It has become apparent that the prevalence of obesity has been steadily increasing worldwide (1). Approximately 65% of the US population is overweight, and 30% are obese. The prevalence of obese patients admitted to the intensive care unit (ICU) is also rising rapidly and poses complex challenges (2). Approximately 30% patients admitted in ICU are obese (body mass index ≥30 kg/m2), and 7% morbidly obese (body mass index, ≥ 40 kg/m2) (3). Obesity compromises the body’s ability to adapt to stress or critical illness and is independently associated with increased morbidity and all-cause mortality (4). Some studies reported that obesity is associated with an improved survival, which has led to the use of the term “obesity paradox” to describe this phenomenon. The original “obesity paradox” refers to a benefit in survival of obese patients, although obesity is a major risk factor in the development of cardiovascular and peripheral vascular disease when acute cardiovascular decompensation occurs, for example, in myocardial infarction or congestive heart failure (5). After admission to the ICU, studies focusing on the effect of obesity on mortality have mixed results. Some investigators found that obese individuals had higher mortality during critical illness (6, 7), whereas others reported that obesity either had no effect (3, 8, 9) or was protective compared with normal weight (10, 11). The influence of obesity on specific ICU populations, such as sepsis, has been the subject of much speculation, but very few experimental data or clinical studies exist on this topic. Sepsis, the syndrome of microbial infection complicated by systemic inflammation, is also a major public health problem associated with significant morbidity and mortality (12). There are interesting pathophysiologic connections between obesity and sepsis. There is increasing awareness that obesity per se is a chronic inflammatory state. Obesity generates a phenotype of enhanced inflammation in the microvasculature of multiple organs (13). When exposed to an acute inflammatory insult, these tissues are more vulnerable to tissue injury via exaggerated inflammation. Experimental models have provided evidence that obesity may exacerbate sepsis-induced inflammation and microvascular dysfunction in the intestinal tract and brain of rodents (14, 15). Clinical data are disputed ranging from harmful (16) to absent (17), with others showing protective effects of obesity on patient outcome in septic shock (18).
Although more and more obese patients are admitted in ICU, available data on effect of obesity in septic shock remain limited and controversial. To the best of our knowledge, the negative effects of obesity in a porcine model of endotoxic shock have never been studied. In this study, we aimed to determine if obesity impairs acute endotoxic shock using minipigs. We assessed the impact of obesity on macrocirculation and microcirculation, oxygenation, inflammation, and metabolic status.
MATERIALS AND METHODS
The Institutional Review Board for Animal Research approved the study (protocol CEEA Nord Pas-de-Calais 132012); care and handling of the animals were in accordance with National Institutes of Health guidelines.
Twenty adult male Yucatan miniature pigs (6 months old) were used in this study. Animals were submitted to a nutritional protocol according to Val-Laillet et al (19). Animals were fed during 10 weeks. Two regimens were used: a standard diet designed to maintain lean phenotype and a Western diet to obtain obese phenotype. The standard diet (SD, 2,463 kcal/kg) had the formula and ration (41.5 g/kg0.75 of live weight once a day at 9:00 AM). The Western diet (3,473 kcal/kg) was enriched with carbohydrates and lipids and offered ad libitum (one ration offered at 9:00 AM and calculated to exceed the daily consumption of the animals). For the experiment, animals were premedicated with intramuscular injection of ketamine (Ketamine 1000, 10 mg/kg of body weight; Virbac, Carros, France) and xylazine (Sédaxylan, 2.5 mg/kg of body weight; CEVA Santé Animale, Libourne, France). Then we used a 4% concentration of isoflurane (Aerrane; Baxter, Maurepas, France) for the intubation process, once intubation realized the maintenance of anesthesia was performed with a continuous infusion of midazolam (Hypnovel, 1–2 mg/kg body weight per hour; Roche, Meylan, France) for the whole experiment. Animals were connected to a constant-volume respirator for mechanical ventilation (Osiris 2; Taema, Antony, France). Animals were mechanically ventilated with a tidal volume 12 mL/kg according to the mean weight of lean pigs, positive end-expiratory pressure 3 cmH2O, FIO2 0.6, and respiratory rate 14 to 20 breaths/min adjusted to maintain normocapnia. We chose to maintain ventilation similar in all animals without changing FIO2 or tidal volume during the experiment. No recruitment maneuvers could be done. Muscle relaxation was obtained by a continuous infusion of cisatracurium besylate (Nimbex, 2 mg/kg body weight per hour; Hospira, Meudon La Forêt, France). Analgesia was achieved by a subcutaneous injection of buprenorphine (Vetergesic, 0.1 mg/kg body weight; Sogeval, Laval, France). Subcutaneous administration of buprenorphine in our animals is known to permit analgesia during 6 to 8 h and avoid intravenous bolus administration. After dissection of neck vessels, catheters were inserted in the pulmonary artery via the right external jugular vein (Swan-Ganz continuous cardiac output, mixed venous oxygen saturation (SvO2) monitoring; Baxter 110 H 7.5F; Baxter Edwards Critical Care, Irvine, Calif) and in the right carotid artery for continuous blood pressure monitoring and blood sampling. An esophageal temperature probe measured core temperature.
Macrocirculatory and oxygenation parameters
Systemic arterial and venous blood samples from carotid and pulmonary arteries were obtained simultaneously. Arterial and venous blood gas tensions, pH, and lactate levels were measured in an acid-base analyzer (ABL-800; Radiometer, Copenhagen, Denmark). Blood oxygen content was calculated from the hemoglobin content and oxygen saturation. Oxygen extraction ratio (OER) was calculated as the arteriovenous O2 content difference divided by the arterial O2 content. Heart rate (HR) and systemic and pulmonary arterial pressures were continuously monitored (90308 PC Express Portable Monitor; Spacelabs, Snoqualmie, Wash) as well as cardiac output and SvO2 (Vigilance monitor; Baxter Edwards, Irvine, Calif). Using standard formulas, we computed cardiac index (CI, L/min per m2), systemic vascular resistance (dyn/s per cm5), oxygen delivery (DO2), and oxygen consumption (VO2). Body surface area was calculated by Wachtel formula (20).
The study was carried out as described in Figure 1. During preparation period, animals received 500 mL 0.9% NaCl to prevent hypovolemia. When all preparations were completed, a 30-min period was allowed to stabilize the measured variables. Macrocirculatory and microcirculatory measurements were taken over a 5-h period: two times at baseline (before [T0] and after [T0′] the stabilization period) and at 30 (T30), 60 (T60), 90 (T90), 150 (T150), and 300 (T300) min. Arterial and venous blood was collected at the same time (except T0) until the study was completed. Four groups of five animals were studied: obese control, lean control, obese lipopolysaccharide (LPS), and lean LPS. After anesthesia, catheterization, and baseline collection (T0′), control groups received an intravenous infusion of 50 mL of 0.9% NaCl over a 30-min period. Lipopolysaccharide groups were administered Escherichia coli LPS (serotype 055:B5; Sigma Chemical Co, St Louis, Mo). The endotoxin was diluted in 50 mL of sterile isotonic saline and infused over a 30-min period intravenously. All the animals received the same dose of endotoxin. This dose was calculated at a rate of 5 µg/kg per min according to the mean weight of lean pigs. Our model is a hypodynamic shock with low level of resuscitation. The only resuscitation end point was mean arterial pressure (MAP). In the two groups submitted to endotoxin challenge, animals received 100 mL/h (from T30 to T300) of 0.9% NaCl. If MAP felt below 50 mmHg, a 50-mL infusion of NaCl 0.9% was given as rescue therapy every 15 min. Bolus infusions were performed to maintain MAP greater than 50 mmHg. We chose this model with a low level of resuscitation to avoid hemodilution and hyperchloride acidosis. Surviving Sepsis Campaign Guidelines (21) recommend crystalloids be used as the initial fluid of choice in the resuscitation of severe sepsis and septic shock. We chose 0.9% NaCl as resuscitation fluid because it is the most commonly used crystalloid fluid (22).
Estimation of body fat percentage
Three body circumferences and leptin levels were measured at baseline according to Witczak et al (23). Circumference measurements were obtained at the following three positions: ventral neck, midabdomen, and widest abdominal girth. Leptin levels were measured by radioimmunoassay (Multi-Species Leptin RIA Kit; Merck Millipore, Darmstadt, Germany).
Skin microvascular blood flow was measured continuously using a laser Doppler flowmeter probe and device (Periflux PF407; Perimed, Järfälla, Sweden). The blood flow was measured in a volume of 1-mm3 solid tissue. The fiber optic probe was applied on the right hind paw of the animals and fixed with an adhesive tape. Laser Doppler signal was continuously registered on a personal computer. Flux zero calibration was performed by readjusting the pen of the recorder to zero when the probe was fixed to a white nonmoving surface. Skin blood flow was measured at rest and during reactive hyperemia, and values were expressed in perfusion units. Reactive hyperemia was produced by arrest of leg blood flow with a pneumatic cuff inflated to a suprasystolic pressure of 200 mmHg for 3 min. On completion of the ischemic period, the occluding cuff was rapidly deflated to zero. Peak flow (PF) was defined as the highest flow signal during the postocclusive phase. Reactive hyperemia was further analyzed (Perisoft 2.5 software, Perimed, Järfälla, Sweden) according to its duration and initial reactive hyperemia uphill slope.
Endothelial and inflammation parameters
von Willebrand factor (vWF) concentrations were measured to evaluate endothelial injury. The quantitative determination of VWF antigen was measured by turbidimetric assay (vWF Ag Reagent; Siemens, Den Haag, the Netherlands) (n = 70–100%). Tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and IL-10 levels were measured in serum and used as markers of inflammation. Plasma levels were detected by enzyme-linked immunosorbent assay method with porcine anti–TNF-α antibodies (Quantikine Porcine TNF-α; R&D Systems, Minneapolis, Minn), anti–IL-6 antibodies (Quantikine Porcine IL-6; R&D Systems, Minneapolis, Minn), and anti–IL-10 antibodies (Quantikine Porcine IL-10; R&D Systems, Minneapolis, Minn). Results were expressed in picograms per milliliter.
The day before starting the study, fasting blood glucose levels were measured in vigil animals. During the study, capillary glucose (Accu-Chek PERFORMA; Roche Diagnostics SAS), insulin, and lipid markers levels were measured. For insulin, blood was collected on plastic thrombin tube. Lipid markers were obtained on EDTA anticoagulated blood. Analyses were made on frozen plasma. Serum insulin levels were measured by immunoradiometric assay (sandwich assay), which uses two monoclonal anti-insulin antibodies (Bi-Insuline RIA; Bio-Rad, Elexience, Verrières-le-Buisson, France). Lipid markers (triglycerides, total cholesterol, and high-density lipoprotein cholesterol levels) were measured by enzymatic assays on Konelab 20 Clinical Chemistry Analyzer (Thermo scientific, Cergy Pontoise, France).
Statistical analysis was performed with GraphPad Prism 6 software. Results were given as median with 25th to 75th interquartile range. Intergroup comparisons were performed with Mann-Whitney U test. Intragroup comparisons were realized by Friedman test with Dunn multiple-comparisons test. A P < 0.05 was considered significant.
Comparison between obese and lean pigs at baseline
Estimation of body fat percentage
Serum leptin levels were significantly higher in obese pigs compared with lean pigs (1.7 [1.5–2.3] vs. 0.8 [0.6–1.6] ng/mL, P = 0.01). Neck, midabdomen, and widest-abdominal girth circumference measurements were significantly (P < 0.0001) greater in obese pigs. Mean weight was significantly higher in obese pigs compared with lean pigs (39 [34–40] vs. 22 [17–23] kg, P < 0.0001).
Macrocirculatory and microcirculatory, oxygenation, and biological parameters
Macrocirculatory and microcirculatory data were constant during the stabilization period. No differences were observed in macrocirculatory, oxygenation, and inflammatory data between obese and lean pigs. However, microcirculation was impaired in obese pigs. Rest flow (RF; 13 [12–16] vs. 22 [17–27] perfusion unit, P = 0.005), PF (25 [20–28] vs. 37 [27–60] perfusion unit, P = 0.01), and slope (0.3 [0.2–0.5] vs. 0.8 [0.5–1.2], P = 0.05) were significantly lower compared with lean swine. In parallel, vWF levels were significantly higher in obese pigs compared with lean pigs (96% [89%–109%] vs. 86% [76%–99%], P = 0.03). Fasting blood glucose levels were similar, but glucose levels at T0′ were significantly higher in obese pigs compared with lean pigs (1.5 [1.3–1.6] vs. 1.2 [1.1–1.4] g/L, P = 0.02). No differences were observed in insulin and lipid markers levels. We observed a significantly higher hemoglobin level in obese pigs (10.5 [10.2–10.7]) than in lean pigs (8.6 [8.1–9.1], P < 0.0001).
Comparison between obese and lean control groups
Macrocirculatory and microcirculatory, oxygenation, and biological parameters remained stable throughout the study. We just observed a progressive decrease in RF and increase in vWF levels during the study without any significant differences between groups.
As there were no significant differences observed between the control groups, only the lean control group is illustrated in Figures 2, 3, 4A, and 5).
Comparison between obese and lean LPS groups
Macrocirculatory and oxygenation parameters
Variations in MAP, HR, CI, and mean pulmonary arterial pressure (MPAP) are illustrated in Figure 2. Variations in SvO2, OER, DO2/VO2 ratio, pulmonary capillary wedge pressure (PCWP), and PaO2/FIO2 ratio are illustrated in Figure 3.
The usual changes previously described (24–27) were observed in groups receiving endotoxin. To avoid differences in volemia before endotoxin challenge, animals received 500 mL 0.9% NaCl during preparation. Despite this administration, we observed a difference in hemodynamic parameters at T0, but these differences were not significant between the groups.
In both LPS groups, hemodynamic evolution and changes were similar and were significantly different from control groups. We observed a progressive arterial hypotension. Mean arterial pressure decreased from 87 (71–105) at baseline to 52 (47–58) mmHg at 300 min in the obese group (P < 0.05) and from 102 (84–108) at baseline to 76 (38–88) mmHg at 300 min in the lean group (not statistically significant). These decreases were associated with a significant increase in HR at 300 min in the obese group (P < 0.05 compared with baseline) and at 150 min in the lean group (P < 0.05 compared with baseline). Throughout the study, fluid was administered to maintain MAP greater than 50 mmHg. The LPS groups received the same amount of vascular filling during the experiment (650 [550–700] mL in the obese group vs. 750 [650–800] mL in the lean group, P = 0.11). In control animals, we observed an increase in MAP at the end of the experiment associated with an increase in HR reflecting vasoconstriction and hypovolemia in this group. In both LPS groups and despite resuscitation, a significant decrease in CI appeared at 150 and 300 min in the LPS groups. The decrease in CI was significantly more pronounced in the obese group at 300 min (1.2 [1.06–1.45] vs. 1.7 [1.57–1.97] L/min per m2, P = 0.008). Cardiac index impairment was associated with DO2 decrease, SvO2 decrease, and OER increase. The latter two variations were significant at 300 min compared with baseline (P < 0.01, respectively, in the obese group and P < 0.05, respectively, in the lean group). The decrease in DO2/VO2 ratio after endotoxin challenge was significant only in the obese LPS group (4.7 [4.5–5] at baseline vs. 2 [1.6–2.5] at 300 min, P < 0.01). Pulmonary capillary wedge pressure increased significantly at the end of the study only in the obese group (6 [5–6] at baseline vs. 12 [9–13.5] mmHg at 300 min, P < 0.05).
With regard to lung function, we observed a dramatic increase in MPAP 30 min after the infusion of endotoxin in the LPS groups. Then MPAP decreased at 60 min. From 90 to 300 min, we observed a progressive rise in MPAP. The increase in MPAP was significantly more important in the obese group (from 18 [16–20.5] at baseline to 42 [39–47] mmHg at 300 min, P < 0.05) compared with the lean group (from 16 [16–17.5] at baseline to 32 [27.5–34] at 300 min, P < 0.05). In the obese group, pulmonary hypertension was coupled with a strong decrease in the PaO2/FIO2 ratio (418 [347–450] at baseline vs. 216 [178–262] mmHg at 300 min, P < 0.05). In the lean group, we observed a nonsignificant decrease in PaO2/FIO2 ratio.
Changes in blood lactate levels, vWF levels, RF, and PF during reactive hyperemia are illustrated in Figure 4.
Blood lactate concentrations significantly increased throughout the study. These increases were associated with a significant decrease in RF, PF, and slope (data not shown). These changes appeared more precociously in lean pigs. Blood lactate increase and microcirculatory parameters (RF, PF, and slope) decrease were significant from 90 to 300 min in lean pigs and from 150 to 300 min in obese pigs. Even so, at the end of the study, lactate levels were significantly higher in obese pigs (5.8 [4.2–6.8] mmol/L) compared with lean pigs (3.9 [2.2–5.5] mmol/L at 300 min, P = 0.04). Moreover, PF was significantly lower in obese pigs (12 [10–14] vs. 20 [17–25] PU at 300 min, P = 0.008). Rest flow and slope seemed also more decreased without reaching significance. von Willebrand factor plasma levels increased significantly in both LPS groups.
Changes in TNF-α, interleukin 6 (IL-6), and IL-10 levels are illustrated in Figure 5. In the lean LPS group, TNF-α started to increase at 60 min, peaked at 90 min (56 [35–69] at baseline vs. 141,075 [100,908–359,875] pg/mL at 90 min, P < 0.01), and subsequently decreased until the end of the experiment without returning to normal levels (19,770 [13,704–28,835] pg/mL at 300 min). Compared with the lean LPS group, TNF-α levels were significantly higher in the obese LPS group at 60 min (269 [178–428] vs. 126 [105–166] ng/mL, P = 0.03). In the lean LPS group, IL-6 levels increased from 90 to 300 min (0 [0–1] at baseline vs. 30,093 [22,421–41,100] pg/mL at 150 min, P < 0.01). Compared with the lean LPS group, IL-6 started increase at 60 min and was significantly higher in the obese LPS group at 300 min (101 [61–142] vs. 52 [36–64] ng/mL, P = 0.03). No significant differences were seen on IL-10 evolution between LPS groups at any time.
The evolution of pH, bicarbonate (HCO3 −), carbon dioxide partial pressure (PCO2), hemoglobin, glucose, and temperature levels is presented in Table 1.
Animals receiving endotoxin developed metabolic acidosis. Compared with baseline, arterial pH and HCO3 − levels decreased significantly over time in the obese LPS group (P < 0.05 and P < 0.001, respectively, at 300 min) and in the lean LPS group (P < 0.05 and P < 0.01, respectively, at 300 min). PCO2 remained stable throughout the study with the adjustment of respiratory rate. We observed a progressive hemoconcentration with a significant increase in hemoglobin level from baseline to 300 min (P < 0.001 in the obese LPS group and P < 0.01 in the lean LPS group), possibly reflecting vascular leakage. At last, the core temperature increased significantly from baseline to the end of the study (P < 0.001 in the obese LPS group and P < 0.001 in the lean LPS group). Regarding metabolic parameters, animals receiving endotoxin developed hypoglycemia during the experiment (blood glucose started to decrease at 150 min). The decrease in blood glucose level was significant only in the obese LPS group (P < 0.05 at 150 min and P < 0.01 at 300 min). This was associated with a peak of blood insulin at 90 min in LPS groups. This peak was more elevated in the obese LPS group (65 [30–182] vs. 36 [23–98] µUI/mL, P = 0.41). In both LPS groups, we observed a significant increase in triglyceride levels from 150 to 300 min and a nonsignificant decrease in high-density lipoprotein cholesterol. No significant differences were seen on lipid markers evolution between the LPS groups at any time.
This was the first time that the impact of obesity was investigated in a large animal model of endotoxic shock. The main goal of this study was to evaluate whether obesity could impair experimental endotoxic shock. The main result of our study was consistent with this hypothesis. In our hypodynamic model of endotoxic shock, obese pigs developed a more severe hemodynamic failure with more pronounced multiple organ dysfunction and proinflammatory response.
Pigs were chosen as a clinically relevant species, resembling to humans in various functions as assessed by cardiovascular, respiratory, and biochemical parameters (24, 28). We deliberately investigated the impact of obesity in the worst hemodynamic conditions associated with sepsis, to maximize the potential detrimental effects of obesity. In fact, our model is a hypodynamic shock with low resuscitation level to avoid hemodilution. We used a low rate of vascular filling to maintain MAP of 50 mmHg or greater rather than keeping volume constant and allowing pressures to vary. However, our obese LPS piglets had a more pronounced hypodynamic shock with a more pronounced hemoconcentration, reflecting hypovolemic state. This porcine model of endotoxic shock was characterized, as previously reported (25–27), by hypotension, vasodilation, and decreased cardiac output, despite administration of fluid resuscitation. The main challenge of our study was to choose the appropriate endotoxin dose for obese pigs. With the large difference in weight between lean and obese pigs, it was impossible to use a dose kilo like in usual models of endotoxic shock (LPS infusion of 5 µg/kg per min over a 30-min period). In order to have comparable groups, all animals were infused with the same endotoxin dose. So we determined a fixed dose by using the usual formula with the mean weight of lean pigs.
The hemodynamic results of our study are consistent with an unfavorable effect of obesity. The decrease in CI was more severe in obese pigs. In our model, the hemodynamic effects of obesity seemed to be related to a decrease in cardiac function rather than in vascular tone. Systemic vascular resistance was not significantly modified in the obese LPS group compared with the lean LPS group (data not shown). It remains to be documented whether this alteration is linked to a decrease in cardiac contractility or a change in diastolic compliance. We hypothesized that the more important proinflammatory response (TNF-α and IL-6) observed in obese pigs played a key role. In fact, we know that several inflammatory mediators, including TNF-α and IL-6, are involved in cardiac injury subsequent to sepsis (29). Moreover, TNF-α increased DNA methyltransferase levels, thus enhancing the methylation in the sarcoplasmic reticulum Ca-ATPases (SERCA2a) promoter region with a result of reducing SERCA2a (30). Acute heart failure in septic shock is linked to downregulation of SERCA2a (31), which plays an essential role in the calcium homeostasis and regulates the cardiac functions. So the exaggerated inflammation due to obesity could participate in the more important cardiac failure.
Endotoxin administration usually results in the development of an acute pulmonary hypertension with hypoxemia. In previous studies in the same animal model, histological findings supported the development of a respiratory distress syndrome with marked pulmonary leukocyte sequestration and interstitial edema (26). In our study, obesity was associated with a more significant increase in endotoxin-induced pulmonary hypertension and a more significant decrease in the PaO2/FIO2 ratio compared with lean pigs. This more marked pulmonary shunt could be explained by a more extended atelectasis due to obesity (32). Moreover, we observed in obese pigs a significant increase in PCWP, which could be responsible for a larger capillary leak in the interstitium and alveoli.
The microcirculatory results of our study confirm the independent variation in microcirculation compared with macrocirculatory variables (33). In fact, the microvascular dysfunction was earlier than hemodynamic impairments in both LPS groups. Second, as already observed in rodent models, obesity exacerbated the microvascular alterations (14, 15). At the end of our study, microcirculatory dysfunction and lactate increase were significantly more pronounced in obese pigs. Nevertheless, these alterations appeared later in obese pigs compared with lean pigs. This kinetic should be explained by the microcirculatory alterations observed in obese pigs at baseline. Indeed, this alteration could impede the transmission of the inflammation signal. In a second time, the information was transmitted, and prior microcirculatory dysfunction could be the cause of a more severe disease. von Willebrand factor increased, suggesting an alteration of endothelial cells and microcirculation. We observe also an increase at the end of the experiment in control animals. This increase was not significant and probably due to vasoconstriction induced by hypovolemia.
Our model presented some limits: the short duration (5 h only, so that the nitric oxide system was hardly activated), LPS bolus rather than continuous intravenous administration (bolus produces much more severe acute pulmonary hypertension and eventually right ventricular failure), and hypodynamic shock with inadequate resuscitation, whereas hyperdynamic shock is more common in ICU (34, 35).
It would have been of interest to assess organ dysfunction by scoring organ histology. However, we could not assess organ dysfunction by histology because we could analyze only the kidney, lung, and liver of three animals per group.
In our acute endotoxic shock porcine model, obese animals presented an exaggerated proinflammatory response with a more severe macrocirculation and microcirculation dysfunction. Interplay between endocrine and immunomodulatory functions in adipose tissue seems to play a key role in our model, but the specific roles determining the impact of various adipokines such as leptin, adiponectin, and resistin remain to be elucidated.
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Keywords:© 2014 by the Shock Society
Obesity; sepsis; organ failure; hemodynamic failure; microcirculatory dysfunction; inflammation