Adrenomedullin (AM) is a vasodilatory peptide isolated from human pheochromocytoma tissue (1). The peptide consists of 52 amino acids and shows a homology with calcitonin gene-related peptide (1). AM has been widely detected in human plasma, adrenal medulla, kidney, lung, and heart (2). AM is produced in two steps: AM-glycine, an intermediate form (iAM) 53-amino acid peptide is processed from an AM precursor, and its C-terminus is then enzymatically amidated, which converts it into a biologically active mature form (mAM). Both iAM and mAM are present in human plasma (3).
Plasma concentrations of AM reportedly increase in patients with abnormal cardiovascular function, such as hypertension (4), renal failure (4), congestive heart failure (5), and septic shock (6). Increased plasma concentrations of AM during cardiac surgery have been reported (7–9). However, these results were obtained with radioimmunoassay (RIA), which recognizes the entire AM molecule (total AM, or tAM). To date, the physiological role of AM remains obscure, partly because mAM levels have not been analyzed. Recently, a sensitive RIA method that specifically measures human plasma mAM has been developed (10).
Postoperative brain damage is one of the most serious complications of cardiopulmonary bypass (CPB), and inadequate cerebral perfusion relative to oxygen metabolism is a possible cause (11). An increase in the transcription rate of the AM gene in ischemic brain has been reported in rats (12). Dogan et al. (13) reported that an IV infusion of AM increases cerebral blood flow and prevents brain injury after middle cerebral artery occlusion in rats. Lang et al. (14) reported that AM dilates cerebral arterioles in rats. These studies suggest a possible relationship between AM and cerebral oxygen balance.
Therefore, we hypothesized that AM may be related to cerebral oxygen balance during cardiac surgery. To test this, we measured the plasma concentrations of mAM from the radial artery and internal jugular bulb blood, as well as jugular venous oxygen saturation (Sjo2), which may reflect cerebral oxygen balance (11,15), during and after CPB in patients undergoing coronary artery bypass grafting.
This study was approved by the IRB. After obtaining written informed consent, the authors studied nine patients, of either gender, who were undergoing elective coronary artery bypass grafting for coronary artery disease. Exclusion criteria were heart failure, hypertension, cerebrovascular disease, or liver, respiratory, or renal dysfunction.
Anesthesia was induced with 0.1 mg/kg midazolam and 4–8 μg/kg fentanyl. To facilitate tracheal intubation, 0.2 mg/kg vecuronium was given, and the lungs were ventilated with 33%–100% oxygen and air so that Paco2 was maintained between 35 and 40 mm Hg. A 4F oximetry catheter (Baxter Healthcare Corporation, Irvine, CA) was connected to an oximeter (Baxter Edwards Critical Care Division, Irvine, CA) and placed in the right jugular bulb, which is usually the dominant side (15), by using a retrograde internal jugular vein approach. Anesthesia was maintained with 0.5%–2% isoflurane and an intermittent bolus dose of 5–10 μg/kg fentanyl and 0.2–0.3 mg/kg midazolam. A continuous infusion of 2–4 mg/h nicorandil, a selective coronary vasodilator (16), was started before anesthesia was induced. Phenylephrine 0.1 mg was given to maintain mean arterial pressure >60 mm Hg. Acetated Ringer’s solution was infused at a rate of 1–15 mL · kg−1 · h−1 to maintain an adequate urinary output and central venous pressure until CPB was started. CPB was introduced and maintained with similar techniques in all patients. A nonpulsatile pump flow rate of 2.2–2.4 L · min−1 · m−2 was maintained by using a membrane oxygenator and an arterial line filter. Nasopharyngeal temperature was maintained at approximately 35°C (tepid hypothermia) in all patients. Paco2, uncorrected for temperature, was adjusted to a normocapnic level. Phenylephrine and nicardipine were used intermittently to maintain a perfusion pressure between 50 and 100 mm Hg. St. Thomas cold cardioplegia (Na+ 120 mEq, K+ 16 mEq, Mg++ 32 mEq, Ca2+ 2.4 mEq, HCO2− 10 mEq, C1− 160 mEq) was introduced via the antegrade aortic root and the retrograde coronary sinus every 30 min. If required, a continuous infusion of dopamine and norepinephrine was given to maintain a cardiac index >2.5 L · min−1 · min−2 and a systolic arterial pressure >90 mm Hg during weaning from CPB.
Blood samples were obtained from the radial artery and jugular bulb at the following times: immediately after an Sjo2 monitor was established (baseline), immediately before aortic cross-clamp (preclamp), immediately after aortic declamp (postclamp), and 20 min after weaning from CPB (post-CPB). To perform plasma assays, blood was placed in lithium heparin tubes and centrifuged. The sample supernatant was collected and stored at −33°C until assayed, and the concentrations of mAM were measured by RIA (Shionogi, Osaka, Japan). The details of this RIA are described elsewhere (10). The lower detection limit of this assay was 1.0 fmol/mL, and the intraassay and interassay coefficients of variance were 4.4%–8.2% and 5.5%–8.3%, respectively.
Data are expressed as mean ± sem. Changes in the concentrations of mAM in the plasma of blood obtained from the jugular bulb and radial artery were analyzed with analysis of variance and Fisher’s protected least significant difference as a post hoc test. Correlations between the concentrations of plasma mAM and Sjo2 at each time point were analyzed by calculating Pearson’s correlation coefficients. P < 0.05 was accepted as significant.
Patient characteristics are shown in Table 1. Table 2 illustrates changes of the plasma mAM concentrations from the radial artery and jugular bulb, as well as Sjo2 values. Plasma mAM concentrations in the radial artery (mAMa) and jugular bulb (mAMj) were significantly increased at postclamp (P < 0.01 for both) and post-CPB (P < 0.01 for both) when compared with baseline values. Post-CPB plasma mAMa and mAMj concentrations were significantly smaller than those obtained at postclamp (P < 0.01 for both). There were no significant differences between the plasma concentrations of mAMa and mAMj. The duration of surgery was significantly correlated with mAMa and mAMj concentrations at postclamp (r = 0.79 and 0.70, respectively) and at post-CPB (r = 0.83 and 0.71, respectively).
Figures 1 and 2 show the relationships between Sjo2 and plasma mAMa and mAMj concentrations, respectively, at each time point. Sjo2 correlated significantly with plasma mAMj concentrations at preclamp (r = 0.79, P < 0.01, n = 9), postclamp (r = 0.71, P < 0.05, n = 9), post-CPB (r = 0.72, P < 0.05, n = 9), and mAMa at preclamp (r = 0.79, P < 0.01, n = 9) and postclamp (r = 0.72, P < 0.05, n = 9).
The principle finding of this study is that the plasma concentrations of mAM in the jugular bulb correlate significantly with Sjo2 at every time point. No significant differences were observed between the values obtained from the radial artery and jugular vein. Significant decreases in plasma concentrations of mAM after CPB were observed.
Sjo2 reflects theoverall balance of cerebral oxygen supply and demand according to the following formula:MATHwhere CMRo2 = cerebral metabolic rate for oxygen and CDRo2 = cerebral delivery rate for oxygen. CDRo2 is calculated as CBF · Cao2, and Sao2 is about 1.0 during cardiac surgery, where CBF = cerebral blood flow and Cao2 = oxygen content. Thus, Sjo2 is a function of both CBF and CMRo2. Dogan et al. (13) reported that the IV administration of AM at 1.0 μg · kg−1 · min−1 increases regional CBF by 40% and reduces ischemic brain injury after middle cerebral artery occlusion in rats. Lang et al. (14) reported that AM 10−6M dilates cerebral arterioles by 40%. Taken together, it seems possible that an increased plasma concentration of mAM might dilate cerebral arterioles and increase CBF, thus explaining the observed increase in Sjo2 in this study. However, many other factors, such as blood pressure, cerebral vascular autoregulation, body temperature, and anesthesia influence cerebral oxygen balance during cardiac surgery. In addition, the effect of anesthesia is another influence. Recently, Hayashi et al. (17) reported that thiopental and etomidate increase and that propofol and midazolam decrease AM production in vascular smooth muscle cells in rats. In this study, anesthetics such as isoflurane, fentanyl, and midazolam may have affected plasma concentration of mAM. Further tightly controlled studies are needed to clarify the relationship between AM and cerebral oxygen balance during cardiac surgery.
We measured the plasma concentrations of mAM from both the radial artery and the jugular bulb and found no significant differences between the values obtained from either location. Recently, Inoue et al. (9) reported that the plasma concentration of tAM in the jugular bulb is significantly more than that found within the radial artery after CPB, and they speculated that AM might be produced in the brain (9). This is not consistent with our results. In the study of Inoue et al., nasopharyngeal temperature was maintained between 30°C and 33°C (mild hypothermia) during CPB. Nakajima et al. (11) reported that Sjo2 was significantly reduced during the rewarming period and that this decrease was related to the rewarming speed. Croughwell et al. (18) reported that 31 of 133 patients exhibited cerebral desaturation (Sjo2 < 50%) during the rewarming period after hypothermic (27°C–28°C) CPB. Wang et al. (12) reported that transcription of the AM gene increased by 20% in the ischemic brain of rats after middle cerebral artery occlusion. Although details regarding the status of cerebral oxygen balance or the rewarming technique used were not described in the report of Inoue et al., it is plausible that a transient cerebral oxygen imbalance stimulated AM production in the brain during the rewarming period. In the absence of a rewarming period, as in the study presented here, Sjo2 was not reduced. This suggests that little AM was produced in the brains of patients in our study. Another explanation is that iAM was generated in the brain and then converted to mAM elsewhere in the body. Little is definitively known about the site or sites of production and conversion of AM during cardiac surgery. Simultaneous measurements of tAM and mAM should prove helpful in clarifying the physiology of AM.
We observed significant decreases in plasma concentrations of mAM after CPB. This is not consistent with previous studies (7–9). In the report of Nishikimi et al. (8), plasma tAM concentrations continued to increase after CPB and peaked six hours after surgery. Inoue et al. (9) reported that plasma tAM concentrations were four times larger after CPB than those measured during CPB. In contrast, Nagata et al. (7) reported that plasma tAM concentrations were slightly smaller after 20 minutes of weaning from CPB than before; however, the differences were not significant. The clearance sites of AM are unknown. Recently, Ornan et al. (19) reported that the injection of I125 AM into the left ventricle resulted in a significant decrease in radioactivity in the lungs of rats. Hirayama et al. (20) reported that plasma mAM was significantly reduced in the pulmonary capillaries of humans, compared with that measured in the pulmonary artery. These results suggest that the lungs are the primary site of AM clearance. If so, it is suggested that the observed increase in mAM concentration during CPB, when the lungs are not being perfused, is, in part, caused by a decrease in its clearance. Therefore, our finding that plasma mAM levels are decreased after CPB seems more likely than the opposite findings mentioned in the aforementioned reports, because after CPB, the lungs are being reperfused and AM is being cleared. The differences noted in the results of our study and those of previous studies can, in part, be attributed to differences among measurement methods. In the previous studies, tAM was measured, whereas we measured only the concentration of mAM by using the newly developed sensitive RIA system. As described in the Introduction, tAM includes both iAM and mAM, and iAM comprises most of the tAM [reported as 80%(21)]. Hirayama et al. (20) reported that mAM levels were significantly reduced in the pulmonary circulation; however, such a reduction was not observed in the concentration of iAM. The post-CPB decrease in plasma mAM observed in this study may not be detected in studies that measure tAM.
In conclusion, the plasma concentration of mAM correlates with the degree of Sjo2 during and after CPB. This suggests that an increased AM concentration might be associated with cerebral oxygen balance during cardiac surgery.
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© 2001 International Anesthesia Research Society
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