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Anesth Analg 2006;102:1617-1622
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000219596.34753.72

CARDIOVASCULAR ANESTHESIA

Autoregulation of Human Jejunal Mucosal Perfusion During Cardiopulmonary Bypass

Andreas Nygren, MD, Anders Thorén, MD, PhD, Erik Houltz, MD, PhD, and Sven-Erik Ricksten, MD, PhD

Department of Cardiothoracic Anesthesia and Intensive Care, Sahlgrenska University Hospital, Göteborg Sweden

Address correspondence and reprint requests to Sven-Erik Ricksten, MD, Department of Cardiothoracic Anesthesia and Intensive Care, Sahlgrenska University Hospital, 41345 Göteborg, Sweden. Address e-mail to sven-erik.ricksten{at}aniv.gu.se.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Animal studies have suggested that autoregulation of intestinal blood flow is severely impaired during cardiopulmonary bypass (CPB). We investigated the jejunal mucosal capacity to autoregulate perfusion during nonpulsatile CPB (34°C) in 10 patients undergoing elective cardiac surgery. Changes in mean arterial blood pressure (MAP) were induced by altering the CPB flow rate randomly for periods of 3 min from 2.4 L/min/m2 to either 1.8 or 3.0 L/min/m2. Jejunal mucosal perfusion (JMP) was continuously recorded by laser Doppler flowmetry. A typical pattern of flow motion (vasomotion) was recorded in all patients during CPB. Variations in CPB flow rates caused no significant changes in mean JMP, jejunal mucosal hematocrit, or red blood cell velocity within a range of MAP from 50 ± 15 to 74 ± 16 mm Hg. The vasomotion frequency and amplitude was positively correlated with CPB flow rate. IV injections of prostacyclin (10 µg, Flolan®) blunted vasomotion and increased JMP from 192 ± 53 to 277 ± 70 (P < 0.05) perfusion units despite a reduction in MAP from 59 ± 12 to 45 ± 10 mm Hg (P < 0.05). Prostacyclin-induced vasodilation resulted in loss of mucosal autoregulation (pressure-dependent perfusion). We conclude that autoregulation of intestinal mucosal perfusion is maintained during CPB in humans.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Splanchnic oxygen delivery decreases during hypothermic cardiopulmonary bypass (CPB) because of a hemodilution-induced decrease in arterial oxygen content and a decreased (1,2) or unchanged (3,4) splanchnic blood flow. Splanchnic ischemia during CPB has been suggested to be a causal factor for the development of systemic inflammatory response syndrome and multiple organ failure after cardiac surgery. The latter is speculated to be attributable to disruption of intestinal mucosal barrier function and translocation of endotoxin and microorganisms, leading to a release of proinflammatory cytokines that contribute to organ ischemia-reperfusion injury (5–7). This hypothesis has been supported by the results of studies on gastric mucosal perfusion during CPB in humans. Using the laser Doppler flowmetry (LDF) technique, it has repeatedly been shown that gastric mucosal perfusion decreases during CPB in humans (8,9) and when systemic oxygen delivery was deliberately maintained at prebypass levels. Furthermore, it has been shown, in an animal model, that intestinal tissue perfusion during CPB is primarily dependent on CPB flow rate (10). A linear relationship between CPB flow rate and intestinal tissue perfusion over a wide range of CPB flow rates was described, indicating a severely disturbed autoregulatory control of intestinal tissue perfusion (10). This impairment of the intestinal autoregulatory control of blood flow could, to some extent, explain how systemic hypotension might induce intestinal ischemia during CPB. Using the LDF technique, we have shown that jejunal mucosal perfusion (JMP) increases during mild hypothermic CPB in humans (11). The aim of the present study was to further characterize the behavior of the vascular bed of the intestinal mucosa during mild hypothermic CPB in humans. Our hypothesis was that the autoregulatory capacity of the intestinal mucosa was impaired during CPB.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study procedures were approved by the Ethics Committee of the University of Göteborg and informed consent was obtained from each patient. Ten patients, 5 male and 5 female, with a mean age of 75 yr (range, 51–84 yr) undergoing elective cardiac valve surgery with or without coronary artery bypass grafting were included in the study. Exclusion criteria were diabetes mellitus, preoperative cerebral infarction or carotid artery disease, bowel disease, or laboratory evidence of liver dysfunction. Seven of the patients were treated with long-acting ß1-selective adrenergic blockers (metoprolol 25–100 mg), including the day of surgery and all patients had a left ventricular ejection fraction >0.4.

The patients were premedicated with oral flunitrazepam (0.5–1 mg) and anesthesia was induced with 0.1–0.2 mg fentanyl and 100–200 mg propofol with 0.1 mg/kg pancuronium given for skeletal muscle relaxation. All patients were orally intubated and mechanically ventilated with oxygen/air to achieve an arterial oxygen tension (Pao2) >15 kPa and a Paco2 level of 4.5–5.5 kPa. Anesthesia was maintained before CPB with an IV infusion of propofol 200–600 mg/h until the LDF catheter was positioned and was then maintained with a combination of fentanyl (total dose, including the induction dose, 7.9 ± 1.5µg/kg) and isoflurane. After induction of anesthesia, a pulmonary artery catheter was inserted during fluoroscopic guidance (7.5F pulmonary artery catheter, Edwards Lifesciences, Irvine, CA). Cardiac output was measured in triplicate with ice-cold boluses of 10-mL saline, not timed to the respiratory cycle, after induction of anesthesia. Before aortic cannulation, heparin 393 ± 24 U/kg (Heparin, Loewens, Ballerup, Denmark) was administered IV and supplemented as required to achieve an activated coagulation time of >480 s. During CPB, anesthesia was maintained by propofol (200–400 mg/h).

The perfusion system consisted of a hollow fiber membrane oxygenator (Dideco Synthesis, Mirandola, Italy), a hard shell venous reservoir, and roller pumps (Jostra HL20). The extracorporeal circuit was primed with 1600 ± 260 mL of Ringer’s acetate® solution (Fresenius-Kabi, Uppsala, Sweden), 100 mL of Tribonate® (Fresenius-Kabi) and 200 mL of mannitol 150 mg/l (Fresenius-Kabi). Cardioprotection was achieved with intermittent cold blood cardioplegia (Plegisol®, Abbott, North Chicago, IL) plus potassium 60 mmol/L and procainamide 2.5 mmol/L. Target flow using nonpulsatile CPB was 2.4 L · min–1 · m–2 at a target body temperature of 34°C, continuously measured by a thermistor in the urinary bladder. During CPB Pao2 was maintained between 15 and 22 kPa and Paco2 between 4.1–5.6 kPa, using {alpha}-stat pH management. The trigger hematocrit for transfusion of erythrocytes was 20%.

A custom-made two-probe laser Doppler catheter (Perimed, Järfälla, Sweden) was placed through the nasogastric route during fluoroscopic guidance endoluminally in the proximal jejunum 20–40 cm distal to the ligament of Treitz. The light source and the receiver of each probe are situated 23 mm and 123 mm from the tip of the catheter. Each probe consists of 3 triangular-placed optical fibers with a diameter of 150 µm and a fiber center separation of 200 µm. One fiber emits light with a wavelength of 780 nm and the other 2 receive the Doppler shifted and backscattered light. The JMP was measured with a sampling frequency of 32 Hz with a laser Doppler flowmeter (Periflux PF 4001 TM; Perimed AB, Järfälla, Sweden). For measurements of JMP, a time constant of 0.2 s and a bandwidth of 20–25 kHz were used and calibration of the probe was performed as recommended by the manufacturer. The laser Doppler equipment used in the present study has the ability to separately analyze the two components of the JMP, jejunal mucosal hematocrit (JMHct) and red blood cell (RBC) flow velocity. The JMP (perfusion units, PU) is thus the product of the JMHct and RBC flow velocity or number of RBC x area–1 x time–1, number of RBC x volume–1, and length x time–1. The JMP, JMHct, and RBC flow velocity values presented in this study were calculated from periods of intestinal quiescence using Perisoft software (Perimed Järfälla Sweden). The frequency, as well as the amplitude, of the cyclic changes in JMP was calculated for each period (mean of the two probes).

At a body temperature of 34°C and a CPB flow rate index of 2.4 L/min/m2, mean arterial blood pressure (MAP), JMP (JMHct and RBC flow velocity), and CPB flow rate were continuously recorded (baseline). Approximately 5 min after the first administration of cardioplegia, 15–20 min after start of CPB, the patients were subjected, in random sequence, to 3-min periods of low CPB flow rate (1.8 L/min/m2), standard CPB flow rate (2.4 L/min/m2), and high CPB flow rate (3.0 L/min/m2). In each patient, this CPB flow rate variation procedure was performed 1–3 times, depending on the duration of the operation. Thereafter, at a CPB flow rate of 2.4 L/min/m2, systemic vasodilation was induced by an IV injection of prostacyclin 10 µg (Flolan®, GlaxoSmith Kline, Parma, Italy) (n = 6) and then the maximal change in MAP and JMP were recorded. During the prostacyclin-induced vasodilation, the CPB flow rate was again randomly altered, as described above, but now only for periods of 30 s at each CPB flow rate. IV injections of prostacyclin were repeated 1–2 times depending on the duration of the surgical procedure.

Student’s paired t-tests were performed for comparing Pao2, Paco2, mixed venous oxygen tension (Svo2), hematocrit, and body temperature before and after the experimental procedure and to evaluate the effects of prostacyclin on JMP and MAP. Analysis of variance for repeated measures followed by contrast analysis were used to evaluate the effects of variations in CPB flow rate on MAP, systemic vascular resistance index (SVRI), Svo2, JMP, JMHct, RBC flow velocity, and vasomotion frequency and amplitude. Mean values for each patient were obtained at each CPB flow rate if more than one CPB flow rate variation procedure was performed. A correlation within subject analysis (12) was also performed to evaluate a potential correlation between MAP and JMP during CPB flow variations, without and with prostacyclin. Values are expressed as mean ± sd.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Cardiac index, MAP, Svo2, hemoglobin, and hematocrit before initiation of CPB were 2.1 ± 0.4 L/min/m2, 81 ± 15 mm Hg, 67% ± 15% (range, 42%–82%), 114 ± 13 g/L, and 35% ± 4%, respectively. The duration of CPB was 117 ± 39 (range, 74–194) min. Pao2, Paco2, Svo2, and body temperature did not change significantly (data not shown), whereas there was a slight increase in hemoglobin (82 ± 13 to 87 ± 17 g/L; P < 0.05) and hematocrit (25.5% ± 4.0% to 27.2% ± 3.4%; P < 0.05) during the experimental procedure. One of the patients received transfusion of erythrocytes before we performed the experimental protocol.

A representative recording of the effects of CPB flow rate variations on MAP and JMP is seen in Figure 1. In six patients we were able to repeat the CPB flow rate variation procedure at least once. The autoregulatory response to flow rate variations did not differ between the first and the subsequent CPB flow variation. Seventeen sequences of variation in CPB flow rate were thus performed in the 10 patients. Individual data on the effects of changes in CPB flow rate index on MAP and JMP are shown in Figure 2. The effects of varying CPB flow rate index on mean MAP, SVRI, Svo2 (venous line of the CPB circuit), and JMP are shown in Table 1. MAP and Svo2 increased whereas SVRI decreased with higher CPB flow rates. JMP, JMHct, and RBC flow velocity were unchanged during the variations in CPB flow rate index. In all patients, Svo2 was ≥70% at a CPB flow rate of 1.8 L/min/m2. Individual data on the relation between MAP and JMP are seen in Figure 3a and the relation between absolute changes in MAP versus absolute changes in JMP in Figure 3b. There was no significant within-subject correlation between MAP and JMP (r = 0.06, P = 0.58).


Figure 14
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  		Figure 1. Individual recording of jejunal mucosal perfusion, arterial blood pressure, and flow rate during cardiopulmonary bypass (CPB). Cyclic oscillations in jejunal mucosal perfusion (vasomotion) are present during CPB at various flow rates. Random variations in CPB flow rate induced no change in the mean mucosal perfusion. Vasomotion frequency and amplitude increased with increasing arterial blood pressures and CPB flow rates. PU = perfusion units.

 

Figure 24
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  		Figure 2. Individual data on the effects of variations in cardiopulmonary bypass (CPB) flow rate index on a) mean arterial blood pressure (MAP) and b) jejunal mucosal perfusion (JMP). Seventeen sequences of CPB flow rate variation were performed in 10 patients. Each dot represents the mean of a 3-min recording period at each CPB flow rate. There was no consistent relation between CPB flow rate index and JMP, indicating intact autoregulation of perfusion. PU = perfusion units.

 

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  		Table 1. Effects of Variations in Cardiopulmonary Bypass (CPB) Flow Rate on Jejunal Mucosal Perfusion

 

Figure 34
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  		Figure 3. Individual data on a) the effects of variations in mean arterial blood pressure on jejunal mucosal perfusion (JMP) and b) on the effects of absolute changes in mean arterial blood pressure and absolutes changes in JMP. Each dot represents the mean of a 3-min recording period at each cardiopulmonary bypass flow rate. There was no consistent relation between mean arterial blood pressure and JMP. PU = perfusion units.

 

Cyclic variation in JMP (vasomotion) was seen in all patients during CPB (Fig. 1). The vasomotion was present during 72% ± 18% of the recorded time. Both vasomotion frequency and amplitude increased with higher CPB flow rates (Table 1).

Six patients received 13 bolus doses of prostacyclin at a CPB flow rate index of 2.4 L/min/m2. A representative recording of the effects of prostacyclin on JMP and perfusion pressure is shown in Figure 4. Prostacyclin abolished the vasomotion waves whereas JMP increased from 192 ± 53 to 277 ± 70 PU (P < 0.05) despite a reduction in MAP from 59 ± 12 to 45 ± 10 mm Hg (P < 0.05). During prostacyclin-induced vasodilation, CPB flow rate variations caused changes in perfusion pressure within a range of 30–69 mm Hg. Individual data on the relation between MAP and JMP during prostacyclin-induced vasodilation are seen in Figure 5a and individual data on the relation between absolute changes in MAP versus absolute changes are seen in JMP in Figure 5b. A within-subject positive correlation between MAP and JMP (r = 0.66, P < 0.0001) was demonstrated during prostacyclin-induced vasodilation, indicating that JMP was pressure-dependent.


Figure 44
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  		Figure 4. Individual recording on the effects of IV prostacyclin (10 µg), on jejunal mucosal perfusion (JMP) and arterial blood pressure during cardiopulmonary bypass (CPB). Typical cyclic oscillations of JMP are seen before prostacyclin injection. Prostacyclin induced a systemic vasodilation, blunted the cyclic oscillations of JMP, and increased JMP. During the influence of prostacyclin, variation in CPB flow rate induced parallel changes in arterial blood pressure and JMP. PU = perfusion units.

 

Figure 54
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  		Figure 5. Individual data on a) the effects of variations in mean arterial blood pressure on jejunal mucosal perfusion (JMP) and b) the effects of absolute changes in mean arterial blood pressure and absolute changes in JMP during the influence of prostacyclin. Twelve sequences of variation in cardiopulmonary bypass flow rate were performed in five patients. Each dot represents the mean of a 30-s recording period. Prostacyclin induced pressure-dependent changes in JMP, indicative of absence of flow autoregulation. PU = perfusion units.

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study we evaluated the autoregulation of JMP during mild hypothermic CPB in patients undergoing elective cardiac surgery. The major findings were that neither JMP nor its composite variables, JMHct and RBC flow velocity, were significantly affected by flow-induced variations in MAP within the pressure range of 50–75 mm Hg. These data indicate that intestinal mucosal autoregulation is maintained during CPB in humans.

Our results are in contrast to previous experimental studies evaluating regional splanchnic circulation during CPB. Mackay et al. (13) and O’Dwyer et al. (14) evaluated the effects of variations in CPB flow rate on regional blood flow in pigs using a microsphere technique. These investigators found that splanchnic blood flow was pressure-dependent, indicating impaired autoregulation. Bastien et al. (10) evaluated the importance of systemic flow for intestinal perfusion, as measured by LDF, during mild hypothermic CPB in rabbits. They found a linear relationship between CPB flow rate and perfusion of gastric, ileal, jejunal, and hepatic regions, further indicating impairment of intestinal autoregulation during CPB. In the latter experiment, intestinal perfusion was measured via the serosal side of the intestinal wall rather than from the lumen as in our study. It is possible that LDF recordings from the exterior of the intestine reflect blood flow to the serosa/muscularis layers rather than the actual mucosa thus explain, at least in part, the discordant findings between this study and prior animal experiments.

Ohri et al. (8) and Sicsic et al. (9) have shown that significant gastric mucosal hypoperfusion, assessed by the LDF technique, occurs during CPB in humans. In contrast, we have previously shown that intestinal mucosal perfusion increases during CPB in humans (11,15). This increase in JMP was accompanied by an increase in RBC velocity and the lack of changes in JMHct despite a decrease in systemic oxygen delivery and systemic hemodilution. That is, data obtained from measurements of gastric mucosal perfusion during CPB may not necessarily be extrapolated as representative of intestinal mucosal perfusion. In the present investigation, we have extended our prior studies of the intestinal microcirculation during CPB and demonstrated that intestinal mucosal autoregulation is maintained during variations in MAP caused by changes in CPB flow rate. Thus, these results from humans suggest that intestinal mucosal perfusion is not compromised during CPB. These results further suggest that the previously described disruption of intestinal mucosal barrier function and translocation of endotoxins and microorganisms during CPB (7,16) might not necessarily be explained by intestinal mucosal hypoperfusion.

The arterioles supplying blood to the capillary network exhibit rhythmic oscillations in vascular tone, independent of external influences such as cardiac, intestinal peristaltic, or respiratory cycles. This phenomenon of periodic diameter variations is referred to as vasomotion and is a natural property observed in most microcirculatory vascular beds (17). The mechanism for vasomotion is believed to be a result of intermittent calcium release from the sarcoplasmic reticulum leading to cyclic smooth muscle depolarization of the blood vessels via activation of chloride channels (17). Cyclic microcirculatory blood flow variations have been described in the human jejunal mucosa (18) but not in the serosa, further emphasizing potential differences between the characteristics of intestinal perfusion between measurement sites (19). The frequency of vasomotion in human jejunal mucosa is usually between 1.9 and 5 cycles per minute (10,18). Jejunal vasomotion has also been observed experimentally as variations in jejunal mucosal tissue oxygenation and microvascular hemoglobin oxygen saturation using a Clark-type surface oxygen electrode and with tissue reflectance spectrophotometry (19,20). The pattern of vasomotion varies considerably between both species and vascular beds and may be affected by vasoactive drugs (21) or changes in MAP, hematocrit, or oxygen tension (22). In the present study, vasomotion amplitude increased in parallel to increased systemic perfusion and vice versa, which could be explained by the myogenic mechanism by which vascular smooth muscle contracts as tension is increased. Changes in vasomotion amplitude to variations in MAP could thus be one mechanism by which the intestinal mucosa autoregulates perfusion.

Increase of cyclic adenosine monophosphate (cAMP) levels has been considered to be a key cellular event to trigger blood vessel relaxation by prostacyclin and its analogues (23). Plasma membrane K+ channels located on the smooth muscle are believed to be the primary downstream effector of prostacyclin mediating smooth muscle cell hyperpolarization and relaxation (23). In our study, prostacyclin induced a 25% decrease in MAP during CPB but JMP increased by 45%, indicating a pronounced prostacyclin-induced arteriolar vasodilation. This vasodilation could also to some extent be attributed to a myogenic autoregulatory response to the decrease in systemic pressure. During prostacyclin injection, intestinal perfusion became pressure-dependent. Furthermore, vasomotion was abolished in all patients with prostacyclin, suggesting that increased intracellular cAMP in vascular smooth muscle cells inhibits intestinal mucosal vasomotion. One mechanism behind the prostacyclin-induced inhibition of vasomotion could be hyperpolarization of the cell membrane, which would block spontaneous depolarization set up by the sarcoplasmic reticulum basic oscillator. It could also be a direct effect of cAMP on the sarcoplasmic reticulum by influencing intracellular calcium availability, uptake, and/or release (17).

Although LDF yields no absolute blood flow values, the LDF values correlate strongly with simultaneously obtained absolute blood flow values using the total venous outflow technique both in humans and animals (24,25). Furthermore, the LDF values from the mucosal side of the jejunum correlate strongly with simultaneously obtained absolute mucosal/submucosal blood flow measurements by hydrogen gas clearance and microsphere techniques (26). One advantage of the LDF technique is that it is possible to measure mucosal perfusion continuously, whereas the drawback is that measurements can be performed only at a local site and during intestinal quiescence because peristalsis causes motion artifacts. Peristalsis is, however, a smaller problem in patients during anesthesia/sedation compared with awake volunteers (27). Furthermore, during CPB, the occurrence of peristalsis is even more uncommon. Another limitation with the present study was that the effects of prostacyclin on intestinal mucosal perfusion were studied only during the influence of bolus doses of prostacyclin and not during a continuous steady-state infusion, which we were not able to obtain because of time restraints. However, the vasodilatory response to bolus prostacyclin lasted at least 90 seconds in all patients, during which time we were able to decrease/increase CPB flow rate from baseline (Fig. 4). It could be argued that decreasing the CPB flow rate to 1.8 L/min/m2 for 3-minute periods could have jeopardized organ perfusion in the present study. We consider this less likely, as Svo2 was ≥70% in all patients at a CPB flow rate of 1.8 L/min/m2. Prebypass values of cardiac index and mixed venous oxygen saturation, at a body temperature of 35°C–36°C, were 2.1 ± 0.4 and 67% ± 15%, respectively.

In conclusion, our results suggest that autoregulation of human JMP is well maintained during mild hypothermic CPB. Intestinal mucosal vasomotion and the capacity of the mucosa to autoregulate perfusion are abolished by vasodilation with prostacyclin.

The authors thank the perfusionists and the nursing staff at Sahlgrenska University Hospital Cardiothoracic Surgery Theater for their helpful assistance.


   Footnotes
 
Accepted for publication February 15, 2006.

Supported, in part, by grants from the Swedish Medical Research Council (13156) and the Göteborg Medical Society.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press