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Anesth Analg 2004;99:1018-1023
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000132551.92524.E7

CARDIOVASCULAR ANESTHESIA

Angiotensin-Converting Enzyme Activity: A Novel Way of Assessing Pulmonary Changes During Total Knee Arthroplasty

Kethy Jules-Elysee, MD, Thomas J. J. Blanck, MD, John D. Catravas, PhD, George Chimento, MD, Alexander Miric, MD, Richard Kahn, MD, Leonardo Paroli, MD, and Thomas Sculco, MD

Department of Anesthesiology, Hospital for Special Surgery, New York, New York

Address correspondence and reprint requests to Kethy Jules-Elysee, MD, Department of Anesthesiology, Hospital for Special Surgery, 535 E. 70th St., New York, NY 10021. Address e-mail to flynne{at}hss.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Emboli after tourniquet release (TR) during total knee arthroplasty (TKA) occur in all patients. This may lead to fat embolism syndrome with lung injury. Angiotensin-converting enzyme (ACE) lines the pulmonary endothelium, and a decrease in ACE metabolism or hydrolysis of 3HBPAP (3H-benzoyl-Phe-Ala-Pro; a substrate specific for ACE) has been associated with lung injury. We evaluated the association of this assay with pulmonary changes during TKA. Eleven consecutive patients undergoing bilateral TKA had the ACE assay performed perioperatively. We determined substrate hydrolysis and pulmonary capillary surface area (capillary perfusion index; CPI) and correlated it with pulmonary vascular resistance (PVR) and clinical outcome. Ten of the 11 patients demonstrated an increase in substrate hydrolysis and CPI along with a decrease in PVR after first or second TR when compared with baseline values (P < 0.05). In the other patient, PVR continued to increase even after TR, whereas CPI and substrate hydrolysis decreased after surgery. Whereas all others did well clinically, this patient developed confusion and hypoxemia. In previous studies, a decrease in PVR with an increase in CPI, as exhibited by the 10 patients, has been associated with pulmonary capillary recruitment. We believe this to be an important mechanism by which the lungs are able to accommodate the burden of emboli at the time of TR.

IMPLICATIONS: The embolic phenomenon to the heart and lungs occurs in all patients undergoing total knee arthroplasty at the time of tourniquet release. This study investigates possible mechanisms that allow most patients to tolerate such insults to their lungs without clinical complications.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The embolic phenomenon after tourniquet release (TR) during total knee arthroplasty (TKA) has been very well described (1–4). According to Berman et al. (1), immediately after TR, echogenic material is seen in the hearts of all patients. Although well tolerated by most, this phenomenon may lead to cardiac arrest or fat embolism syndrome (FES) in specific patients (5,6). The hallmarks of FES include respiratory and cerebral involvement, which are experienced in 75% and 80% of patients with the syndrome, respectively (7). In patients experiencing cardiac arrest or FES, increased pulmonary arterial pressure with increased pulmonary vascular resistance (PVR) and decreased arterial oxygen saturation are typically seen (8,9). Given that the occurrence of emboli at the time of TR is universal, why are the manifestations of FES so uncommon? This study explores possible mechanisms by which the lungs adapt to the effects of TR.

Pulmonary endothelial dysfunction is an early and sensitive index of lung injury (LI) (10,11). Angiotensin-converting enzyme (ACE), which lines the pulmonary endothelium, has been extensively studied in various models of lung injury (LI). It is a dipeptidyl carboxypeptidase with its catalytic site exposed to the vascular lumen (12–14). It converts angiotensin I to the potent vasoconstrictor angiotensin II. ACE inhibition, assessed by its ability to metabolize the substrate 3HBPAP (3H-benzoyl-Phe-Ala-Pro), has been used as a measure of the degree of LI (15–17). It has also been used to estimate changes in the pulmonary capillary surface area of the lung. 3HBPAP is pharmacologically inert and specific for ACE and has been studied both in animal models and in humans. This assay, with the ability to detect LI before clinical manifestations, has never been assessed in the setting of joint replacement. We used it in our patients undergoing bilateral TKA in an attempt to monitor pulmonary changes—including ACE metabolism and alterations in pulmonary capillary surface area—that can occur in that setting. This was subsequently correlated with hemodynamic variables and clinical outcome.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After IRB approval and informed consent, 14 consecutive patients scheduled for bilateral TKA were enrolled. All 14 patients received combined spinal/epidural anesthesia (CSE) performed at L3-4. They were all monitored with electrocardiogram and pulse oximetry. A radial arterial catheter (20 gauge) and a thermodilution pulmonary artery catheter (Edwards Swan-Ganz; Baxter Health Care Corporation, Edward Critical Care Division, Irvine, CA) were inserted in each patient before CSE.

The single arterial blood sample technique, according to Toivonen et al. (18), was used in the study to measure ACE activity level. The patient was injected with a bolus of 1 mL of saline containing trace amounts of 3HBPAP (20 µCi) through a central line, as previously described.1 Simultaneously, 20 mL of blood was withdrawn from the radial artery and added to 30 mL of 1 mmol/L captopril in saline to prevent further hydrolysis of the substrate by blood ACE. The blood was then assayed for 3HBPAP and its metabolite 3H-benzoyl-phenylalanine by acid separation and scintillation counting of tritium. Cardiac output (CO) and hemodynamic functions were obtained by using the thermodilution technique immediately after the ACE assay. The assay was performed before tourniquet inflation, 5 min after first TR, and 2 h after admission to the postanesthesia care unit (PACU) (the tourniquet was inflated before incision and deflated after insertion of all components). In five patients, the assay was also performed before the induction of CSE.

Each sample obtained after injection of the substrate was mixed and centrifuged for 10 min at 3000 rpm to separate blood cells from plasma. Two 1.5-mL aliquots of the supernatant were transferred into polyethylene scintillation vials. Total radioactivity was estimated with the first aliquot in the presence of Ecoscint A scintillation cocktail by a liquid scintillation spectrometer. To separate metabolite from parent compound, 9 mL of 4 g/L Omnifluor in toluene was added to the second 1.5-mL aliquot, which contained 7.5 mL of 0.12 N hydrochloric acid. Radioactivity was estimated within 30 min of equilibrium.

Transpulmonary substrate use was measured by applying the integrated Henri-Michaelis-Menten equation under first-order kinetics as proposed by Ryan (19):


Formula 1

where V is the transpulmonary substrate hydrolysis of 3HBPAP, [E] is the microvascular enzyme concentration, tc is the reaction time (microvascular mean transit time), kcat is the catalytic rate constant, [S0] = [3HBPAP] + [3H-benzoyl-phenylalanine] (initial substrate concentration in arterial plasma), [S] is [BPAP] (final concentration of surviving substrate in the arterial plasma), and Km is the Michaelis constant, which reflects the concentration of substrate required to achieve half the maximum velocity of the enzyme.

Because ACE is distributed homogeneously over the pulmonary endothelial luminal surface, the amount of capillary surface area exposed determines how much ACE is available to interact with a substrate. Under first-order kinetics, the pulmonary capillary perfusion index (CPI) is proportional to enzyme mass and, hence, to the perfused capillary surface area. Consequently, data were further analyzed with the integrated Henri-Michaelis-Menten equation as modified by Catravas and White (17). CPI or Amax/Km as a measure of pulmonary capillary surface area was calculated as follows:


Formula 2



Formula 3

where E is the total enzyme mass as described previously, Qp is pulmonary plasma flow, and Qpmv is the microvascular plasma volume, which can be altered by changes in hematocrit (Hct). When Km and kcat are constant, Amax is proportional to the available enzyme mass. Vmax is the maximum enzyme catalytic activity and is proportional to total enzyme concentration; %M is the percentage of substrate metabolized.

Patients were observed for any sign of clinical pulmonary abnormality. Arterial blood gases on a 3-L nasal cannula were analyzed for the presence of hypoxemia (PaO2 <60 mm Hg). Hct was measured before the cementing of joint prostheses, immediately afterward, and 2 h after wound closure while in the recovery room. Pulmonary artery pressures, PVR, and CO were also monitored closely and recorded at the same time blood gases were drawn. Pulmonary capillary surface area (CPI) and pulmonary substrate utilization (ln S0/S) were correlated with hemodynamic changes, clinical signs, and eventual outcome. Hct, drawn at the different stages of the study, was used to calculate CPI and correct for any changes in plasma volume.

Data were analyzed with analysis of variance for repeated measures. Differences were considered significant at P < 0.05. Patient 4 had postoperative confusion. Data from this patient were compared with those of the other patients to assess differences.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Of the 14 patients, 2 were eliminated from data analysis because they were receiving ACE inhibitors, which interfered with the assay (Patients 5 and 6; Table 1). Very low values for the percentage of substrate metabolism (5%–10%) and hydrolysis (ln S0/S) were seen in these patients. They were enrolled in the study before we knew that they were taking ACE inhibitors. Patient 2 was also excluded from analysis because surgery was changed from bilateral TKA to unilateral TKA because of a history of pulmonary fibrosis and a chest radiograph showing bilateral interstitial infiltrates.


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  		Table 1. Demographics
 
Data from the remaining 11 patients were analyzed and are presented in Tables 1–3. There were six women and five men. The mean age was 70 ± 7 yr. The mean weight was 90 ± 31 kg. Only three had hypertension, but none was taking ACE inhibitors. One patient was a smoker. To assess possible effects of CSE on our results, five of these patients had the assay performed before the induction of CSE. A decrease in PVR after placement of CSE was seen in all five of these patients (–21% ± 12%; Patients 3, 9, 10, 12, and 14), but of these five patients, an increase in substrate hydrolysis was noted in two (29% ± 10%; Patients 9 and 14), and an increase in CPI was noted in three (35% ± 35%; Patients 3, 9, and 14). There was no correlation between CO and changes in PVR, CPI, and substrate hydrolysis (ln S0/S).


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  		Table 2. Hemodynamic Variables and Lung Indices at Different Stages of Bilateral Knee Replacement
 

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  		Table 3. Comparison and Percentage Change in Hemodynamic Variables and Lung Indices at Different Stages of Bilateral Knee Replacement
 
Every patient had the assay performed post-CSE, after first TR, and 2 h after wound closure. Among all patients except Patient 4, a decrease in PVR occurred after first TR compared with either preepidural or post-epidural values. This was accompanied by an increase in substrate hydrolysis (33% ± 24%) and an increase in CPI (40% ± 33%) in 9 (90%) of 10 of these patients (Tables 2 and 3); in Patient 1, these values decreased slightly (P > 0.05).

In nine patients (Patients 4 and 13 were excluded), PVR was still lower compared with either pre- or post-epidural values 2 h after wound closure while in the PACU (Tables 2 and 3). Among this group, CPI and substrate hydrolysis increased by 93% ± 150% and 87% ± 133%, respectively, in eight patients and remained mainly unchanged in Patient 12 (Table 3). Patient 13, who initially had a decrease in PVR after the first TR, had an increase in PVR in the recovery room compared with baseline, but CPI remained almost unchanged. In Patient 4, PVR increased by 4% at the time of first TR and continued to increase in the PACU (12%), whereas CPI increased by 7% after first TR but then decreased by 42% when it was measured in the PACU (Table 3).

When the 10 patients who did not become confused were considered as a group, PVR decreased after first TR and did not increase after surgery, whereas substrate hydrolysis and capillary surface area increased (Fig. 1; all changes were significant with P > 0.05, analyzed with analysis of variance for repeated measures). In contrast, in Patient 4, who developed postoperative confusion, CPI markedly decreased after surgery, whereas PVR remained increased (Fig. 2). No correlation could be made with a history of smoking. Forty-five percent of patients were ex-smokers, whereas only one was a current smoker. There was no correlation with age, sex, weight, or height in terms of changes in CPI, PVR, or substrate hydrolysis with TR.


Figure 1
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  		Figure 1. PVR, substrate hydrolysis (ln S0/S), and CPI during the perioperative period; data are mean with SE bars (excluding Patient 4). PVR = pulmonary vascular resistance; CPI = capillary perfusion index; ln S0/S = transpulmonary hydrolysis of 3H-benzoyl-Phe-Ala-Pro; RR = recovery room.

 

Figure 2
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  		Figure 2. Comparison of PVR and CPI during the perioperative period for Patient 4 and the group mean. PVR = pulmonary vascular resistance; CPI = capillary perfusion index.

 
All patients did well clinically, and none developed hypoxemia (PaO2 < 60 mm Hg) throughout the hospital course. None had pulmonary complications or mental status changes, except for Patient 4, who had some mild postoperative confusion. She was also mildly hypoxemic (PaO2 < 60 mm Hg), with an increased alveolar-arterial gradient from baseline, but had a normal chest radiograph. No other cause for the hypoxemia or mental status changes could be found.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
TR is a critical time during TKA. It is associated with showers of fat, marrow, and thrombovascular emboli reaching the heart and lungs (1). Increased PVR appears to be associated with the size of the emboli. However, not all patients who have large emboli subsequently develop FES. What allows patients to tolerate such events without complications is unclear (1).

Studies of oxygen-induced LI in animal models have shown altered metabolism and use of substrate by ACE during early phases of lung damage, even without morphological or clinical signs of pulmonary dysfunction (11). Consequently, we used the ACE assay to assess pulmonary effects of TR. The validity of the ACE assay was confirmed by the two patients who were receiving ACE inhibitors. These drugs should inhibit the metabolism of 3HBPAP by the ACE found on the pulmonary endothelium. They were excluded from analysis because the ACE inhibition interfered with the assay, according to the low metabolism noted (5%–10%) and the minimal transpulmonary hydrolysis (ln S0/S). Furthermore, the results of this ACE assay have been found to be highly reproducible in patients. Values of ln S0/S and CPI vary by 6% and 8%, respectively, among successive determinations within the same stable subject, suggesting that the accumulation of errors in the calculation of these two variables is minimal (20).

Our study revealed a decrease in PVR within 5 minutes of TR in 10 of 11 remaining patients compared with either pre- or post-CSE values. This was also associated with an increase in substrate use and pulmonary capillary surface area. The only way to have such an effect is with greater availability of ACE from the pulmonary endothelium. 3HBPAP has a very short half-life, which would prevent its accumulation in blood. Because ACE is also found in blood, a stop solution was used to prevent an interaction between blood ACE and 3HBPAP in our samples, thus making this a very unlikely possibility. The most likely explanation for the observed increase in pulmonary capillary surface area (CPI) is recruitment of unused capillary beds lined by ACE on their endothelial surface. This is substantiated by a decrease in PVR. Toivonen and Catravas (21), using the same assay to assess changes in CPI, were able to demonstrate evidence for the same phenomenon of microvascular recruitment seen in our patients in a rabbit model with more blood flow through the lungs. This was accompanied by a decrease in PVR and an increase in CPI, as seen in our patients. They attributed this to the increased blood flow. As CO or blood flow increased to the lungs, unused pulmonary capillaries opened to accommodate the increased flow, thus leading to a decrease in PVR. In our patients, CO increased minimally in some but not all patients, making this unlikely to be the main factor. Another possibility is the release of nitric oxide (NO), known to be a major regulator of vascular tone, at the time of TR (22). The endothelium releases vasoactive mediators, including NO, that act locally to affect the behavior of smooth muscle cells (23,24). It should be noted that changes in PVR should be interpreted cautiously, with consideration to the compound nature of the variable and the fact that it reflects contributions from both CO and pulmonary arterial pressure. Other studies are needed to investigate this further.

The decrease in PVR was unexpected in our patients because TR and release of emboli to the lungs has been associated with increased vascular resistance. A possible reason for this unexpected response may be related to the size of the emboli. With smaller emboli, PVR may not increase (1). Our patients did not have an intraoperative echocardiogram performed to determine this, but it was assumed in accordance with previous studies that all patients have detectable emboli in their hearts at the time of TR. In many of the reports on TKA and the risk of FES, patients have had general anesthesia (1). At our institution, a major orthopedic hospital, most of our patients undergo regional anesthesia for joint replacement. Increased pulmonary arterial pressure and PVR after TR are rare. We looked into the use of CSE as a possible contributing factor to our results. Although a decrease in PVR was seen in the five patients who had the assay performed before placement of the epidural catheter, there was no consistent correlation between PVR and CPI.

Interestingly, the only patient who had any possible sign of FES (Patient 4), postoperative mental status changes, and hypoxemia had an increase in PVR with a decrease in substrate use and CPI two hours after wound closure. Although more patients need to be studied, this study indicates that vasodilation of the pulmonary bed with capillary recruitment does occur in most patients after TR. This may be the mechanism by which the lungs are able to accommodate the burden of emboli at the time of TR, thus preventing an increase in PVR and its subsequent consequences.


   Footnotes
 
1Catravas JD, Cziriki A, Shapiro M. Reduction in the transpulmonary hydrolysis [3H]-benzoyl-Phe-Ala-Pro by capillary endothelium-bound angiotensin-converting enzyme in patients diagnosed with the adult respiratory distress syndrome [abstract]. Am J Respir Crit Care Med 1995;151:A73. Back


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Berman AT, Parmet JL, Harding SP, et al. Emboli observed with use of transesophageal echocardiography immediately after tourniquet release during total knee arthroplasty with cement. J Bone Joint Surg Am 1998; 80: 389–96.[Abstract/Free Full Text]
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  3. McGrath BJ, Hsia J, Boyd A, et al. Venous embolization after deflation of lower extremity tourniquets. Anesth Analg 1994; 78: 349–53.[Web of Science][Medline]
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Accepted for publication April 27, 2004.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press