Oddveig Lyng

Effect of increased intraabdominal pressure on cardiac output and tissue blood flow assessed by color-labeled microspheres in the pig

BackgroundStudies of the hemodynamic effects associated with the pneumoperitoneum have had controversial results. We set out to investigate the effect of increased intraabdominal pressure (IAP) on cardiac output and tissue blood flow in various intraabdominal and extraabdominal organs using the color-labeled microsphere (CLM) technique.MethodsIAP was induced by CO2 insufflation in anesthetized pigs; 0,5, and 10 mmHg was used in the low-pressure group and 0, 15, and 24 mmHg in the high-pressure group. Tissue blood flow (ml.min−1.g−1) and cardiac output (CO) (ml/min) were determined by the CLM technique.ResultsCO decreased at IAP≥15 mmHg. Arterial PaCO2 and hydrogen ion concentration increased in response to all levels of IAP. Arterial PaO2, oxygen saturation, and bicarbonate ion concentration remained unchanged. Low IAP did not influence tissue blood flows in most of the organs. However, in the spleen, pancreas, esophagus, and gastric mucosal specimens, tissue blood flow was significantly decreased at 24 mmHg.ConclusionThe level of IAP used in current practice (10–12 12 mmHg) appears to be safe with regard to hemodynamic variables and tissues blood flow; however, higher levels may induce a decrease in cardiac output and tissue blood flow.

Continuous monitoring of the bronchial epithelial lining fluid by microdialysis.

BackgroundContents of the epithelial lining fluid (ELF) of the bronchi are of central interest in lung diseases, acute lung injury and pharmacology. The most commonly used technique broncheoalveolar lavage is invasive and may cause lung injury. Microdialysis (MD) is a method for continuous sampling of extracellular molecules in the immediate surroundings of the catheter. Urea is used as an endogenous marker of dilution in samples collected from the ELF. The aim of this study was to evaluate bronchial MD as a continuous monitor of the ELF.MethodsMicrodialysis catheters were introduced into the right main stem bronchus and into the right subclavian artery of five anesthetized and normoventilated pigs. The flowrate was 2 μl/min and the sampling interval was 60 minutes. Lactate and fluorescein-isothiocyanate-dextran 4 kDa (FD-4) infusions were performed to obtain two levels of steady-state concentrations in blood. Accuracy was defined as [bronchial-MD] divided by [arterial-MD] in percent. Data presented as mean ± 95 percent confidence interval.ResultsThe accuracy of bronchial MD was calculated with and without correction by the arteriobronchial urea gradient. The arteriobronchial lactate gradient was 1.2 ± 0.1 and FD-4 gradient was 4.0 ± 1.2. Accuracy of bronchial MD with a continuous lactate infusion was mean 25.5% (range 5.7–59.6%) with a coefficient of variation (CV) of 62.6%. With correction by the arteriobronchial urea gradient accuracy was mean 79.0% (57.3–108.1%) with a CV of 17.0%.ConclusionUrea as a marker of catheter functioning enhances bronchial MD and makes it useful for monitoring substantial changes in the composition of the ELF.

Substance P may attenuate gastric hyperemia by a mast cell-dependent mechanism in the damaged gastric mucosa

Calcitonin gene-related peptide (CGRP) released from sensory neurons, which are closely apposed to mast cells and blood vessels, mediates gastric hyperemia in response to acid challenge of the damaged mucosa. Substance P (SP) is coreleased with CGRP from sensory neurons, but the role of this peptide in gastric blood flow regulation is largely unknown. Chambered rat stomachs were exposed to 1.5 M NaCl and acidic saline after treatment with SP, aprotinin (serine protease inhibitor), and the mast cell stabilizers ketotifen and sodium cromoglycate (SCG). Gastric hyperemia (measured with a laser Doppler flow velocimeter) after hypertonic injury and acid challenge was nearly abolished by SP. Aprotinin infused together with SP and pretreatment with ketotifen and SCG before SP restored the gastric hyperemia. Ketotifen and SCG inhibited mast cell degranulation in SP-treated rats. Preservation of gastric hyperemia was correlated with improved mucosal repair. These data suggest that impaired hyperemia by SP during acid challenge of the gastric mucosa may be mediated by a mast cell-dependent mechanism involving the release of proteases from mast cells.Calcitonin gene-related peptide (CGRP) released from sensory neurons, which are closely apposed to mast cells and blood vessels, mediates gastric hyperemia in response to acid challenge of the damaged mucosa. Substance P (SP) is coreleased with CGRP from sensory neurons, but the role of this peptide in gastric blood flow regulation is largely unknown. Chambered rat stomachs were exposed to 1.5 M NaCl and acidic saline after treatment with SP, aprotinin (serine protease inhibitor), and the mast cell stabilizers ketotifen and sodium cromoglycate (SCG). Gastric hyperemia (measured with a laser Doppler flow velocimeter) after hypertonic injury and acid challenge was nearly abolished by SP. Aprotinin infused together with SP and pretreatment with ketotifen and SCG before SP restored the gastric hyperemia. Ketotifen and SCG inhibited mast cell degranulation in SP-treated rats. Preservation of gastric hyperemia was correlated with improved mucosal repair. These data suggest that impaired hyperemia by SP during acid challenge of the gastric mucosa may be mediated by a mast cell-dependent mechanism involving the release of proteases from mast cells.

Effect of carbon dioxide pneumoperitoneum on tissue blood flow in the peritoneum, rectus abdominis, and diaphragm muscles

Background: Changes in local blood flow may play a role in the pathogenesis of port-site metastasis. This study aimed to investigate the effect of pneumoperitoneum induced by carbon dioxide (CO2) on the blood flow in the peritoneum and abdominal wall muscle layers, which are target structures for this phenomenon. Methods: The study was performed on domestic farm swine of both genders weighing 20 to 25 kg. Intraabdominal pressures (IAP) of 0, 5, and 10 mmHg were produced by either CO2 (n = 9) or helium (He) (n = 6) insufflations. The colored microsphere technique was used to measure blood flow distributions in the parietal peritoneum, rectus abdominis, and diaphragm muscles. Results: Insufflation of CO2 was associated with a threefold increase in blood flow of the parietal peritoneum at both 5 and 10 mmHg IAP (p < 0.001 for both pressure levels). In contrast, insufflation of He caused a significant decrease in blood flow in the parietal peritoneum at both 5 and 10 mmHg (p < 0.05). In the rectus abdominis and diaphragm muscles, blood flow remained unchanged after insufflation of CO2 at both 5 and 10 mmHg IAP. However, after insufflation of He, there was a substantial decrease in blood flow both in the rectus abdominis and diaphragm muscles at both 5 mmHg (p < 0.01 and p < 0.05, respectively) and 10mmHg (p < 0.001 and p < 0.01, respectively). Conclusions: Despite high intraabdominal pressure, tissues surrounding the abdominal cavity, particularly the peritoneum, respond to insufflation of CO2 with increased blood flow, which may favor the growth of tumor cells.

Pharmacology of Intravenous Insulin Administration: Implications for Future Closed-Loop Glycemic Control by the Intravenous/Intravenous Route

BACKGROUND Our group is attempting to construct an artificial pancreas based on intravenous glucose monitoring and intravenous insulin delivery. To do so, the pharmacology of intravenous insulin administration must be studied. We used a pig model to determine the inherent lag time in the insulin/blood glucose system. The goal was to suggest a method that reduces the blood glucose level in a rapid and yet predictable manner. METHODS Six pigs received continuous intravenous insulin infusions at 0.04, 0.08, or 0.4 IU/kg/h for 60 min. Two pigs received short-term intravenous infusions at 0.4 IU/kg/h for 2 min, repeated five times at 60-min intervals. Four animals received five intravenous insulin bolus injections at 60-min intervals, two at 0.01 IU/kg and two 0.02 IU/kg, with a final dose of 0.04 IU/kg. The blood glucose level was measured every 1-5 min. RESULTS A high rate of intravenous insulin infusion led to rapid declines in blood glucose levels. The same rapid decline was achieved when the infusion was halted after 2 min. Using the latter method and with intravenous insulin boluses, blood glucose levels started to rise again after approximately 15-20 min. Insulin boluses led to a first detectable decrease in blood glucose level after 2-6 min and to a maximum rate of decrease shortly thereafter. CONCLUSIONS We found that intravenous bolus injections of insulin lowered blood glucose levels rapidly and predictably. Repetitive small intravenous insulin boluses together with an accurate and fast-responding intravascular continuous glucose monitor should be studied as a method of closed-loop glycemic control.

Bronchial microdialysis of cytokines in the epithelial lining fluid in experimental intestinal ischemia and reperfusion before onset of manifest lung injury.

Today, there is no continuous monitoring of the bronchial epithelial lining fluid. This study used microdialysis as a method of continuous monitoring of early lung cytokine response secondary to intestinal ischemia-reperfusion in pigs. The authors aimed to examine bronchial microdialysis for continuous monitoring of IL-1&bgr;, TNF-&agr;, IL-8, and fluorescein isothiocyanate Dextran 4,000 Da (FD-4). The superior mesenteric artery was cross-clamped for 120 min followed by 240 min of reperfusion (ischemia group, n = 8). Four sham-operated pigs served as controls. The pigs were anesthetized and normoventilated (peak inspiratory pressure, <20 cm H2O; positive end-expiratory pressure, 7 cm H2O). Samples from bronchial and luminal intestinal and arterial microdialysis catheters (flow-rate of 1 &mgr;L/min) were collected during reperfusion in 60-min fractions. Samples were analyzed for TNF-&agr;, IL-1&bgr;, IL-8, and FD-4. Data are presented as median (interquartile range). A lung biopsy was collected at the end of the experiment. During reperfusion, there was an increase in bronchial concentrations of both IL-8 (3.70 [1.47-8.93] ng/mL per h vs. controls, 0.61 [0.47-0.91] ng/mL per h; P < 0.001) and IL-1&bgr; (0.32 [0.05-0.56] ng/mL per h vs. controls, 0.07 [0.04-0.10] ng/mL per h; P = 0.008). In the intestinal lumen, IL-8 was increased in the ischemia group (6.33 [3.13-9.23] ng/mL per h vs. controls, 0.89 [0.21-1.86] ng/mL per h; P < 0.001). The FD-4 did not differ between groups. Pulmonary vascular resistance and pulmonary shunt increased versus controls. During reperfusion, PaO2/FiO2 ratio decreased in the ischemia group. Histology was normal in both groups. Bronchial microdialysis detects altered levels of cytokines in the epithelial lining fluid and can be used for continuous monitoring of the immediate local lung cytokine response secondary to intestinal ischemia-reperfusion.

Blood Glucose Control Using a Novel Continuous Blood Glucose Monitor and Repetitive Intravenous Insulin Boluses: Exploiting Natural Insulin Pulsatility as a Principle for a Future Artificial Pancreas

The aim of this study was to construct a glucose regulatory algorithm by employing the natural pulsatile pattern of insulin secretion and the oscillatory pattern of resting blood glucose levels and further to regulate the blood glucose level in diabetic pigs by this method. We developed a control algorithm based on repetitive intravenous bolus injections of insulin and combined this with an intravascular blood glucose monitor. Four anesthetized pigs were used in the study. The animals developed a mildly diabetic state from streptozotocin pretreatment. They were steadily brought within the blood glucose target range of 4.5–6.0 mmol/L in 21 to 121 min and kept within that range for 128 to 238 min (hypoglycemic values varied from 2.9 to 51.1 min). The study confirmed our hypotheses regarding the feasibility of this new principle for blood glucose control, and the algorithm was constantly improved during the study to produce the best results in the last animals. The main obstacles were the drift of the IvS-1 sensor and problems with the calibration procedure, which calls for an improvement in the sensor stability before this method can be applied fully in new studies in animals and humans.

Cardiac power integral: a new method for monitoring cardiovascular performance

Cardiac power (PWR) is the continuous product of flow and pressure in the proximal aorta. Our aim was to validate the PWR integral as a marker of left ventricular energy transfer to the aorta, by comparing it to stroke work (SW) under multiple different loading and contractility conditions in subjects without obstructions in the left ventricular outflow tract. Six pigs were under general anesthesia equipped with transit time flow probes on their proximal aortas and Millar micromanometer catheters in their descending aortas to measure PWR, and Leycom conductance catheters in their left ventricles to measure SW. The PWR integral was calculated as the time integral of PWR per cardiac cycle. SW was calculated as the area encompassed by the pressure–volume loop (PV loop). The relationship between the PWR integral and SW was tested during extensive mechanical and pharmacological interventions that affected the loading conditions and myocardial contractility. The PWR integral displayed a strong correlation with SW in all pigs (R2 > 0.95, P < 0.05) under all conditions, using a linear model. Regression analysis and Bland Altman plots also demonstrated a stable relationship. A mixed linear analysis indicated that the slope of the SW‐to‐PWR‐integral relationship was similar among all six animals, whereas loading and contractility conditions tended to affect the slope. The PWR integral followed SW and appeared to be a promising parameter for monitoring the energy transferred from the left ventricle to the aorta. This conclusion motivates further studies to determine whether the PWR integral can be evaluated using less invasive methods, such as echocardiography combined with a radial artery catheter.

Hemodynamic and tissue blood flow responses to long-term pneumoperitoneum and hypercapnia in the pig

BackgroundIncreased peritoneal blood flow may influence the ability of cancer cells to adhere to and survive on the peritoneal surface during and after laparoscopic cancer surgery. Carbon dioxide (CO2) pneumoperitoneum is associated with a marked blood flow increase in the peritoneum. However, it is not clear whether the vasodilatory effect in the peritoneum is related to a local or systemic effect of CO2.MethodsIn this study, 21 pigs were exposed to pneumoperitoneum produced with either CO2 (n = 7) or helium (He) (n = 7) insufflation at 10 mmHg for 4 h, or to two consecutive levels of hypercapnia (7 and 11 kPa) (n = 7) produced by the addition of CO2 to the inhalational gas mixture. Tissue blood flow measurements were performed using the colored microsphere technique.ResultsBlood flow in peritoneal tissue increased during CO2, but not He, pneumoperitoneum, whereas it did not change at any level of hypercapnia alone. There was no change in blood flow in most organs at the partial pressure of CO2 (PaCO2) level of 7 kPa. However, at a PaCO2 of 11 kPa, blood flow was increased in the central nervous system, myocardium, and some gastrointestinal organs. The blood flow decreased markedly in all striated muscular tissues during both levels of hypercapnia.ConclusionThe effect of CO2 on peritoneal blood flow during laparoscopic surgery is a local effect, and not attributable to central hemodynamic effects of CO2 pneumoperitoneum or high systemic levels of CO2.

Bronchial microdialysis monitoring of inflammatory response in open abdominal aortic aneurysm repair; an observational study.

Aortic surgery results in ischemia–reperfusion injury that induces an inflammatory response and frequent complications. The magnitude of the inflammatory response in blood and bronchi may be associated with the risk of immediate complications. The purpose of the study was to evaluate bronchial microdialysis as a continuous monitoring of cytokines in bronchial epithelial lining fluid (ELF) and to determine whether bronchial ELF cytokine levels reflect the ischemia–reperfusion injury and risk for complications during open abdominal aortic aneurysm (AAA) repair. We measured cytokines in venous blood using microdialysis and in serum for comparison. Sixteen patients scheduled for elective open AAA repair were included in a prospective observational study. Microdialysis catheters were introduced into a bronchi and a cubital vein. Eighteen cytokines were measured using a Bio‐Plex Magnetic Human Cytokine Panel. Samples were collected before and during cross‐clamping of the aorta as well as from 0 to 60 min and from 60 to 120 min of reperfusion. The ELF levels of several cytokines changed significantly during reperfusion. In particular, IL‐6 increased more than 10‐fold and IL‐13 more than 5‐fold during ischemia and reperfusion. Also, the venous levels of several inflammatory and anti‐inflammatory cytokines increased and exhibited their highest concentration during reperfusion. Both bronchial and venous cytokine levels correlated with duration of the procedure, intensive care days, and preoperative kidney disease. Three patients suffered organ failure as a direct consequence of the procedure, and in these patients the bronchial ELF concentrations of 17 of 18 cytokines differed significantly from patients without such complications. Bronchial microdialysis is suited for continuous monitoring of inflammation during open AAA repair. The bronchial ELF cytokine levels may be useful in predicting immediate complications such as organ failure in patients undergoing vascular surgery.