies; transcutaneous liver
                                 oxygenation measurement not
                                 feasible in adults

Orthogonal polarisation          Semi-quantitative; sublingual
spectral imaging                 measurements may not represent
                                 splanchnic perfusion; operator-
                                 dependent

Indocyanine green clearance      Multiple variables determine
                                 results (hepatic blood flow,
                                 hepatocellular uptake,
                                 excretion into bile)

Hepatic vein catheterisation     Invasive; requires radiological
                                 guidance; dual hepatic blood
                                 flow limits use

Plasma D -lactate                Assay not commonly available; not
                                 a direct measure of gastrointestinal
                                 perfusion; unable to detect rapid
                                 changes in perfusion

TABLE 2
Clinical studies reporting the effects of splanchnic perfusion
abnormalities on mortality in critically ill patients

Reference     n     Patients                      Splanchnic
(year)                                            perfusion

(65) (2003)   95    Ventilated critically ill     P[co.sub.2] gap

(87) (2000)   210   Critically ill                pHi

(66) (1997)   62    Critically ill                pHi
                                                  P[co.sub.2] gap

(67) (1998)   19    Critically ill trauma         pHi

(68) (1997)   19    Paediatric septic             P[co.sub.2] gap
                                                  pHi

(69) (1996)   57    Trauma with organ failure     pHi

(70) (1995)   8     Paediatric septic shock       pHi

(71) (1995)   35    Severe sepsis                 pHi

(72) (1994)   20    Critically ill trauma         pHi

(73) (1993)   30    Ventilated critically ill     pHi

(74) (1993)   83    Acute circulatory failure     pHi

(86) (1992)   260   Intensive care                pHi

(75) (1991)   80    Intensive care                pHi

(76) (1998)   114   Trauma                        pHi P[co.sub.2] gap
                                                  -

(77) (1999)   68    Cardiac surgery               pHi P[co.sub.2] gap

(78) (2005)   28    Sepsis (severe sepsis         pHi P[co.sub.2] gap
                    excluded)                     ICGC

(79) (2001)   21    Septic shock                  ICGC

(80) (2002)   336   Critically ill                ICG-PDR

(81) (1984)   39    Critically ill surgical       ICGC

(82) (2004)   6     Ventilated with septic SIRS   IS[O.sub.2] IHB

(83) (2006)   37    Septic shock                  D-lactate

Reference           Prediction of mortality
(year)

(65) (2003)         OR 1.57 (95% CI 1.10-2.24)

(87) (2000)         pHi lower in non-survivors

(66) (1997)         pHi but not P[co.sub.2] gap predicted
                    mortality

(67) (1998)         RR 4.5; Mortality 50% vs. 11%

(68) (1997)         P[co.sub.2] gap but not pHi predicted
                    mortality

(69) (1996)         Mortality 54% vs. 7%

(70) (1995)         Mean pHi lower in non-survivors

(71) (1995)         pHi lower in non-survivors

(72) (1994)         Mortality 50 vs. 0%

(73) (1993)         pHi predicts mortality

(74) (1993)         Likelihood ratio 2.32

(86) (1992)         pHi lower in non-survivors

(75) (1991)         Mortality 65% vs. 44%

(76) (1998)         OR 4.6
                    OR 2.9

(77) (1999)         No difference between survivors
                    and non-survivors

(78) (2005)         OR 4.8 (95% CI 1.5-14.6)
                    OR 3.0 (95% CI 1.4-6.3)
                    OR 3.9 (95% CI 1.1-13.8)

(79) (2001)         Low value and failure to increase
                    in non-survivors

(80) (2002)         Lowest value lower in non-
                    survivors than in survivors

(81) (1984)         Lower in non-survivors

(82) (2004)         Observed mortality 83% vs.
                    predicted mortality 25%
(83) (2006)         Decrease between day 1 and 2 in
                    survivors

Reference           Comments
(year)

(65) (2003)         After 24 hours
                    Automated air tonometry

(87) (2000)         Intervention trial, pHi guided
                    resuscitation

(66) (1997)

(67) (1998)

(68) (1997)         After 24 hours
                    ROC AUC 0.7

(69) (1996)         Failure to normalise pHi
                    predicts mortality

(70) (1995)

(71) (1995)         At 0, 4, and 24 h

(72) (1994)         Low pHi on admission that
                    did not correct after 24 hours

(73) (1993)

(74) (1993)         After 24 hours

(86) (1992)         Intervention trial, pHi guided
                    resuscitation

(75) (1991)         On admission

(76) (1998)

(77) (1999)         On admission and after 12 hours

(78) (2005)         Regional but not global variables
                    predict mortality after
                    stabilisation

(79) (2001)

(80) (2002)         ROC AUC 0.8

(81) (1984)

(82) (2004)         Unexpectedly high
                    observed mortality

(83) (2006)

pHi= intramucosal pH; P[co.sub.2] gap= gastric mucosal-arterial
gradient of P[co.sub.2],; ICGC= indocyanine green clearance; ICG-PDR=
indocyanine green plasma disappearance rate; IS[O.sub.2] endoscopic
reflectance spectrophotometry recorded index of gastroduodenal
mucosal oxygen saturation; IHb= endoscopic reflectance
spectrophotometry recorded index of gastroduodenal mucosal
haemoglobin concentration; OR= Odds Ratio; RR= Risk Ratio; ROC
AUC=Receiver operating characteristic area under curve.

TABLE 3
Prospective randomised controlled studies reporting the effects of
tonometry-based resuscitation on outcome

Reference      n       Patients
(year)

(67) (1996)    57      Trauma

(83) (1998)    55      Elective repair AAA

(84) (1992)    260     Intensive care; stratified
                       according to admission pHi

(85) (2000)    210     Intensive care; stratified
                       according to admission pHi

(86) (2005)    151     Trauma

Reference      Intervention target              Outcome
(year)

(67) (1996)    pHi >7.3 vs. maintenance         No difference in
               of supranormal oxygen            mortality, MOF
               delivery and consumption

(83) (1998)    pHi >7.32 vs. standard           No difference in
               therapy                          mortality, LOS

(84) (1992)    pHi >7.35 vs. standard           Mortality reduced in
                                                protocol group only in
                                                patients with normal
                                                pHi on admission

(85) (2000)    pHi >7.35 vs. standard           No difference in
                                                mortality, LOS, MOF

(86) (2005)    pHi >7.25 [+ or -] additional    No difference in
               ischaemia-reperfusion-           mortality, LOS, MOF
               based therapy vs. standard

Reference      Comments
(year)

(67) (1996)    Optimisation time predictive
               of mortality

(83) (1998)    Low and persistently low
               pHi associated with more
               complications

(84) (1992)    See text

(85) (2000)    Intervention group received
               more dobutamine and blood

(86) (2005)    See text

AAA=abdominal aortic aneurysm; MOF=multiple organ failure; LOS=length
of stay; APACHE II=Acute Physiology and Chronic Health Evaluation II.
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