Vasopressin V1A receptors mediate the increase in gastric mucosal oxygenation during hypercapnia

in Journal of Endocrinology

Hypercapnia (HC) improves systemic oxygen delivery (DO2) and microvascular hemoglobin oxygenation of the mucosa (μHbO2). Simultaneously, HC increases plasma levels of vasopressin. Although vasopressin is generally regarded a potent vasoconstrictor particularly in the splanchnic region, its effects on splanchnic microcirculation during HC is unclear. The aim of this study was to evaluate the role of endogenous vasopressin on gastric mucosal oxygenation and hemodynamic variables during physiological (normocapnia) and hypercapnic conditions. Five dogs were repeatedly anesthetized to study the effect of vasopressin V1A receptor blockade ([Pmp1,Tyr(Me)2]-Arg8-Vasopressin, 35 μg/kg) on hemodynamic variables and μHbO2 during normocapnia or HC (end-tidal CO2 70 mmHg). In a control group, animals were subjected to HC alone. μHbO2 was measured by reflectance spectrophotometry, systemic DO2 was calculated from intermittent blood gas analysis, and cardiac output was measured by transpulmonary thermodilution. Data are presented as mean±s.e.m. for n=5 animals. During HC alone, DO2 increased from 12±1 to 16±1 ml/kg per min and μHbO2 from 70±4 to 80±2%. By contrast, additional vasopressin V1A receptor blockade abolished the increase in μHbO2 (80±2 vs 69±2%) without altering the increase in DO2 (16±1 vs 19±2 ml/kg per min). Vasopressin V1A receptor blockade (VB) during normocapnia neither affected DO2 (13±1 vs 14±1 ml/kg per min) nor μHbO2 (75±3 vs 71±5%). Vasopressin V1A receptor blockade abolished the increase in μHbO2 during HC independent of DO2. Thus, in contrast to its generally vasoconstrictive properties, the vasopressin V1A receptors seem to mediate the increase in gastric microcirculatory mucosal oxygenation induced by acute HC.

Abstract

Hypercapnia (HC) improves systemic oxygen delivery (DO2) and microvascular hemoglobin oxygenation of the mucosa (μHbO2). Simultaneously, HC increases plasma levels of vasopressin. Although vasopressin is generally regarded a potent vasoconstrictor particularly in the splanchnic region, its effects on splanchnic microcirculation during HC is unclear. The aim of this study was to evaluate the role of endogenous vasopressin on gastric mucosal oxygenation and hemodynamic variables during physiological (normocapnia) and hypercapnic conditions. Five dogs were repeatedly anesthetized to study the effect of vasopressin V1A receptor blockade ([Pmp1,Tyr(Me)2]-Arg8-Vasopressin, 35 μg/kg) on hemodynamic variables and μHbO2 during normocapnia or HC (end-tidal CO2 70 mmHg). In a control group, animals were subjected to HC alone. μHbO2 was measured by reflectance spectrophotometry, systemic DO2 was calculated from intermittent blood gas analysis, and cardiac output was measured by transpulmonary thermodilution. Data are presented as mean±s.e.m. for n=5 animals. During HC alone, DO2 increased from 12±1 to 16±1 ml/kg per min and μHbO2 from 70±4 to 80±2%. By contrast, additional vasopressin V1A receptor blockade abolished the increase in μHbO2 (80±2 vs 69±2%) without altering the increase in DO2 (16±1 vs 19±2 ml/kg per min). Vasopressin V1A receptor blockade (VB) during normocapnia neither affected DO2 (13±1 vs 14±1 ml/kg per min) nor μHbO2 (75±3 vs 71±5%). Vasopressin V1A receptor blockade abolished the increase in μHbO2 during HC independent of DO2. Thus, in contrast to its generally vasoconstrictive properties, the vasopressin V1A receptors seem to mediate the increase in gastric microcirculatory mucosal oxygenation induced by acute HC.

Introduction

The gastrointestinal tract is a complex organ system with multiple functions. Apart from being responsible for nutrient absorption, it is an important metabolic and immunological system, functioning as an effective barrier against endotoxin and bacteria from the intestinal lumen. To maintain this barrier, adequate perfusion and oxygenation of the mucosa are vital (Trzeciak et al. 2008).

However, during severe illness, the blood flow is redistributed to preserve perfusion of more vital organs (i.e. heart and brain) and thus splanchnic oxygenation is impaired early (Jakob & Takala 2000, Schwartges et al. 2010). An impaired mucosal barrier function resulting from insufficient microcirculatory oxygen supply has been shown to enable translocation of bacteria and bacterial toxins into portal venous and local lymphatic circulation (Deitch et al. 2004) and to mediate an inflammatory response syndrome (Chen et al. 2003). Therefore, adequate splanchnic perfusion and in particular oxygenation of the gastrointestinal mucosa are considered crucial for the prevention and therapy of critical illness (Trzeciak et al. 2008). Thus, growing effort is made to develop strategies to improve splanchnic mucosal oxygenation.

In this context, we have recently shown that hypercapnia (HC) improves systemic oxygen delivery (DO2) and microvascular oxygenation of the gastric mucosa not only during physiological conditions (Schwartges et al. 2008) but also during hemorrhagic shock (Schwartges et al. 2010). Apart from these effects on macro- and microcirculation, HC exerts multiple other changes in homeostasis, like an increase in vasopressin plasma level (Philbin et al. 1970, Forsling & Rees 1975, Farber et al. 1982, Rose et al. 1984) with subsequent binding to the vasopressin V1A receptors that could mediate or modulate the effects on microcirculation. Vasopressin is regarded as a potent vasoconstrictor particularly in the splanchnic region and reduces systemic DO2, cardiac output, and jejunal mucosal oxygen partial pressure (Knotzer et al. 2005). Thus, the positive effects on microcirculatory oxygenation induced by acute HC might be partially counteracted by an increase in vasopressin levels.

However, the effects of vasopressin on the splanchnic microcirculation were recently controversially discussed (Asfar et al. 2006). The expected negative effects of vasopressin could not be observed in a septic animal model (Knotzer et al. 2006) and even an improvement of gut microcirculatory flow is possible (Asfar et al. 2003). Furthermore, the effect seems to depend on flow. In animals with high systemic flow per se, gut microcirculatory flow was even increased additionally due to terlipressin (Asfar et al. 2003). By contrast, during low flow conditions, terlipressin infusion increased mortality (Asfar et al. 2003). However, despite its generally vasoconstrictive properties, vasopressin and its V1A receptor exert vasodilation as well (Evora et al. 1993). Little is known about the effect of exogenous vasopressin on regional oxygenation. The dosage applied seems to be an important factor, though studies are rare (Asfar et al. 2006). But most studies focused on macro- and microcirculatory hemodynamic variables (Asfar et al. 2008). Thus, the impact of endogenous vasopressin and its receptor on splanchnic oxygenation remains unclear, particularly during non-physiological situations like acute HC. The aim of our study was to evaluate the role of endogenous vasopressin during normo- and HC on gastric mucosal oxygenation in healthy animals.

Materials and methods

Animals

The data were derived from repetitive experiments on five dogs (female foxhounds, weighing 28±1 kg) treated in accordance with NIH guidelines for animal care and performed with approval of the local animal care and use committee.

Before the experiments, food was withheld for 12 h with water ad libitum to ensure complete gastric depletion and to avoid changes in perfusion and oxygenation due to digestive activity. Each dog underwent each experimental protocol in randomized order and served as its own control. Experiments were performed at least 3 weeks apart to prevent carryover effects. In each experiment, the dogs received an i.v. catheter that was removed at the end of the experiment. The experiments were performed under general anesthesia. General anesthesia was induced via the i.v. catheter (application of 4 mg/kg propofol) and maintained with inhalation of sevoflurane (end-tidal concentration 3.0%, 1.5 minimum alveolar concentration (MAC) in dogs). The animals were mechanically ventilated after endotracheal intubation (semi-closed circle ventilation, inspiratory oxygen concentration FiO2=0.3, tidal volume=12.5 ml/kg, a normal tidal volume for dogs) with the respiratory frequency adjusted to achieve normocapnia (end-expiratory concentration of CO2 etCO2=35 mmHg), verified by continuous capnography (Capnomac Ultima, Datex Instrumentarium, Helsinki, Finland). After induction of anesthesia and during the experiments, the dogs were placed on their right side covered with warming blankets to maintain body temperature within the physiological range for dogs (37–38.5 °C, continuous arterial measurement). Throughout the experiments, no additional fluid replacement was administered to avoid volume effects that could influence tissue perfusion and oxygenation. However, after each blood withdrawal, normal saline was infused three times the sampling volume to maintain blood volume.

Measurements

Gastric mucosal oxygenation

Microvascular oxygen saturation (μHbO2) of the gastric mucosa was continuously assessed by tissue reflectance spectrophotometry (O2C, LEA Medizintechnik, Gießen, Germany), as detailed previously (Frank et al. 1989). Briefly, after induction of anesthesia, the flexible light-guide probe is introduced into the stomach non-traumatically via an orogastric silicone tube. White light (450–1000 nm) is transmitted to the tissue of interest, in this case the gastric mucosa, via the micro-light guide and the reflected light is then analyzed in vivo. The wavelength-dependent absorption of the applied white light can be used to calculate the percentage of oxygenated hemoglobin (Kuchenreuther et al. 1996).

As light is totally absorbed in vessels with a diameter >100 μm, only microvascular oxygenation of nutritive vessels of the mucosa is measured. The biggest fraction of the blood volume is stored in venous vessels; therefore, mainly postcapillary oxygenation is measured that represents the critical partial pressure of oxygen (pO2) for ischemia.

The flexible light-guide probe introduced into the stomach is positioned facing the greater curvature (Scheeren et al. 2002), a site demonstrated to represent the microvascular oxygenation of other gastric and upper intestinal mucosa regions (Temmesfeld-Wollbruck et al. 1998). Online evaluation of the signal quality throughout the experiments allows verification of the correct position of the probe tip. The μHbO2 values reported are the means of the last 5 min (150 spectra, 2 s each) of the respective intervention under steady state conditions. This method allows detection of splanchnic ischemia with similar precision as laser flowmetry (Leung et al. 1987), intra-vital microscopy (Bellamy et al. 1997), or hydrogen gas clearance (Machens et al. 1995). The non-traumatic instrumentation and in particular non-traumatic access to the gastric mucosa allows the determination of mucosal oxygenation in the absence of surgical stress. This is particularly desirable with respect to the marked alterations surgical stress exerts on splanchnic circulation (Gelman 1976). In this situation, reflectance spectrophotometry reliably detects even clinically asymptomatic reductions in mucosal oxygenation (Fournell et al. 2003) and highly correlates with the morphologic severity and extent of gastric mucosal tissue injury (Sato et al. 1986).

Systemic hemodynamics and oxygenation

For continuous measurement of mean arterial pressure, a catheter (PiCCO 4.2 non-US, PULSION Medical Systems, Munich, Germany) was inserted via the left carotid artery into the aorta. This catheter was connected to a pressure transducer (MAP, Gould-Statham pressure transducers P23ID, Elk Grove, IL, USA) and mean arterial pressure was continuously recorded. Via this catheter, blood samples were withdrawn intermittently for measurement of blood gas tensions (arterial CO2 tension, arterial oxygen tension, and arterial oxygen saturation) and acid–base-related variables like pH and bicarbonate (Rapidlab 860, Bayer AG). Blood lactate concentrations could only be obtained in 13 of 15 experiments. Arterial oxygen content (CaO2) and systemic DO2 (DO2=CaO2×cardiac output) were calculated. Cardiac output was determined via transpulmonary thermodilution (PiCCO 4.2) at the end of each intervention, at least every 30 min, as described previously (von Spiegel et al. 1996). Briefly, cold saline was injected intravenously. The temperature of injected saline was measured at the injection site (PiCCO 4.2). The subsequent change in blood temperature measured at the site of the arterial catheter depends on cardiac output that was calculated with the Stewart–Hamilton equation.

Heart rate (HR) was continuously measured by electrocardiography (Powerlab, ADInstruments, Castle Hill, NSW, Australia). All hemodynamic and respiratory variables were recorded on a personal computer after analog to digital conversion (Powerlab, ADInstruments) for later analysis.

Vasopressin receptor blockade

Vasopressin receptor blockade was induced by i.v. infusion of 35 μg/kg [Pmp1,Tyr(Me)2]-Arg8-Vasopressin (Peptide Institute, Inc., 4-1-2 Ina, Minoh-shi Osaka, 562-8686, Japan), a selective V1A receptor antagonist (Howl & Wheatley 1995), as single dose. Complete receptor blockade was confirmed by administration of vasopressin (250 mU, [Arg8]-Vasopressin, Sigma–Aldrich) at the end of each experiment. This dose had no effect on hemodynamic variables at the end of the observation period but increased mean arterial pressure by about 20 mmHg without preceding vasopressin receptor blockade.

Vasopressin plasma level

Vasopressin plasma levels during HC were determined only exemplarily in single experiments because increase in vasopressin plasma levels during HC has been observed before (Philbin et al. 1970, Forsling & Rees 1975, Farber et al. 1982, Rose et al. 1984). Blood samples were collected in EDTA-containing tubes, immediately centrifuged, and stored at −20 °C for later analysis by an external laboratory (Labor Limbach, Heidelberg, Germany). Vasopressin plasma levels during vasopressin receptor blockade are not of informative value and were not determined.

Experimental program

Following the instrumentation, 30 min were allowed to establish steady state conditions and baseline values were recorded before the animals were randomized to the respective protocol (Fig. 1).

Figure 1
Figure 1

Experimental protocol: hypercapnia per se (HC), HC with subsequent vasopressin receptor blockade (HCVB), and vasopressin receptor blockade (VB) during normocapnia in dogs.

Citation: Journal of Endocrinology 217, 1; 10.1530/JOE-12-0526

Hypercapnia (HC)

As control group, effects of HC on μHbO2 were tested without vasopressin receptor blockade. End-tidal CO2 was continuously increased from 35 to 70 mmHg over 30 min via reduction in respiratory frequency as described previously (Schwartges et al. 2008). HC was maintained for 2 h.

Vasopressin receptor blockade during hypercapnia (HCVB)

To analyze the effects of HC during vasopressin V1A receptor blockade (HCVB), HC was induced as in control experiments. After 60 min of HC, vasopressin V1A receptor blockade was initiated as described earlier with an additional observation period of 60 min.

Vasopressin receptor blockade (VB)

Effects of vasopressin V1A receptor blockade alone were tested during normocapnia. After baseline conditions, vasopressin V1A receptor blockade was initiated as described earlier with an additional observation period of 60 min. At the end of each intervention, blood samples were obtained for blood gas analysis.

Statistical analysis

Data for analysis were obtained during the last 5 min of each intervention under steady state conditions. Normal data distribution was assessed in Q-Q plots (IBM SPSS Statistics, International Business Machine Corp.). All data are presented as absolute values of mean (±s.e.m.) for n=5 animals. Differences within the groups and between the groups were tested using an ANOVA for repeated measurements (ANOVA) and a Fisher's PLSD test as post hoc test (StatView V4.1, SAS Institute Inc., Cary, NC, USA); P<0.05 was considered significant.

Results

HC increased μHbO2 from 70±4 to 80±2% after 2 h of HC (Fig. 2). Subsequent vasopressin V1A receptor blockade (HCVB) abolished the HC-induced increase in μHbO2 (80±2 vs 69±2%). By contrast, vasopressin V1A receptor blockade (VB) during normocapnia had no effect on μHbO2 (75±3 vs 71±5%).

Figure 2
Figure 2

Microvascular hemoglobin oxygenation. Effects on microvascular hemoglobin oxygenation (μHbO2) during hypercapnia (HC), HC with subsequent vasopressin receptor blockade (HCVB), and vasopressin receptor blockade during normocapnia (VB) with corresponding baseline values (C) in dogs. Data are presented as absolute values for n=5 dogs, mean±s.e.m., *P<0.05.

Citation: Journal of Endocrinology 217, 1; 10.1530/JOE-12-0526

During HC, systemic DO2 increased from 12±1 to 16±1 ml/kg per min similar to the increase in μHbO2. This increase mainly resulted from increased cardiac output during HC (from 86±6 to 111±8 ml/kg per min). However, while the increase in μHbO2 was abolished during additional vasopressin V1A receptor blockade, DO2 increased both during HC and vasopressin V1A receptor blockade (Fig. 3). The relationship between μHbO2 and DO2 is shown in Fig. 4. HC with intact vasopressin system increases μHbO2 and DO2 in parallel, while during vasopressin V1A receptor blockade HC selectively increased DO2. Cardiac output increased both during HC and vasopressin V1A receptor blockade (from 80±8 to 118±10 ml/kg per min). The increase in cardiac output both under HC and HC with vasopressin V1A receptor blockade is related to a similar increase in stroke volume (from 23±2 and 22±2 to 29±3 and 29±3 ml respectively) without differences between both groups. The additional increase in CO and DO2 in group HCVB could be attributed to the changes in HR, which did not change during HC (104±4 to 109±5 per min) but significantly increased during additional vasopressin V1A receptor blockade (104±3 to 113±4 per min).

Figure 3
Figure 3

Systemic oxygen delivery (DO2). Effects on systemic DO2 during hypercapnia (HC), HC with subsequent vasopressin receptor blockade (HCVB), or vasopressin receptor blockade during normocapnia (VB) with corresponding baseline values (C) in dogs. Data are presented as absolute values for n=5 dogs, mean±s.e.m., *P<0.05.

Citation: Journal of Endocrinology 217, 1; 10.1530/JOE-12-0526

Figure 4
Figure 4

Relationship between mucosal oxygenation and systemic oxygen transport. Relationship between regional mucosal oxygenation (μHbO2) and systemic oxygen transport (DO2) under hypercapnia (HC, group HC) and HC with subsequent vasopressin receptor blockade (HCVB, group HCVB) in dogs. To compensate for individual baseline differences, the respective effects were zero-referenced in this figure.

Citation: Journal of Endocrinology 217, 1; 10.1530/JOE-12-0526

By contrast, during vasopressin V1A receptor blockade under physiological conditions, DO2 remained unchanged according to cardiac output, which did not change either. Likewise, neither HR nor stroke volume changed.

Systemic vascular resistance (SVR) decreased in the HC and HCVB groups; however, SVR tended to be lower in the HCVB group, while vasopressin V1A receptor blockade under normocapnic conditions did not change SVR.

Arterial CO2 tension (PaCO2) was increased in the hypercapnic groups and pH was accordingly reduced. This was not influenced by vasopressin V1A receptor blockade. Blood lactate concentrations remained almost unchanged in all groups. Vasopressin V1A receptor blockade under physiological conditions did not affect blood gas tensions. Further hemodynamic variables are shown in Table 1 and blood gas tensions in Table 2.

Table 1

Microvascular oxygenation and hemodynamic variables in dogs. Effects on systemic vascular resistance (SVR), cardiac output (CO), stroke volume (SV), mean arterial pressure (MAP), and heart rate (HR) during vasopressin blockade during normocapnia (VB) and during hypercapnia (HCVB) as well as hypercapnia per se (HC); data presented as absolute values, n=5, mean±s.e.m.

VariableGroupBaselineEndpoint (±HC±VB)
SVR (mmHg/l per min)HC26±223±2*
HCVB29±322±2*
VB29±227±1
CO (ml/kg per min)HC86±6111±8*
HCVB80±8118±10*
VB81±684±4
SV (ml)HC23±229±3*
HCVB22±229±3*
VB21±222±1
MAP (mmHg)HC62±269±3*
HCVB61±270±2*
VB64±163±1
HR (per min)HC104±4109±5
HCVB104±3113±4*
VB108±2110±4

*P<0.05 vs baseline.

Table 2

Blood gas tensions, pH, bicarbonate, hemoglobin, lactate, and potassium in dogs. Effects of vasopressin receptor blockade on arterial oxygen saturation (SaO2), arterial CO2 tension (PaCO2), arterial oxygen tension (PaO2), pH, HCO3, hemoglobin (Hb), lactate, and potassium (K+) during normocapnia (VB) and during hypercapnia (HCVB) as well as hypercapnia per se (HC); data presented as absolute values, n=5, mean±s.e.m.

VariableGroupBaselineEndpoint (HC±VB)
SaO2 (%)HC98±195±1*
HCVB99±196±1*
VB99±199±1
PaCO2 (mmHg)HC39±167±1*
HCVB39±166±1*
VB38±139±1
PaO2 (mmHg)HC154±5119±6*
HCVB153±4120±3*
VB153±3155±4
pHHC7.33±0.017.15±0.01*
HCVB7.37±0.017.18±0.01*,
VB7.4±0.017.4±0.01
HCO3 (mmol/l)HC20±123±1*
HCVB22±124±1*,
VB23±123±1
Hb (g/100 ml)HC11±111±1*
HCVB12±112±1*
VB12±112±1
Lactate (mmol/l)HC2.1±0.31.2±0.1*
HCVB1.9±0.20.8±0.1*,
VB1.6±0.41.4±0.3
K+ (mmol/l)HC4.0±0.14.3±0.1*
HCVB3.9±0.14.4±0.1*
VB3.9±0.14.1±0.1*

*P<0.05 vs baseline, P<0.05 vs HC group at the same time.

Vasopressin plasma levels

In two representative pilot experiments, vasopressin plasma levels increased from 17 ng/ml in one animal and 13 ng/ml in another one under baseline conditions to 33 and 22 ng/ml after 30 min of HC and was almost doubled after 60 min of HC (34 and 24 ng/ml).

Discussion

Interpretation of the results

The main results from our experiments are that i) vasopressin V1A receptor blockade abolished the increase in gastric mucosal oxygenation during HC. ii) DO2 increased during vasopressin V1A receptor blockade under HC without effect on μHbO2. iii) Vasopressin V1A receptor blockade did not alter systemic or regional microcirculation during normocapnic (physiological) conditions.

The results lead to the following conclusions that will be discussed in detail.

  1. Vasopressin V1A receptors mediate hypercapnic increases in gastric mucosal oxygenation.
  2. HC modulates μHbO2 mainly independently of systemic DO2.
  3. Vasopressin V1A receptors are not involved in regulation of gastrointestinal microvascular oxygenation under physiological conditions.

The vasopressin V1A receptors are responsible for the increase in μHbO2 during HC. This effect might be related to an increase in endogenous vasopressin. In our study, vasopressin plasma levels seemed to increase during HC as measured exemplarily only in two representative experiments without statistical analysis because increase in vasopressin plasma levels during HC is already well known (Philbin et al. 1970, Forsling & Rees 1975, Farber et al. 1982, Rose et al. 1984). Although the relation between increased vasopressin plasma levels and the effect of the V1A receptors might indicate an effect of vasopressin, we cannot exclude the effect of other possible ligands, e.g. oxytocin, on the receptor. However, vasopressin has a 30-fold higher affinity to the receptor than oxytocin (Holmes et al. 2003), indicating a rather minor role of oxytocin. Additionally, one study suggests that vasodilatory effects of the V1 receptors are linked to binding of vasopressin (Evora et al. 1993).

This supports the hypothesis that the increase in gastric mucosal oxygenation via the V1A receptors might be mediated by an increase in vasopressin, although the application of exogenous vasopressin exerts rather negative effects on splanchnic perfusion. However, vasopressin is known to have vasodilatory properties as well (Holmes et al. 2003).

Accordingly, many studies have recently shown that effects of vasopressin are not confined to vasoconstriction in the splanchnic region solely and our study contributes another novel fact to the unexpected new understanding of vasopressin and its receptor (Asfar et al. 2006). While vasopressin is known to jeopardize splanchnic circulation (Knotzer et al. 2005), this effect is abolished in the same model during endotoxemia (Knotzer et al. 2006). Another study using terlipressin has shown even increased hepatic arterial blood flow with unaffected splanchnic DO2 (Asfar et al. 2005). On the other hand, cardiac output decreased in several studies (Knotzer et al. 2005). This was not the case in our study under physiological conditions, probably because we did not apply vasopressin exogenously. Another explanation might be that physiological plasma levels are too low to exert those effects. During HC – and hence higher vasopressin plasma levels – receptor blockade increased CO in our model concordant with the mentioned studies. Thus, once activated, release of vasopressin exerts substantial effects on cardiac output and splanchnic circulation. Therefore, those effects seem to be concentration dependent and vasopressin plasma levels under physiological conditions do not exert substantial effects on cardiac output and splanchnic circulation. Concentration-dependent effects of vasopressin have been observed in human beings as well (Russell 2011). Additionally, effects of vasopressin differ between organs and therefore different splanchnic organs have to be regarded separately (Asfar et al. 2006).

Nevertheless, vasopressin V1A receptor blockade might increase vasopressin binding to the other vasopressin receptors. But other receptors are either not involved in regulation of vascular tone or – in case of endothelial oxytocin receptors and V2 receptors – mediate vasodilation (Holmes et al. 2004). Increased binding to other receptors would thus rather increase μHbO2 during HC instead of abolishing this effect.

The effect of the vasopressin V1A receptor on gastric oxygenation during HC seems to be confined to regional hemodynamic variables as vasopressin receptor blockade during HC solely affects μHbO2 and does not reduce any of the other parameters like cardiac output or systemic oxygen transport that could have been an alternative reason for changes in μHbO2.

An alternative explanation for the increased μHbO2 might be an increased shunting of oxygen to the venular compartment, which represents the biggest fraction of μHbO2. However, in this case, lactate levels might increase as an indicator of insufficient oxygen supply, which could not be observed (Table 2). Thus, the reason for these unexpected results might rather be a vasopressin receptor-mediated redistribution of cardiac output (Asfar et al. 2008) in favor of gastric mucosa during HC. However, this remains speculative as we do not have any direct evidence. During HC and vasopressin V1A receptor blockade, the increased systemic DO2 does not seem to reach the gastric mucosal microcirculation (Fig. 4). Redistribution of cardiac output might be due to different vasopressin receptor expression, which can be decreased, e.g. in models of sepsis. Whether vasopressin receptor expression is decreased during HC as well is so far unknown.

Each dog underwent each protocol in a randomized order and hence served as its own control. Therefore, interindividual differences can be eliminated. This approach allows use of a small group size of n=5 animals.

Thus, the results from this study extend our knowledge from previous studies. Vasopressin is increased during epidural anesthesia to maintain blood pressure (Picker et al. 2001). Additionally, it is increased during anesthesia with high doses (3 MAC) of sevoflurane (Picker et al. 2004). With regard to our results, the role of vasopressin and its receptor seems to be of minor importance under physiological conditions with low vasopressin plasma levels, but it is necessary, e.g. to maintain blood pressure, under a variety of pathological conditions. According to our results, HC is one of those pathological conditions with major importance of vasopressin that exerts so far unknown properties.

Clinical impact

Our results indicate one new possible mechanism of hypercapnic improvement of microcirculatory oxygenation and demonstrate for the first time a new role of the V1A receptors in regulating splanchnic oxygenation apart from vasoconstriction. This is of particular interest as permissive HC is widely used in the intensive care unit especially in critically ill patients, e.g. sepsis-associated acute respiratory distress syndrome (ARDS) and exogenous vasopressin remains a possible therapeutic option for severe hemodynamic instability. Thus, it is important to know about the interaction of HC with vasopressin and about the effects on splanchnic oxygenation, which is vital for these patients in particular. However, especially in these patients, vasopressin maintains systemic blood pressure at the expense of splanchnic microcirculation, which is normally impaired due to vasopressin (Boerma et al. 2005). Still, despite clinical trials, there is no definite answer to whether vasopressin affects mortality.

The effect of HC on μHbO2 can still be observed during hemorrhagic shock (Schwartges et al. 2010), a situation that leads to extended release of vasopressin with subsequent binding to the vasopressin V1A receptors (Fujisawa et al. 1994). Whether this extended release of vasopressin is involved in increasing μHbO2 during hemorrhage has to be studied yet but might lead to further interesting results of clinical importance.

Summarizing recently published studies, it still seems difficult to draw a definite conclusion on the effects of vasopressin on splanchnic hemodynamics (Asfar et al. 2008). While many studies analyzed effects of exogenous vasopressin with diverse results, our study helps to understand physiological effects of vasopressin V1A receptors on splanchnic hemodynamics during physiological and hypercapnic conditions. In addition, most studies focused on macro- and microcirculatory hemodynamic variables, while only some studies addressed local oxygenation (Asfar et al. 2008). Thus, our results provide first evidence of the vasopressin V1A receptors to increase regional oxygenation during HC.

Conclusions

Vasopressin V1A receptor blockade during HC suppressed the HC-induced increase in μHbO2. Thus, in contrast to its generally vasoconstrictive properties, the vasopressin V1A receptors seem to mediate hypercapnic increase in gastric mucosal oxygenation. This increase in μHbO2 during HC is independent of systemic oxygen transport.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Acknowledgements

The authors thank Dr Pablo Verde (Head of Biostatistics, Coordinating Centre for Clinical Trials, University Hospital Duesseldorf) for guidance and review of statistical analysis.

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  • BoermaECvan der VoortPHInceC2005Sublingual microcirculatory flow is impaired by the vasopressin-analogue terlipressin in a patient with catecholamine-resistant septic shock. Acta Anaesthesiologica Scandinavica4913871390. (doi:10.1111/j.1399-6576.2005.00752.x)

    • Search Google Scholar
    • Export Citation
  • ChenLWEganLLiZWGretenFRKagnoffMFKarinM2003The two faces of IKK and NF-kappaB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia–reperfusion. Nature Medicine9575581. (doi:10.1038/nm849)

    • Search Google Scholar
    • Export Citation
  • DeitchEAForsytheRAnjariaDLivingstonDHLuQXuDZRedlH2004The role of lymph factors in lung injury, bone marrow suppression, and endothelial cell dysfunction in a primate model of trauma-hemorrhagic shock. Shock22221228. (doi:10.1097/01.shk.0000133592.55400.83)

    • Search Google Scholar
    • Export Citation
  • EvoraPRPearsonPJSchaffHV1993Arginine vasopressin induces endothelium-dependent vasodilatation of the pulmonary artery. V1-receptor-mediated production of nitric oxide. Chest10312411245. (doi:10.1378/chest.103.4.1241)

    • Search Google Scholar
    • Export Citation
  • FarberMORobertsLRWeinbergerMHRobertsonGLFinebergNSManfrediF1982Abnormalities of sodium and H2O handling in chronic obstructive lung disease. Archives of Internal Medicine14213261330. (doi:10.1001/archinte.1982.00340200086019)

    • Search Google Scholar
    • Export Citation
  • ForslingMLReesM1975Proceedings: effects of hypoxia and hypercapnia on plasma vasopressin concentration. Journal of Endocrinology6762P63P.

    • Search Google Scholar
    • Export Citation
  • FournellASchwarteLAKindgen-MillesDMullerEScheerenTW2003Assessment of microvascular oxygen saturation in gastric mucosa in volunteers breathing continuous positive airway pressure. Critical Care Medicine3117051710. (doi:10.1097/01.CCM.0000063281.47070.53)

    • Search Google Scholar
    • Export Citation
  • FrankKHKesslerMAppelbaumKDummlerW1989The Erlangen micro-lightguide spectrophotometer EMPHO I. Physics in Medicine and Biology3418831900. (doi:10.1088/0031-9155/34/12/011)

    • Search Google Scholar
    • Export Citation
  • FujisawaYMiyatakeAHayashidaYAkiYKimuraSTamakiTAbeY1994Role of vasopressin on cardiovascular changes during hemorrhage in conscious rats. American Journal of Physiology267H1713H1718.

    • Search Google Scholar
    • Export Citation
  • GelmanSI1976Disturbances in hepatic blood flow during anesthesia and surgery. Archives of Surgery111881883. (doi:10.1001/archsurg.1976.01360260049012)

    • Search Google Scholar
    • Export Citation
  • HolmesCLLandryDWGrantonJT2003Science review: vasopressin and the cardiovascular system part 1 – receptor physiology. Critical Care7427434. (doi:10.1186/cc2337)

    • Search Google Scholar
    • Export Citation
  • HolmesCLLandryDWGrantonJT2004Science review: vasopressin and the cardiovascular system part 2 – clinical physiology. Critical Care81523. (doi:10.1186/cc2338)

    • Search Google Scholar
    • Export Citation
  • HowlJWheatleyM1995Molecular pharmacology of V1a vasopressin receptors. General Pharmacology2611431152. (doi:10.1016/0306-3623(95)00016-T)

    • Search Google Scholar
    • Export Citation
  • JakobSMTakalaJ2000Gut perfusion in the critically ill. Intensive Care Medicine26813815. (doi:10.1007/s001340051253)

  • KnotzerHPajkWMaierSLadurnerRKleinsasserAWenzelVDunserMWUlmerHHasibederWR2005Arginine vasopressin reduces intestinal oxygen supply and mucosal tissue oxygen tension. American Journal of Physiology. Heart and Circulatory Physiology289H168H173. (doi:10.1152/ajpheart.01235.2004)

    • Search Google Scholar
    • Export Citation
  • KnotzerHMaierSDunserMWHasibederWRHausdorferHBrandnerJTorgersenCUlmerHFrieseneckerBIannettiC2006Arginine vasopressin does not alter mucosal tissue oxygen tension and oxygen supply in an acute endotoxemic pig model. Intensive Care Medicine32170174. (doi:10.1007/s00134-005-2858-z)

    • Search Google Scholar
    • Export Citation
  • KuchenreutherSAdlerJSchutzWEichelbronnerOGeorgieffM1996The Erlanger Microlightguide Photometer: a new concept for monitoring intracapillary oxygen supply of tissue – first results and a review of the physiological basis. Journal of Clinical Monitoring12211224. (doi:10.1007/BF00857642)

    • Search Google Scholar
    • Export Citation
  • LeungFWMorishitaTLivingstonEHReedyTGuthPH1987Reflectance spectrophotometry for the assessment of gastroduodenal mucosal perfusion. American Journal of Physiology252G797G804.

    • Search Google Scholar
    • Export Citation
  • MachensHGPalluaNMailaenderPPaselJFrankKHReimerRBergerA1995Measurements of tissue blood flow by the hydrogen clearance technique (HCT): a comparative study including laser Doppler flowmetry (LDF) and the Erlangen micro-lightguide spectrophotometer (EMPHO). Microsurgery16808817. (doi:10.1002/micr.1920161208)

    • Search Google Scholar
    • Export Citation
  • PhilbinDMBaratzRAPattersonRW1970The effect of carbon dioxide on plasma antidiuretic hormone levels during intermittent positive-pressure breathing. Anesthesiology33345349. (doi:10.1097/00000542-197009000-00016)

    • Search Google Scholar
    • Export Citation
  • PickerOSchindlerAWScheerenTW2001Endogenous endothelin and vasopressin support blood pressure during epidural anesthesia in conscious dogs. Anesthesia and Analgesia9315801586.table of contents (doi:10.1097/00000539-200112000-00054)

    • Search Google Scholar
    • Export Citation
  • PickerOSchwarteLARothHJGreveJScheerenTW2004Comparison of the role of endothelin, vasopressin and angiotensin in arterial pressure regulation during sevoflurane anaesthesia in dogs. British Journal of Anaesthesia92102108. (doi:10.1093/bja/aeh025)

    • Search Google Scholar
    • Export Citation
  • RoseCEJrAndersonRJCareyRM1984Antidiuresis and vasopressin release with hypoxemia and hypercapnia in conscious dogs. American Journal of Physiology247R127R134.

    • Search Google Scholar
    • Export Citation
  • RussellJA2011Bench-to-bedside review: vasopressin in the management of septic shock. Critical Care15226. (doi:10.1186/cc8224)

  • SatoNKawanoSKamadaTTakedaM1986Hemodynamics of the gastric mucosa and gastric ulceration in rats and in patients with gastric ulcer. Digestive Diseases and Sciences3135S41S. (doi:10.1007/BF01309321)

    • Search Google Scholar
    • Export Citation
  • ScheerenTWSchwarteLALoerSAPickerOFournellA2002Dopexamine but not dopamine increases gastric mucosal oxygenation during mechanical ventilation in dogs. Critical Care Medicine30881887. (doi:10.1097/00003246-200204000-00028)

    • Search Google Scholar
    • Export Citation
  • SchwartgesISchwarteLAFournellAScheerenTWPickerO2008Hypercapnia induces a concentration-dependent increase in gastric mucosal oxygenation in dogs. Intensive Care Medicine3418981906. (doi:10.1007/s00134-008-1183-8)

    • Search Google Scholar
    • Export Citation
  • SchwartgesIPickerOBeckCScheerenTWSchwarteLA2010Hypercapnic acidosis preserves gastric mucosal microvascular oxygen saturation in a canine model of hemorrhage. Shock34636642. (doi:10.1097/SHK.0b013e3181e68422)

    • Search Google Scholar
    • Export Citation
  • von SpiegelTWietaschGBurschJHoeftA1996Cardiac output determination with transpulmonary thermodilution. An alternative to pulmonary catheterization?Der Anaesthesist4510451050. (doi:10.1007/s001010050338)

    • Search Google Scholar
    • Export Citation
  • Temmesfeld-WollbruckBSzalayAMayerKOlschewskiHSeegerWGrimmingerF1998Abnormalities of gastric mucosal oxygenation in septic shock: partial responsiveness to dopexamine. American Journal of Respiratory and Critical Care Medicine15715861592.

    • Search Google Scholar
    • Export Citation
  • TrzeciakSMcCoyJVPhillip DellingerRArnoldRCRizzutoMAbateNLShapiroNIParrilloJEHollenbergSM2008Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Medicine3422102217. (doi:10.1007/s00134-008-1193-6)

    • Search Google Scholar
    • Export Citation

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    Experimental protocol: hypercapnia per se (HC), HC with subsequent vasopressin receptor blockade (HCVB), and vasopressin receptor blockade (VB) during normocapnia in dogs.

  • View in gallery

    Microvascular hemoglobin oxygenation. Effects on microvascular hemoglobin oxygenation (μHbO2) during hypercapnia (HC), HC with subsequent vasopressin receptor blockade (HCVB), and vasopressin receptor blockade during normocapnia (VB) with corresponding baseline values (C) in dogs. Data are presented as absolute values for n=5 dogs, mean±s.e.m., *P<0.05.

  • View in gallery

    Systemic oxygen delivery (DO2). Effects on systemic DO2 during hypercapnia (HC), HC with subsequent vasopressin receptor blockade (HCVB), or vasopressin receptor blockade during normocapnia (VB) with corresponding baseline values (C) in dogs. Data are presented as absolute values for n=5 dogs, mean±s.e.m., *P<0.05.

  • View in gallery

    Relationship between mucosal oxygenation and systemic oxygen transport. Relationship between regional mucosal oxygenation (μHbO2) and systemic oxygen transport (DO2) under hypercapnia (HC, group HC) and HC with subsequent vasopressin receptor blockade (HCVB, group HCVB) in dogs. To compensate for individual baseline differences, the respective effects were zero-referenced in this figure.

  • AsfarPPierrotMVealNMoalFObertiFCroquetVDouayOGalloisYSaumetJLAlquierP2003Low-dose terlipressin improves systemic and splanchnic hemodynamics in fluid-challenged endotoxic rats. Critical Care Medicine31215220. (doi:10.1097/00003246-200301000-00033)

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    • Export Citation
  • AsfarPHauserBIvanyiZEhrmannUKickJAlbiciniMVogtJWachterUBrucknerUBRadermacherP2005Low-dose terlipressin during long-term hyperdynamic porcine endotoxemia: effects on hepatosplanchnic perfusion, oxygen exchange, and metabolism. Critical Care Medicine33373380. (doi:10.1097/01.CCM.0000152253.45901.FB)

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    • Export Citation
  • AsfarPRadermacherPHauserB2006Vasopressin and splanchnic blood flow: vasoconstriction does not equal vasoconstriction in every organ. Intensive Care Medicine322123. (doi:10.1007/s00134-005-2867-y)

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    • Export Citation
  • AsfarPBrachtHRadermacherP2008Impact of vasopressin analogues on the gut mucosal microcirculation. Best Practice & Research. Clinical Anaesthesiology22351358. (doi:10.1016/j.bpa.2008.02.009)

    • Search Google Scholar
    • Export Citation
  • BellamyMCMullaneDO'BeirneHAYoungYPollardSGLodgeJP1997Dopexamine and microcirculatory flow in transplanted small bowel: the Leeds experience. Transplantation Proceedings2918471849. (doi:10.1016/S0041-1345(97)00093-6)

    • Search Google Scholar
    • Export Citation
  • BoermaECvan der VoortPHInceC2005Sublingual microcirculatory flow is impaired by the vasopressin-analogue terlipressin in a patient with catecholamine-resistant septic shock. Acta Anaesthesiologica Scandinavica4913871390. (doi:10.1111/j.1399-6576.2005.00752.x)

    • Search Google Scholar
    • Export Citation
  • ChenLWEganLLiZWGretenFRKagnoffMFKarinM2003The two faces of IKK and NF-kappaB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia–reperfusion. Nature Medicine9575581. (doi:10.1038/nm849)

    • Search Google Scholar
    • Export Citation
  • DeitchEAForsytheRAnjariaDLivingstonDHLuQXuDZRedlH2004The role of lymph factors in lung injury, bone marrow suppression, and endothelial cell dysfunction in a primate model of trauma-hemorrhagic shock. Shock22221228. (doi:10.1097/01.shk.0000133592.55400.83)

    • Search Google Scholar
    • Export Citation
  • EvoraPRPearsonPJSchaffHV1993Arginine vasopressin induces endothelium-dependent vasodilatation of the pulmonary artery. V1-receptor-mediated production of nitric oxide. Chest10312411245. (doi:10.1378/chest.103.4.1241)

    • Search Google Scholar
    • Export Citation
  • FarberMORobertsLRWeinbergerMHRobertsonGLFinebergNSManfrediF1982Abnormalities of sodium and H2O handling in chronic obstructive lung disease. Archives of Internal Medicine14213261330. (doi:10.1001/archinte.1982.00340200086019)

    • Search Google Scholar
    • Export Citation
  • ForslingMLReesM1975Proceedings: effects of hypoxia and hypercapnia on plasma vasopressin concentration. Journal of Endocrinology6762P63P.

    • Search Google Scholar
    • Export Citation
  • FournellASchwarteLAKindgen-MillesDMullerEScheerenTW2003Assessment of microvascular oxygen saturation in gastric mucosa in volunteers breathing continuous positive airway pressure. Critical Care Medicine3117051710. (doi:10.1097/01.CCM.0000063281.47070.53)

    • Search Google Scholar
    • Export Citation
  • FrankKHKesslerMAppelbaumKDummlerW1989The Erlangen micro-lightguide spectrophotometer EMPHO I. Physics in Medicine and Biology3418831900. (doi:10.1088/0031-9155/34/12/011)

    • Search Google Scholar
    • Export Citation
  • FujisawaYMiyatakeAHayashidaYAkiYKimuraSTamakiTAbeY1994Role of vasopressin on cardiovascular changes during hemorrhage in conscious rats. American Journal of Physiology267H1713H1718.

    • Search Google Scholar
    • Export Citation
  • GelmanSI1976Disturbances in hepatic blood flow during anesthesia and surgery. Archives of Surgery111881883. (doi:10.1001/archsurg.1976.01360260049012)

    • Search Google Scholar
    • Export Citation
  • HolmesCLLandryDWGrantonJT2003Science review: vasopressin and the cardiovascular system part 1 – receptor physiology. Critical Care7427434. (doi:10.1186/cc2337)

    • Search Google Scholar
    • Export Citation
  • HolmesCLLandryDWGrantonJT2004Science review: vasopressin and the cardiovascular system part 2 – clinical physiology. Critical Care81523. (doi:10.1186/cc2338)

    • Search Google Scholar
    • Export Citation
  • HowlJWheatleyM1995Molecular pharmacology of V1a vasopressin receptors. General Pharmacology2611431152. (doi:10.1016/0306-3623(95)00016-T)

    • Search Google Scholar
    • Export Citation
  • JakobSMTakalaJ2000Gut perfusion in the critically ill. Intensive Care Medicine26813815. (doi:10.1007/s001340051253)

  • KnotzerHPajkWMaierSLadurnerRKleinsasserAWenzelVDunserMWUlmerHHasibederWR2005Arginine vasopressin reduces intestinal oxygen supply and mucosal tissue oxygen tension. American Journal of Physiology. Heart and Circulatory Physiology289H168H173. (doi:10.1152/ajpheart.01235.2004)

    • Search Google Scholar
    • Export Citation
  • KnotzerHMaierSDunserMWHasibederWRHausdorferHBrandnerJTorgersenCUlmerHFrieseneckerBIannettiC2006Arginine vasopressin does not alter mucosal tissue oxygen tension and oxygen supply in an acute endotoxemic pig model. Intensive Care Medicine32170174. (doi:10.1007/s00134-005-2858-z)

    • Search Google Scholar
    • Export Citation
  • KuchenreutherSAdlerJSchutzWEichelbronnerOGeorgieffM1996The Erlanger Microlightguide Photometer: a new concept for monitoring intracapillary oxygen supply of tissue – first results and a review of the physiological basis. Journal of Clinical Monitoring12211224. (doi:10.1007/BF00857642)

    • Search Google Scholar
    • Export Citation
  • LeungFWMorishitaTLivingstonEHReedyTGuthPH1987Reflectance spectrophotometry for the assessment of gastroduodenal mucosal perfusion. American Journal of Physiology252G797G804.

    • Search Google Scholar
    • Export Citation
  • MachensHGPalluaNMailaenderPPaselJFrankKHReimerRBergerA1995Measurements of tissue blood flow by the hydrogen clearance technique (HCT): a comparative study including laser Doppler flowmetry (LDF) and the Erlangen micro-lightguide spectrophotometer (EMPHO). Microsurgery16808817. (doi:10.1002/micr.1920161208)

    • Search Google Scholar
    • Export Citation
  • PhilbinDMBaratzRAPattersonRW1970The effect of carbon dioxide on plasma antidiuretic hormone levels during intermittent positive-pressure breathing. Anesthesiology33345349. (doi:10.1097/00000542-197009000-00016)

    • Search Google Scholar
    • Export Citation
  • PickerOSchindlerAWScheerenTW2001Endogenous endothelin and vasopressin support blood pressure during epidural anesthesia in conscious dogs. Anesthesia and Analgesia9315801586.table of contents (doi:10.1097/00000539-200112000-00054)

    • Search Google Scholar
    • Export Citation
  • PickerOSchwarteLARothHJGreveJScheerenTW2004Comparison of the role of endothelin, vasopressin and angiotensin in arterial pressure regulation during sevoflurane anaesthesia in dogs. British Journal of Anaesthesia92102108. (doi:10.1093/bja/aeh025)

    • Search Google Scholar
    • Export Citation
  • RoseCEJrAndersonRJCareyRM1984Antidiuresis and vasopressin release with hypoxemia and hypercapnia in conscious dogs. American Journal of Physiology247R127R134.

    • Search Google Scholar
    • Export Citation
  • RussellJA2011Bench-to-bedside review: vasopressin in the management of septic shock. Critical Care15226. (doi:10.1186/cc8224)

  • SatoNKawanoSKamadaTTakedaM1986Hemodynamics of the gastric mucosa and gastric ulceration in rats and in patients with gastric ulcer. Digestive Diseases and Sciences3135S41S. (doi:10.1007/BF01309321)

    • Search Google Scholar
    • Export Citation
  • ScheerenTWSchwarteLALoerSAPickerOFournellA2002Dopexamine but not dopamine increases gastric mucosal oxygenation during mechanical ventilation in dogs. Critical Care Medicine30881887. (doi:10.1097/00003246-200204000-00028)

    • Search Google Scholar
    • Export Citation
  • SchwartgesISchwarteLAFournellAScheerenTWPickerO2008Hypercapnia induces a concentration-dependent increase in gastric mucosal oxygenation in dogs. Intensive Care Medicine3418981906. (doi:10.1007/s00134-008-1183-8)

    • Search Google Scholar
    • Export Citation
  • SchwartgesIPickerOBeckCScheerenTWSchwarteLA2010Hypercapnic acidosis preserves gastric mucosal microvascular oxygen saturation in a canine model of hemorrhage. Shock34636642. (doi:10.1097/SHK.0b013e3181e68422)

    • Search Google Scholar
    • Export Citation
  • von SpiegelTWietaschGBurschJHoeftA1996Cardiac output determination with transpulmonary thermodilution. An alternative to pulmonary catheterization?Der Anaesthesist4510451050. (doi:10.1007/s001010050338)

    • Search Google Scholar
    • Export Citation
  • Temmesfeld-WollbruckBSzalayAMayerKOlschewskiHSeegerWGrimmingerF1998Abnormalities of gastric mucosal oxygenation in septic shock: partial responsiveness to dopexamine. American Journal of Respiratory and Critical Care Medicine15715861592.

    • Search Google Scholar
    • Export Citation
  • TrzeciakSMcCoyJVPhillip DellingerRArnoldRCRizzutoMAbateNLShapiroNIParrilloJEHollenbergSM2008Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Medicine3422102217. (doi:10.1007/s00134-008-1193-6)

    • Search Google Scholar
    • Export Citation