Microdialysis is a novel technique enabling the study of the biochemistry of extracellular space in living tissue. It is used in vivo to determine concentration of endogenous substances and drugs in humans. The microdialysis technique entails the insertion of a small catheter (also referred to as microdialysis probe) into the tissue. The microdialysis probe is a double lumen, concentric catheter that is perfused with an aqueous solution. The tip of the probe contains a semipermeable membrane. Small solutes from the extracellular compartment can cross this membrane. After a period of equilibration, the solution, dialysate leaving the probe, is collected. A special analyst then measures the concentration of certain solutes. In this study the tissue of interest was the peritoneal cavity. The substances studied—glucose, glycerol, lactate, and pyruvate^1–3—are related to cell metabolism and integrity.

Microdialysis is used in abdominal surgery to predict early ischemia that renders the gastrointestinal tract a source of bacteria, endotoxins, free radicals, and inflammatory agents with detrimental effects to health. Lactate and pyruvate and their ratio (lactate / pyruvate, L/P) is of particular interest.^3–5

Lactate is increased in cases of increased physical stress (i.e., in cases of severe sepsis, cardiogenic shock, etc.) with severe effects to mesenteric circulation and gastrointestinal tract perfusion. Lactate is also increased in cases of localized digestive system and peritoneal cavity physical stress, such as bacterial peritonitis or local ischemia. In other words, either global or local bowel ischemia promotes the generation of lactate. Regardless of the cause, lactate behaves similarly in both the intestinal tract and the peritoneal cavity.^5–7

In anaerobic conditions, energy is produced when pyruvic acid is reduced to lactic acid mediated by lactic dehydrogenase. Therefore, the L/P (lactate-to-pyruvate) ratio serves as an indirect index of the balance between aerobic and anaerobic metabolism. During ischemia, lactate concentration normally increases and pyruvate concentration normally decreases or, alternatively, there is a disproportionate increase of lactate in relation to pyruvate, which is metabolized into lactate, due to the delayed activation of oxidative phosphorylation. This results in an increase in the L/P ratio and a decrease in the consumed glucose concentration. During a serious inflammation, there is also a high lactate concentration, due to hypermetabolism. Intraperitoneal microdialysis offers a unique way of diagnosing local ischemia and/or inflammation, two conditions essential in surgical patient outcome prognosis.^7,8

High glycerol levels have been reported in inducible ischemia models in guinea pigs. Glycerol is a component of the cell membrane. In anaerobic conditions, phospholipase is activated and glycerol is released into the surrounding environment, and the increased levels indicate cellular destruction.^9,10

The purpose of this study was to measure intraperitoneal microdialysis values (glucose, glycerol, pyruvate, and lactate) in patients hospitalized in ICU with an underlying abdominal surgical condition and to correlate these values with patients' outcomes.

Materials and Methods

The sample study comprised 21 patients (11 males) with a variety of underlying diseases, all being related to abdominal surgery. These patients were admitted to ICU during a 3-year period and their closest relative or the patients gave informed consent to study participation. Anonymity was a prerequisite. Thirteen patients had undergone surgery before or during ICU hospitalization. The case mix of patients is a mixture of acute and programmed admissions. The acute admissions are comprised of patients with acute abdomen and severe deterioration of homeostasis. The programmed admissions refer to patients that had major abdominal surgery and also had significant comorbidities.

Metabolites values were measured for three consecutive days, the first being the admission day. The first 2 measurements were discarded in order to exclude false measurements because of catheter insertion technique. A thin peritoneal catheter was inserted in the abdominal cavity of all participants. Samples were collected at 4-hours intervals. Lactate, pyruvate, glucose, and glycerol were measured. Each patient was equipped with a catheter for microdialysis (CMA 70 Brain Microdialysis Catheter, 10 mm membrane length, 20 kDa cut off, CMA, Stockholm, Sweden), bearing a gold tip, for CT scan. The duration of peritoneal monitoring for study purpose was continued for 3 days.

The CMA 600 analyzer (Harvard Apparatus, M Dialysis AB, Sweden) was used for photometric sample analysis (LABpilot TM Software). The CMA 62 microdialysis catheter was used for peritoneal study. The one tip was connected to an effusion pump (CMA 107) and the other to a collection chamber. Microdialysis solution features were as follows: Na 147 mmol/L, K 4 mmol/L, Ca 2.3 mmol/L, Cl 1.56 mmol/L, ph 6.0, osmolarity 290 mOsm/kg. Microdialysis values are all expressed in mmol/L.

Results

Thirteen patients had undergone surgery. Mean patient age was 68.10 ± 8.02 years. Nine patients died. Mean age of deceased patients was 69.66 ± 6.57 years versus 66.5 ± 8.45 of survivors (difference not statistically significant). Regarding simplified acute physiology score (SAPS), survivors had statistically significantly lower score than deceased 42.58 ± 14.13 versus 64.22 ± 16.29 (P = 0.004).

No statistically significant difference was observed based on underlying disease (Table 1).

Table 1 Underlying disease and outcome

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Survivors had greater lactate (mean: 3 days value) values than deceased 41.98 ± 29.84 versus 21.25 ± 5.92, P = 0.07 (Table 2), while third day glucose was significantly different between the two groups: 6.61 ± 2.01 versus 3.67 ± 1.62 respectively (Table 3).

Table 2 Metabolic marker values in relation with outcome and days of hospitalization

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Table 3 Metabolic markers values the first 3 days of ICU hospitalization*

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All survivors had a mean 3-day L/P ratio over 25.94 compared with deceased group (difference statistically significant at P = 0.006; Table 4).

Table 4 Three-day L/P and outcome

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When a logistic regression model adjusted for age was applied with outcome as the dependent variable and third glucose and L/P ratio as independent variables, lower L/P values were related to increased survival probability by 59% (1/0.628; Table 5).

Table 5 Outcome prediction model

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Discussion

Microdialysis was used to explore changes in biochemical parameters related to peritoneal cell energy balance and peritoneal cell viability. A high concentration of glycerol, a high L/P ratio, and low concentration of glucose were the main findings during the first days of hospitalization in the patients who finally died. Those patients had higher intraperitoneal glycerol concentration than survivors from the very beginning of their hospitalization, being raised to 50% on the third day. High glycerol levels have been observed in animal ischemia models. Glycerol is a key component of cell membrane and, in anaerobic conditions, phospholipase and glycerol are released to extracellular interstitial space as a result of cell destruction.^11,12

Glucose metabolism in the intensive care setting is quite complex. The neuroendocrine and inflammatory response to stress leads to alterations in glucose metabolism. The end result is the appearance of stress related hyperglycaemia. Glucose levels in the blood are further influenced by the concomitant administration of intravenous insulin, the nutritional status of the patient, liver function, and the existence or not of diabetes. Mesenteric ischemia leads to significant reduction of glucose that is offered to the intestinal cells. In animal experiments, strangulation of intestinal vessels eventually provokes severe depletion of glucose. Glucose levels are reduced inside the mesenteric vessels, intraluminally, but also intraperitoneally.¹³

During this study, the L/P ratio remained at high levels for the first 3 days of hospitalization. In fact, an L/P ratio of 25.94 is recommended as a baseline value, over which the survival rate is significantly decreased, as clearly observed in this study. Previous studies, in patients who had undergone colectomy, showed that the intraperitoneal L/P ratio went over 20, and did not decrease during the first postoperative days, indicative of a visceral ischemia as well as a prognostic factor for avoiding future anastomosis breakdown.^14–16

The intraperitoneal microdialysis is useful in assessing local ischemia and/or inflammation both being critical for outcome prognosis in surgical patients. Previous studies in patients who underwent colectomy have shown that when intraperitoneal L/P ratio values exceed 20 and L/P ratio is not decreasing during the first postsurgery days, splanchnic ischemia is strongly suspected. It is also a sign of anastomotic leak in the near future.¹⁷ In the present study, L/P ratio remained during the first 3 days of hospitalization. We further propose the value 25, 94 as a reference value. Above this cutoff point, the odds of survival are considerably diminished. This is probably a sign that in surgical patients with unfavorable outcome, marked anaerobic metabolism, indicative of ischemia, takes place early in the postoperative course. Detecting subtle metabolic changes early may enhance prompt treatment with obvious benefits.

A high L/P ratio suggests an increased intraperitoneal lactate concentration along with a decreased pyruvate concentration. Glucose is the main supplier of intracellular pyruvate, with pyruvate concentration decreasing when glucose supply is decreased and aerobic glycolysis is concluded, as in cases of ischemia, and when there is a decreased substrate and oxygen supply; in other words, the cell does not have the required resources to continue its normal functions.¹⁸ This suggests that these changes take place early in surgical patients, with unfavorable outcomes, during their hospitalization, and early detection could potentially mean a more successful treatment intervention.

The findings of the present study indicate that inflammation is triggered by local enteric ischemia leading to decreased flow of substrates and oxygen and tissue necrosis. Given the heterogeneity of the underlying diseases in the sample study, this mechanism appears to be common in surgical patients, regardless of the underlying disease. The potential early prognosis of a surgical patient's outcome based on microdialysis values may enhance prompt localization of septic foci and proper treatment. Intraperitoneal microdialysis may be a useful research tool in understanding the pathophysiology of enteric ischemia and predicting outcome. The metabolites measured may be useful markers in clinical trials targeting at reducing enteric ischemia in surgical patients. The findings of the present study facilitate the creation of a conceptual framework for a future, larger study on peritoneal microdialysis and outcomes in surgical ICU patients.