At a consensus conference in 2004, the World Society of the Abdominal Compartment Syndrome defined intra-abdominal hypertension (IAH) as an intra-abdominal pressure (IAP) of 12 mmHg or greater and abdominal compartment syndrome (ACS) as an IAP of 20 mmHg or greater with a previously not apparent single or multiple organ dysfunction (1).
According to the hypothesis of the two-hit model, IAH induced by a first hit provokes the release of proinflammatory cytokines, which induces a systemic inflammatory response (second hit) triggering fatal multiple organ failure (MOF) (2, 3). In line with this, traumatized patients with subsequent ACS after damage-control surgery develop MOF more often than do patients without ACS (32% vs. 8%) (4). Furthermore, mortality reaches 43% in patients with ACS compared with 12% in patients without ACS. Most impressively, mortality is 85% in patients with ACS and subsequent MOF (4).
Once organ dysfunction is triggered by the second hit, it is not connected to the actual pressure level in the abdomen anymore. Although immediate improvement or even normalization of organ dysfunction upon surgical decompression is seen in patients with full-blown ACS, the development to MOF may not be prevented. Thus, for a successful treatment of ACS, the decrease in IAH must take place before the crucial cytokine release has occurred.
In the presence of IAH, pressure monitoring alone may not be sufficient to guide the modality and timing of therapy. Additional functional monitoring such as microdialysis may refine diagnosis and monitoring of critical IAH to guide a timely decompression (5). Improved monitoring may also decrease the number of unnecessary abdominal decompressions with subsequent temporary abdominal closure.
Microdialysis is an established technology to monitor energy metabolism in the experimental and clinical setting. This technique allows a continuous or periodic measurement of extracellular metabolites of virtually any tissue. Bedside monitoring with this technique is well established in clinical practice. Accordingly, it has been used in severe brain injury (6), liver transplantation (7), plastic surgery (8), and cardiovascular surgery (9). Moreover, intestinal ischemia can successfully be monitored by microdialysis (10, 11). Thereby, glycerol has evolved as a good marker to monitor cell membrane damage, whereas an increased lactate/pyruvate (LP) ratio indicates ischemia (12–15).
In a previous study, we could show that the compartment pressure of the rectus sheath was similar to the IAP in rats (16). Recently, CRPS was further evaluated in a pig model as an alternative to indirect IAP measurement techniques such as intravesical pressure (IVP) measurement (17). Introducing microdialysis with this new concept, we could demonstrate in a rat model that microdialysis of the rectus abdominis muscle (RAM) shows an early and more pronounced increase in lactate, LP ratio, and glycerol compared with intra-abdominal organs during IAH (5). In the present study, we analyzed now, whether these interesting findings are also valid in a porcine model, which may be more appropriate to simulate a clinically relevant setting than a rodent model. For this purpose, we evaluated microdialysis at a normal physiological IAP as well as in the situation of critical IAH (IAP = 20 mmHg) and full-blown ACS at 30 mmHg.
MATERIALS AND METHODS
All experiments were performed in accordance with the German legislation on protection of animals and the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Thirty domestic male pigs (Swabian Hall strain; mean body weight, 34 ± 3 kg) were used for the study. The animals were kept at 21°C ± 1°C with daylight and free access to tap water and daily standard chow. After an acclimation period of 8 days, the animals were kept fasting overnight with free access to water.
Anesthesia and surgical preparation
After an intramuscular injection of ketamine hydrochloride (30 mg/kg, Ketavet; Pfizer, Karlsruhe, Germany), xylazine hydrochloride (2.5 mg/kg, Rompun; Bayer Schering, Leverkusen, Germany), and 1 mg atropine (Braun, Melsungen, Germany) for premedication, general anesthesia was induced by i.v. injection of etomidate (1 mg/kg, Etomidat-Lipuro; Braun). Analgosedation was maintained by continuous i.v. administration of thiopental sodium (Trapanal; ALTANA Pharma Deutschland GmbH, Konstanz, Germany) and piritramide (Dipidolor; Janssen-Cilag, Neuss, Germany). Oral intubation was performed (7.5 ET tube; Portex, Hythe, UK), and the animals were mechanically ventilated (Evita; Dräger, Lübeck, Germany), volume cycled with a tidal volume of 10 mL/kg, an inspiratory oxygen concentration of 30%, and a positive end-expiratory pressure of 2 cmH2O. These ventilation settings were kept unchanged throughout the experiment. The respiratory rate was adapted between 10 and 15 breaths/min according to arterial blood gas analysis to keep PaCO2 constant between 30 and 45 mmHg. O2 saturation was monitored by pulse oximetry. A triple-lumen 7F central line in the left jugular vein (JV) served for fluid replacement (Ringer’s lactate [10 mL · kg-1 · h-;1]), administration of i.v. medication, and monitoring of mean central venous pressure (CVP).
Femoral vein pressure (FVP) and IVP measurements were performed as described by Gudmundsson et al. (18). The bladder catheter was placed by a suprapubic mini–midline laparotomy. For IVP measurement, the bladder was primed with 10 mL of physiological saline solution (18). A midline laparotomy was performed. The superior mesenteric artery (SMA) was identified cephalad of the renal vein, and a 4-mm ultrasound flow probe (small animal blood flow meter, T206; Transonic System Inc, Ithaca, NY) was placed without restriction of the vessel approximately 10 mm distally to its root. The portal vein (PV) was identified in the hepatoduodenal ligament, and a small inflowing gastroduodenal vein was cannulated with a Portex catheter, with its tip being placed in the PV (Portex fine bore, polyethene tubing, internal diameter 0.58 mm/outer diameter 0.96 mm; FA Smiths Medial ASD Inc, Keene, NH).
Microdialysis catheters (CMA/20; CMA Microdialysis AB, Stockholm, Sweden) were carefully placed in the parenchyma of the liver and the right kidney, as well as in the ventral aspect of the gastric wall and underneath the serosal layer of the jejunum. Another catheter was placed into the RAM about 50 mm caudal to the xiphoid process and 20 mm lateral to the midline. This catheter was placed through a small incision of the anterior rectus sheath. The last microdialysis catheter, which served as a distant control, was placed within the substance of the anterior cervical muscles.
A laparoscopy port (Endopath 512 mm; Ethicon Endosurgery Inc, Cincinnati, Ohio) was inserted at the upper end of the laparotomy. Here, the fascia was closed in a purse string manner around the port to seal the peritoneal cavity. The remaining laparotomy incision was closed with a running suture of the fascia.
After surgical preparation, the animals were allowed to stabilize for 30 min. The midaxillary line served as zero reference for IAP measurement. The IAP was measured before CO2 insufflation (baseline). Either IAP was then kept at the physiological pressure (sham group), or it was increased to 20 mmHg (IAH20 group) and 30 mmHg (IAH30 group) by CO2 insufflation, respectively. The increase in IAP was established by an automatically controlled insufflator (Electronic Laparoflator 264300 20; Karl Storz GmbH & Co, Tuttlingen, Germany). The pressure readings from the insufflator served as direct IAP measurement values. Intra-abdominal pressure was then kept at the designated levels (either 20 or 30 mmHg) over 6 h.
Hemodynamic and pulmonary parameters such as mean arterial pressure (MAP), systolic and diastolic blood pressure, CVP, FVP, heart rate (HR), blood flow of the SMA, and peak inspiratory pressure (PIP) were recorded at baseline conditions and measured every 60 min thereafter throughout the entire experiment. Abdominal perfusion pressure (APP) was calculated as APP = MAP − IAP. Arterial blood gas analysis, urinary output (UOP), and body core temperature were also recorded hourly.
The interstitial concentrations of lactate, pyruvate, and glycerol were measured as previously described in detail (19). For our experiments, we used microprobes (CMA/20; CMA Microdialysis AB) carrying a microcell, which was perfused by a microinjection pump (CMA/100; CMA Microdialysis AB). The membrane of the microcell had a molecular cutoff of 20,000 Da. An outlet tube was connected to a fraction collector (CMA/200 F; CMA Microdialysis AB). To reduce fluid loss, we used a colloid (albumin 3%) for continuous perfusion of the microcell (20, 21). The flow rate was set to 0.8 μL/min for the entire experiment. Microdialysis samples were collected in 30-min fractions for baseline measurements followed by 60-min fractions for the 6-h observation period.
Repetitive blood samples from the different venous inflow regions were taken every 60 min, i.e., femoral vein (FV) for lower extremity, PV blood for intestine, and JV as control. Lactate levels were measured under baseline conditions and every 60 min during the experiment. Interleukin (IL) 6 concentrations were measured at baseline as well as after 3 and 6 h of IAH. Samples from the JV were taken at baseline and at the end of the experiment for platelet counts and the determination of serum bilirubin and creatinine according to standard methods. At the end of the experiment, the animals were killed with an overdose of thiopental sodium.
In the clinical setting, organ failure may be defined using the Sepsis-Related Organ Failure Assessment (SOFA) score (22). This score ranges for each organ (respiratory system, nervous system, cardiovascular system, liver, coagulation, renal system) from 0 (normal) to 4 (most abnormal). According to Malbrain et al. (23), organ failure was defined as a SOFA organ subscore of 3 or greater. However, we are well aware that the use of this clinical score may not be used in a large animal model without restrictions. Subclinical organ dysfunction was defined as detection of anaerobic metabolism or cell membrane damage by microdialysis with a SOFA organ subscore of 2 or less in the presence of IAH. The subscore for the nervous system was not applied.
All data are given as mean (SD). After proving the assumption of normality and equal variance, differences between the different study groups (sham, IAH20, IAH30) at corresponding time points were compared using one-way analysis of variance with Bonferroni post hoc test. One-way analysis of variance for repeated measures with Bonferroni post hoc test was used to compare different time points with baseline conditions within individual groups. When only one measurement was performed during the experiment, such as for certain blood tests, we used the paired t test to compare those values with baseline conditions within individual groups. Statistics were performed using the SigmaStat software package (Jandel, San Raphael, Calif). P < 0.05 was considered statistically significant.
In sham animals, cardiovascular parameters such as MAP, HR, CVP, FVP, and APP remained at baseline levels throughout the experiment (Table 1). In contrast to the IAH20 group, there was a continuous decrease in MAP in the IAH30 group. This decrease was consistent with a SOFA subscore of 3, thus fulfilling the criteria for organ failure. Central venous pressure significantly increased in both IAH20 and IAH30 animals compared with baseline. Femoral vein pressure was significantly higher in the IAH20 and IAH30 groups compared with CVP throughout the experiment (Table 1).
Of interest, APP, which is a clinically relevant and a prognostic parameter in the situation of IAH (24), dropped significantly in both IAH groups compared with baseline conditions (Table 1). However, APP did not fall below 50 mmHg in the IAH20 group, which is considered a resuscitation end point and predictor for patient survival in the clinical setting (24). In the IAH30 group, APP already fell below this value shortly after induction of IAH and further declined continuously throughout the experiment, reaching levels below 40 mmHg after 5 h of IAH.
Impaired abdominal circulation was also demonstrated by the results recorded from the SMA flow measurement probe (Table 1). In the sham group, the flow of the SMA increased up to levels of 120% of baseline levels. In the IAH20 group, the flow was found reduced with values around 80% of baseline. In contrast, in the IAH30 group, the flow decreased markedly throughout the experiment, falling below 50% after 6 h (Table 1).
The hourly measured UOP remained constant in the sham group. In the IAH20 group, UOP was significantly reduced after 2 to 6 h compared with baseline. However, UOP remained above the threshold of 1 mL · kg-1 · h-1 throughout the experiment (Table 1). In contrast, UOP dropped significantly and below this threshold in IAH30 animals already 1 h after induction of IAH. Serum creatinine did not show any inner or intergroup differences (data not shown). Thus, organ dysfunction (SOFA subscore of 3) was evident only in the IAH30 group because of the decreased UOP.
Pulmonary system and arterial blood gases
In the presence of IAH, PIP was significantly increased when compared with sham animals (Table 1). Arterial blood gas analysis demonstrated the development of a mixed respiratory and metabolic acidosis in the groups of IAH20 and IAH30 animals (Table 1), whereby the acidosis was more pronounced in the IAH30 group. Mean PaO2 remained constantly above 100 mmHg, and mean SO2 did not drop below 93% in all groups during the entire experiment (data not shown). No organ dysfunction greater than 1 was observed according to the SOFA organ subscore in any of the study groups.
Coagulation and liver
We did not find any inner or intergroup statistical differences between the study groups regarding serum bilirubin concentration and platelet counts (data not shown).
Venous lactate and IL-6 levels
The lactate concentration was significantly higher in the superficial femoral vein (SFV) throughout the entire experiment in the IAH30 group when compared with baseline values and with the sham group (Fig. 1A). Noteworthy, we found a first peak after 1 h of IAH, followed by a slight recovery and a rather steep increase after 4 h of IAH. In the IAH20 group, a similar course of the lactate concentration was observed during the first 3 h of the experiment. However, in contrast to the IAH30 group, the recovery continued in the second half without recurrent increase. In the PV, no difference was evident between sham animals and the two IAH groups (Fig. 1B). In the JV, the lactate concentration was significantly increased only in the IAH30 group at 5 and 6 h after induction of IAH when compared with the IAH20 animals (Fig. 1C).
The comparison of IL-6 levels from the SFV between the different study groups showed a significant elevation in the IAH30 group after 3 and 6 h of IAH compared with baseline conditions (Fig. 2A). In the other two groups, IL-6 levels remained constant throughout the experiment. Similar results were found for the IL-6 measurements in the PV and the JV (Fig. 2, B and C).
Microdialysis of the anterior cervical muscles demonstrated that IAH did not affect concentrations of lactate, LP ratio, and glycerol in this distant control tissue (Fig. 3A, 4A, and 5A).
Analysis of lactate concentrations in the RAM and in all investigated intra-abdominal organs except for the jejunum did not show any relevant alterations compared with baseline and between the study groups (Fig. 3, B–E). The jejunal wall demonstrated a significant difference of the tissue lactate concentration in the IAH30 group compared with sham animals starting at 2 h after induction of IAH and lasting throughout the time of elevated IAP (Fig. 3F). In the IAH20 group, the difference to sham reached a significant value not before 6 h of IAH. This difference originated mainly from a continuous decrease in the tissue lactate concentration in the sham animals and less from an increase in the IAH groups.
In sham animals, the LP ratio of the RAM remained at baseline values throughout the experiment (Fig. 4B). In contrast, in the IAH20 group, the RAM exhibited a 2.5-fold increase in the LP ratio after 6 h when compared with baseline (Fig. 4B). In the IAH30 group, this increase amounted to almost 700%. In the liver and the gastric wall, the LP ratio was significantly increased compared with baseline throughout the duration of IAP elevation in the IAH30 group (Fig. 4, C and E). This increase was less pronounced in the kidney (Fig. 4D) whereas no difference at all was observed in the jejuna wall (Fig. 4F).
In the IAH30 group, the RAM revealed a continuous increase in the glycerol concentration throughout the entire experiment (Fig. 5B). After 3 and 4 h, the difference reached a significant level compared with the sham and the IAH20 groups, respectively. In all the other analyzed organs, the glycerol concentrations showed only minor changes (Fig. 5, C–F).
In summary, in the IAH30 group, the RAM demonstrated an early and distinguished increase for ischemia (LP ratio) and cell membrane damage (glycerol) markers compared with intra-abdominal organs. In the IAH20 group, tissue ischemia but no structural damage was detected, whereas conventional parameters such as APP, UOP, blood gas analysis, or the SOFA organ subscores failed to pick up the deterioration.
The main findings of our study are that in the porcine model (a) an IAH of 20 mmHg for 6 h does not provoke any significant organ derangements detectable by either conventional monitoring, or by selective lactate or IL-6 measurements; (b) an IAH of 30 mmHg shows pathophysiological alterations consistent with ACS in otherwise healthy animals; (c) subclinical organ impairment is detectable by microdialysis; and (d) the RAM is more susceptible to IAH than all the other analyzed intra-abdominal organs. As in our model, the increase in the ischemia marker LP was more pronounced than that of the other microdialysis parameters under investigation (lactate, glycerol); LP monitoring of the RAM may be a potential tool for early detection of critical IAH before the development to full-blown ACS with its fatal consequences occurs.
General effects of IAH in our model
In the herein presented porcine model, we could see all the known deleterious effects of IAH such as depression of MAP and APP when the IAP was increased to 30 mmHg for 6 h. We also found a significant reduction of SMA blood flow in our study groups compared with sham animals. Central venous pressure and PIP were significantly increased, and UOP diminished in the presence of IAH. Blood gas analysis demonstrated the typical picture of a mixed respiratory and metabolic acidosis with reduced pH, bicarbonate levels, and a negative base excess.
Of interest, an IAH of 20 mmHg applied for 6 h in the previously healthy animals did not provoke the classic pathophysiological changes consistent with the established definition of ACS (1, 23). Although we could observe some effects, most of them were rather mild and would not justify the criteria for organ dysfunction and the diagnosis of ACS. These observations are in accordance with previous reports on large animal models (25). In this respect, the IAH20 group of our experimental study represented a condition with increased IAP but with no obvious organ dysfunction detectable by conventional monitoring tools currently in use.
In the clinical setting, venous lactate levels are routinely used to assess ischemia and to monitor the effects of fluid resuscitation in hypovolemic patients. However, lactate levels may also be elevated in hypermetabolism. Thus, lactate alone may not be a reliable marker of ischemia (14). This may be valid not only for venous lactate levels but also tissue lactate concentrations. In fact, in the present study, tissue lactate levels were elevated only in the jejunum of the IAH30 group compared with sham animals. However, when compared with baseline conditions, the alterations were not significant.
Of interest, venous lactate samples taken from three different veins (SFV, PV, and JV) did not show any relevant alterations in sham animals and in the IAH20 group. The lactate levels increased significantly only in the IAH30 group after 4 to 6 h of IAH. This increase is in line with earlier observations from experimental works (26). Serum lactate concentrations showed a similar course in all sampled veins but were most pronounced in the SFV in our study. Increased IAP increases FVP. Recent clinical research has shown that FVP correlates well with IAP in the situation of IAP of greater than 20 mmHg (27). Thus, perfusion pressure of the lower extremities is similar to APP in critically elevated IAP. In contrast, perfusion pressure of the head and upper extremities is higher because of the lower CVP compared with FVP. Together with our results from tissue lactate measurements, this would support the view that lactate acidosis origins more from the muscle-rich lower extremities than from the intra-abdominal organs. Because of the increased FVP and lowered MAP microcirculation, these tissues may be impaired with subsequent ischemia.
Alteration of LP ratio
In contrast to tissue lactate measurements, the LP ratio demonstrated a more pronounced increase in the RAM compared with all abdominal organs studied. The increase was less prominent but still significant in the IAH20 group. As the LP ratio has been proven to be a superior marker of ischemia than lactate alone (14), this observation may indicate that the metabolic deterioration in the RAM starts earlier and is more severe than that in other organs. However, these alterations were not as pronounced as observed in our previous rodent study (5). Thus, it may be speculated that the surgical procedure and the experimental burden are less tolerated by rodents, making them more susceptible to IAH. As mentioned before, an IAH of 20 mmHg over 6 h did not cause pathophysiological alterations consistent with ACS in the previously healthy large animals. The increase in the LP ratio with progressing time of IAH may indicate that—besides the magnitude of IAH—the duration of IAH is also a relevant factor for the development of organ ischemia and dysfunction (28).
Alteration of tissue glycerol
Previous studies could demonstrate that glycerol is a good marker for cell membrane damage, ischemia, and energy failure (14, 15). We could demonstrate a continuing rise of glycerol concentrations in the RAM of the IAH30 group, whereas no relevant changes were seen in all other organs studied. In the IAH20 group, the glycerol levels of the RAM were not different from those of the sham group, indicating that this level of IAH may have caused tissue ischemia but did not cause any cell membrane damage following insertion trauma. Thus, ischemia but no cell damage was observed when the animals were exposed to an IAP of 20 mmHg. Accordingly, an IAH of 20 mmHg may represent the threshold between compensated IAH and beginning organ dysfunction, which was not yet detectable by conventional means in our experimental setting.
Shah et al. (29) described a clinically relevant pig model of ACS. An initial hemorrhage was induced followed by standardized fluid resuscitation. The effects of peritoneal packing with increased mesenteric pressure up to 30 mmHg were simulated by tightening a previously placed PV snare. Analysis of the peritoneal fluid demonstrated increased concentrations of IL-6 and TNF-α levels. Rezende-Neto et al. (2) showed that IAH provokes the release of proinflammatory cytokines. It is well known from experimental and clinical studies that excessive levels of IL-1β, IL-6, and TNF-α are associated with increased morbidity and mortality. The potential sources of increased IL-6 are multiple and include the gut (30, 31), liver (32), and lung (33). Bathe et al. (34) investigated the role of the gut as a source of cytokine release in a porcine endotoxemia model. They observed a significant increase in IL-6 3 h after application of endotoxin. However, there was no difference between IL-6 levels taken from the PV and carotid artery. They concluded that ischemic gut is not associated with gut release of IL-6. In our study, we could not identify a clear source of IL-6 release, either. There was no significant difference between the samples from the FV, the PV, and the JV, respectively. Intra-abdominal hypertension did provoke an increase in IL-6, but only in the IAH30 group. In line with the analysis of other parameters, an IAH of 20 mmHg did not cause relevant IL-6 alterations.
Limitations of the model
Our animals were previously healthy, and thus, the effect of IAH may be different from the clinical situation in which most patients develop IAH due to severe multiple trauma, rigorous fluid resuscitation, major surgery, an overwhelming infection, or other serious pathological conditions (2, 3, 35). Critical IAH has been identified to act as a potential second hit. In this situation, IAH provokes an overwhelming release of proinflammatory cytokines such as IL-6 by primed granulocytes, leading to fatal MOF. Because we studied formerly healthy animals, which were not exposed to a first hit, we do not know about the magnitude of IL-6 release in these animals at different IAH levels with formerly primed granulocytes. To evaluate the value of microdialysis, in particular of the RAM as a potential “early warning organ,” microdialysis and its relationship to cytokine release need to be evaluated and compared with monitoring modalities currently in use in a clinically relevant two-hit model.
Different large animal models have been described in the literature (36–43). Whereas severe hemorrhage, administration of bacteria, or endotoxic shock were used to act as first hits, IAP as a second hit was mainly artificially increased to study the effects of IAH and ACS. In contrast, Shah et al. (44) described a very interesting model in which ACS was reproduced without artificial IAP increase. They used a hemorrhage-resuscitation sequence followed by subtotal obstruction of the PV to create bowel edema, causing critical IAH with organ dysfunction. Their findings regarding physiological alterations during IAH were comparable to our results. However, mortality was as high as 33% in their experimental setting.
We observed the effects of IAH only for 6 h. Longer times of observation may be necessary to analyze IAH particularly in the “gray zone” with IAP values between 15 and 20 mmHg. In fact, Schachtrupp et al. (28) showed that even a slight increase in the IAP to 15 mmHg but maintained for as long as 24 h causes a decrease in UOP as well as an increase in PIP and low-grade necrosis of liver, kidney, and bowel mucosa.
The key to lower morbidity and mortality of critical IAH lies in the early detection of critical IAH and the initialization of countermeasures to effectively decrease IAP before the sequence cascades to full-blown ACS with the fatal development to MODS have been started. A refinement of our diagnostic tools and monitoring techniques such as those demonstrated in our study may allow the early identification of those patients exposed to critical IAH in the future.
The authors appreciate the excellent technical assistance of Elisabeth Gluding and Janine Becker.
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