Influence of Oxygen Ventilation on Doppler Microemboli Signals in Patients With Artificial Heart Valves
Background and Purpose The purpose of this study was to evaluate the influence of inhalation of 100% oxygen on microembolic signal (MES) counts in patients with artificial cardiac valves.
Methods A total of 134 outpatients were examined. Transcranial Doppler baseline monitoring (45-minute duration) was performed in all patients under resting conditions. The first 30 patients subsequently underwent transcranial Doppler monitoring for at least 20 minutes under noninvasive positive pressure ventilation with 100% oxygen and for an additional 30 minutes under resting conditions. The same protocol was applied to all following patients with a baseline MES count ≥10, while the examination was discontinued in the remaining patients.
Results Baseline MES counts <10, which remained unchanged during oxygen inhalation and the subsequent resting period, were observed in 26 of 30 initial patients. A total of 46 patients with MES counts ≥10 were identified. Oxygen application was feasible in 43 patients. An exponential MES decrease was noted in 42 patients during oxygen inhalation (statistically significant in 38 patients), followed by a subsequent increase in 38 of 43 patients (statistically significant in 25 patients) under resting conditions.
Conclusions The exponential reduction of MES counts observed in this study corresponds to blood denitrogenation, thus strongly arguing for nitrogen bubbles as underlying embolic material in prosthetic valve carriers.
Detection of MES with the use of TCD has been described in various patient groups. A major drawback of this technique is its failure to provide conclusive information concerning the underlying embolic material. This issue is particularly important in the evaluation of individual risk profiles and application of adequate antihemostatic treatment.
The description of MES in prosthetic heart valve carriers1–5 initially caused significant concern because of the well-documented high stroke risk of these patients. However, the anticipated relationship between MES and prevalence of neurological complications could not be demonstrated, since recent studies reported no4,5 or at best marginally significant2,3 differences in MES counts between symptomatic and asymptomatic patients. Assumption of gaseous underlying material could explain this discrepancy, since microbubbles are bound to remain asymptomatic both by imploding or by crossing over to the venous circulation through the capillary bed. Several reports supported a gaseous nature of MES in valve patients, including the recent description of significant changes in MES counts during decompression6,7 or inspiration of 100% oxygen.7 The latter reports were weakened by both the very small sample size (a total of 3 patients undergoing decompression and 5 patients inhaling 100% oxygen) and the partially contradictory results.
We undertook this study to evaluate the influence of oxygen inhalation on MES counts in patients with different types of mechanical prosthetic heart valves.
Subjects and Methods
One hundred eighty-five outpatients with artificial heart valves were selected from the surgical database and contacted by mail to attend ultrasound monitoring. The medical records of all cases were reviewed, and the presence of hemodynamically significant carotid disease (>70% lumen stenosis on continuous-wave Doppler) served as an exclusion criterion. One hundred thirty-four patients finally attended. No temporal window was found in 11 patients, leaving 123 patients for further examination (66 males and 57 females; mean±SE age, 63±1 years; range, 16 to 80 years), in whom ATS (n=51), CM (n=36), and SJM (n=36) valves were inserted in the aortic (n=74), mitral (n=20), or both mitral and aortic positions (n=29). The time between valve insertion and TCD monitoring was 17±1 months (mean±SE; range, 2 to 28 months). None of the examined patients suffered from chronic obstructive airway disease.
The examination protocol entailed 45 minutes of TCD monitoring while the patient was breathing room air, a minimum of 20 minutes (this time period was extended depending on the patient’s cooperation) while the patient was breathing 100% oxygen, and an additional 30 minutes of TCD monitoring under resting conditions. An interim analysis was performed after examination of the first 30 patients. The remaining 93 patients were examined according to the aforementioned protocol if MES count in the initial 45 minutes was ≥10. Otherwise monitoring was interrupted after the 45-minute monitoring.
Monitoring was performed bilaterally with the 2-MHz probes of a pulsed Doppler machine (Pioneer 4040, EME) with the use of a Marc 500 head frame (Spencer Technologies). All sessions were saved on DAT tapes with an eight-channel DAT recorder (TASCAM DA 88). Settings of the Doppler machine were kept unchanged through each examination (window overlap, 44%; sample volume, 7 to 10 mm; depth, 50 to 58 mm; gain was as low as possible, so that the background middle cerebral artery signal appeared pale blue).
MES were recognized, according to standard criteria according to a recent consensus,8 by a single examiner who was present during all monitoring sessions. In short, detection criteria were (1) characteristic acoustic quality, (2) unidirectionality of signal, (3) random appearance within the cardiac cycle, and (4) intensity increase ≥3 dB above background. The provided MES counts represent the sum of both middle cerebral arteries. Differences between the two sides were not evaluated for the purposes of this report.
Evaluation of the reliability of MES counts was performed by distributing 10 randomly selected tapes (≈20 hours of material) to two additional experienced observers, blinded to the initial results or the monitoring details. These observers were asked to note both the position of each high-intensity signal identified as MES on tape (using the tape counter of the DAT recorder) and the total MES count per patient.
Application of Oxygen
Noninvasive positive pressure ventilation was performed in all cases with the use of an Evita 2 ventilator (Draeger). Patients were breathing spontaneously through a clear facial mask. This was placed over mouth and nose and held in place by an examiner, providing downward pressure with thumb and first finger to ensure a tight seal. The respirator was set to apply a PEEP of 5 cm H2O, while oxygen flow was set to 60 L/min and oxygen concentration at 100%. Patients were instructed to breathe normally, avoid hyperventilation or hypoventilation, and immediately give notice if breathing became uncomfortable or other respiratory or cardiac complaints occurred. End-expiratory CO2, PEEP, and total minute ventilation were continuously registered. Thus, leakage of the mask and alterations of inspiratory oxygen concentration could be immediately detected by decrease of PEEP under the preset value of 5 cm H2O. The duration of oxygen application was subject to tolerability. Patients unable to tolerate the minimum of 20 minutes were excluded from the study. Maximum duration was planned as 3 hours.
Normally and nonnormally distributed data were expressed as mean±SE, median, and 95% confidence intervals. Unpaired t and Mann-Whitney tests were used to compare normally and nonnormally distributed data, and the χ2 test was applied for comparison of frequencies. MES counts were expressed as total during each period and as counts during each 5-minute subperiod. The latter approach was applied to acquire enough data to compare intraindividual changes in MES counts. Ideally, at least six 5-minute MES values while the patient was breathing 100% O2 were available from each patient and were compared with the nine and six 5-minute values during the initial and subsequent resting phases, respectively, using the Mann-Whitney test.
To graphically display the acquired data, the total MES value of the initial 45 minutes was divided by 9 and set at 100%. All MES counts measured on subsequent 5-minute subperiods were expressed as a percentage of the initial value. Median and 95% confidence intervals of these counts were calculated from all patients undergoing assisted ventilation. Nonlinear regression was performed to evaluate the best fit of the data.
Interobserver variability was assessed by comparing MES counts provided by each examiner. Since the exact position of each high-intensity signal on tape was also noted, a separate evaluation of the number of signals unanimously accepted as MES was performed. This count was compared with the total number of signals characterized as MES by a single examiner. Significance was declared at the P<.05 level.
The results of the 24 of 30 initial patients with low (<10 in 45 minutes) MES counts are listed in Table 1⇓. No significant changes in MES counts were evident under oxygen inhalation or in the subsequent 30 minutes. However, in aggregate, the total number of MES present initially decreased from 36 to 12.
A total of 47 patients (38.2%) had MES counts ≥10 in the initial 45 minutes. Three of these patients did not tolerate oxygen inhalation long enough (3, 5, and 17 minutes, respectively), while the mask could not be tightly applied in 1 additional patient because of facial hair. Duration of oxygen inhalation in the remaining 43 patients was 50±3 minutes (mean±SE; range, 20 to 190 minutes). The influence of oxygen inhalation on MES counts is displayed in Table 2⇓. A reduction in MES counts was found when we compared the individual values in 42 of 43 patients (97.6%). This reached statistical significance in 38 patients (88.3%). A significant increase in MES counts was observed in a single patient (patient 31). This patient complained of chest tightness and dizziness that led to immediate termination of oxygen application, after which his symptoms promptly ceased. Two additional patients complained of perioral paresthesia during the last 2 minutes of oxygen application. This was attributed to hyperventilation and subsided within the first 2 minutes of breathing under resting conditions. These were the only adverse effects observed in this study. The normalized results of all examined patients are displayed in the Figure⇓, panel A. An exponential decay equation (Figure⇓, panel A) provided the best data fit (R2=.96), according to the formula y=63×e−1.2 t (/5 min)+36, which corresponds to y=63/e0.24 t (min) +36. The half-life was calculated as 0.49 t=2.5 min.
An increase in MES counts after termination of oxygen inhalation was observed in 38 patients (88.3%) and reached statistical significance in 25 patients (58.1%). A statistically insignificant reduction of MES counts was observed in 3 patients (7%), while counts of the remaining 2 patients (4.6%) remained unchanged. Evaluation of the normalized data demonstrated that the best fit (R2=.67) was provided by an exponential association equation (Figure⇑, panel B), according to the formula y=93.8×(1−e−1.4 t [/5 min]), which corresponds to y=93.8×(1−1/e0.28 t [min]). The half life was calculated as 0.63 t=3.15 min.
Comparison of the baseline MES counts (45 minutes) with the 30-minute monitoring after oxygen application revealed a significant count reduction in 12 (27.9%), a statistically insignificant reduction in 17 (38.8%), no change in 2 (4.6%), and a statistically insignificant increase in 12 patients (27.9%) (Table 2⇑).
The interobserver variation in MES counts was low (observer 1 versus observer 2, P=.88; observer 1 versus observer 3, P=.90; observer 2 versus observer 3, P=.79). A total of 1028 high-intensity signals (82.6%) were identified as MES by all observers, an additional 125 (12.4%) by two observers, and 50 (5%) by only one observer.
Some basic physiological considerations must be taken into account before our results are analyzed. Inspiration of 100% oxygen initially leads to alveolar denitrogenation. According to a recent study, this occurs in an exponential function, whereby approximately 83% of nitrogen content is eliminated during the first minute, followed by a further 9% in each additional minute.9 Thus, approximately 3 minutes are warranted for complete alveolar denitrogenation. At the same time, nitrogen washout from blood also occurs exponentially, requiring approximately 3 hours for a 90% reduction of nitrogen storage (M.P.S., unpublished data, 1960). Thus, assuming nitrogen bubbles as underlying embolic material in patients with artificial heart valves, one would expect (1) an exponential reduction in MES counts under 100% oxygen respiration and (2) a complete elimination of MES after at least 3 hours of oxygen application. The first condition is in accordance with our results: only 5 minutes were required for the initial MES count decline from 100% to 50%, while the further reduction from 50% to 30% was far slower, taking almost 60 minutes. Unfortunately, the duration of oxygen application in this study was shorter than intended, since respiration through a tightly fitting facial mask was only tolerable for limited time periods. Statistically reproducible results were therefore only obtained for the first 60 minutes of oxygen inhalation, providing definitive statements over a potential elimination of MES.
The significant increase of MES counts observed only in patient 31 is difficult to explain, in particular in the absence of obvious differences between this and remaining patients. Unfortunately, the patient was reluctant to repeat the study because of the aforementioned adverse effects. Thus, it remains uncertain if the observation was coincidental or due to a specific constellation of this particular case. The duration of oxygen inhalation in the 4 patients demonstrating an insignificant decrease of MES counts was not shorter than in the remaining patients (20, 25, 55, and 125 minutes; Table 2⇑). Individual differences in the temporary requirements of the denitrogenation procedure (in particular depending on lung function) could cause this finding. Additionally, we must note that although hemodynamically significant carotid disease was excluded in all patients, a portion of the detected MES could still arise from coexisting aortic or native cardiac embolic sources. The quantity of these MES would obviously not be affected by oxygen inhalation. The observed increase of MES after termination of oxygen inhalation in the majority of patients also argues against our findings being coincidental.
Oxygen application in 5 MES-positive patients with artificial heart valves with a closely fitting facial mask, resulting in an immediate, complete elimination of MES in 4 patients, was recently described by Kaps et al.7 The immediacy of this elimination is in contrast to both our results and the physiology of the denitrogenation process described above. This finding is even more surprising when one takes into account that oxygen was applied by a tightly fitting mask without the use of assisted ventilation. The fraction of inspired oxygen that actively reaches the lungs under this regimen is always less than the concentration delivered because of the mixing of incoming oxygen with ambient room air entrained by the mask10 and is strongly dependent on the breathing pattern,11 further increasing the temporary requirements of the denitrogenation process. We can provide no explanation for this discrepancy and can only suggest that this was due to the preliminary character of the report of Kaps et al and the low number of examined patients.
The low interobserver variability observed in this study could be due in part to the fact that MES in prosthetic valve carriers are of higher intensity than those in patients with native embolic sources12 and thus easier to identify. Additionally, all observers were trained in the same vascular laboratory and used identical identification criteria for MES.
It must be stressed that our results only apply to patients with prosthetic cardiac valves and cannot be extrapolated to other patients with potential native cardiac or arterial embolic sources. While one could assume that cavitation bubbles could be formed in patients with carotid disease through the acceleration of blood distal to or the deceleration proximal to the stenosed segment, the local velocities and pressure gradients required for formation of cavitation bubbles (13 m/s and 670 mm Hg, respectively)13 are hardly reached even by the tightest carotid stenosis. Additionally, if the underlying embolic material in these patients consisted of cavitation bubbles, the intraindividual rate of microembolism would be constant because the pressure gradients depend solely on the degree of stenosis and are hardly expected to change within the time of the examination. Similarly, no differences in MES counts between neurologically symptomatic and asymptomatic patients would be expected because cavitation bubbles would easily cross over to the venous side without causing major vessel obstruction. These conditions, however, are in contrast to the results of numerous studies in patients with carotid disease.14–18
Our results thus suggest that cavitation bubbles are responsible for a large proportion of the MES in patients with prosthetic heart valves. In vitro studies in circulatory mock loops have estimated the diameter of such bubbles to be approximately 10 μm,19 which is in agreement with the size estimations of Russel and Brucher,20 which were based on the intensity of MES signals. Still, the collapse time of cavitation bubbles, as assessed with Rayleigh’s formula,21 is determined as approximately 0.1 msec, which is in agreement with observations in circulatory mock loops.19,22 Additionally, cavitation thresholds assessed in vitro suggest that these are higher in BSM and SJM than in MH valves.19 MES counts, however, are highest in patients with BSM valves, significantly lower in SJM valve carriers, and lowest in those with MH valves.3,4 While this result provides a further discrepancy in the theory that cavitation is the underlying mechanism in MES generation, it refers to the total count of cavitation bubbles. Formation of larger cavitation bubbles, which are energetically more stable, has been reported.23 We hypothesize that a proportion of these could survive long enough to enter the systemic circulation and that MES should thus be related to the amount of larger bubbles rather than to the total count of cavitation bubbles. Additionally, water or normal saline was used as a circulating fluid in most in vitro models, preventing the evaluation of potential interactions between bubbles and blood, which could increase both bubble stability and life span.
In summary, the present study equivocally demonstrated that respiration of 100% oxygen causes a reduction of MES counts in patients with prosthetic heart valves. This observation suggests that the principle underlying embolic material for the majority of MES in these patients consists of nitrogen bubbles, released from solution through fluid acceleration and deceleration caused by valve closure.
Selected Abbreviations and Acronyms
|PEEP||=||positive end-expiratory pressure|
|SJM||=||St Jude Medical|
|TCD||=||transcranial Doppler sonography|
- Received June 30, 1997.
- Revision received July 22, 1997.
- Accepted August 14, 1997.
- Copyright © 1997 by American Heart Association
Braekken KS, Russell D, Brucher R, Svennevig J. Incidence and frequency of cerebral embolic signals in patients with a similar bileaflet mechanical heart valve. Stroke. 1995;26:1225–1230.
Sliwka U, Diehl RR, Meyer B, Schönhube F, Noth J. Transcranial Doppler ‘high-intensity transient signals’ in the acute phase and long-term follow-up of mechanical heart valve implantation. J Stroke Cerebrovasc Dis. 1995;5:139–146.
Georgiadis D, Grosset DG, Kelman AW, Faichney A, Lees KR. Incidence and characteristics of intracranial microemboli signals in patients with different types of prosthetic cardiac valves. Stroke. 1994;25:587–592.
Georgiadis D, Kaps M, Berg J, Mackay TG, Herlein FW, Wheatley DJ, Lees KR. TCD detection of microemboli in prosthetic heart valve patients: dependency upon valve type. Eur J Cardiothorac Surg. 1996;10:253–258.
Spencer MP. Hyperbaric compression and Doppler-detected microemboli in prosthetic valve patients. Cerebrovasc Dis. 1996;6(suppl 3):69. Abstract.
Kaps M, Hansen J, Weiher M, Tiffert K, Kayser I, Droste DW. Clinically silent microemboli in patients with artificial prosthetic aortic valves are predominantly gaseous and not solid. Stroke. 1997;28:322–326.
Consensus Committee of the Ninth International Cerebral Hemodynamics Symposium: Basic identification criteria of Doppler microembolic signals. Stroke. 1995;26:1123.
Berry CB, Myles PS. Preoxygenation in healthy volunteers: a graph of oxygen ’washin’ using end-tidal oxygraphy. Br J Anaesth. 1994;72:116–118.
Goldstein RS, Young J, Rebuck AS. Effect of breathing pattern on oxygen concentration received from standard face masks. Lancet. 1982;27:1188–1190.
Grosset DG, Georgiadis D, Kelman AW, Lees KR. Quantification of emboli from cardiac, carotid source. Stroke. 1993;24:1922–1924.
Siebler M, Sitzer M, Rose G, Benfeldt D, Steinmetz H. Silent cerebral embolism caused by neurologically symptomatic high-grade carotid stenosis: event rates before and after carotid endarterectomy. Brain. 1993;116:1005–1015.
Babikian VL, Hyde C, Pochay V, Winter MR. Clinical correlates of high-intensity transient signals detected on transcranial Doppler in patients with cerebrovascular disease. Stroke. 1994;25:1570–1573.
Siebler M, Nachtmann A, Sitzer M, Rose G, Kleinschmidt A, Rademacher J, Steinmetz H. Cerebral microembolism and the risk of ischemia in asymptomatic high-grade internal carotid artery stenosis. Stroke. 1995;26:2184–2186.
Sitzer M, Siebler M, Steinmetz H. Silent emboli and their relation to clinical symptoms in extracranial carotid artery disease. Cerebrovasc Dis. 1995;5:121–123.
Forteza AM, Babikian VL, Hyde C, Winter M, Pochay V. Effect of time and cerebrovascular symptoms on the prevalence of microembolic signals in patients with cervical carotid stenosis. Stroke. 1996;27:687–690.
Russel, D, Brucher R. The size of cerebral micromboli in prosthetic heart valve patients. Stroke. 1995;26:733. Abstract.
Rayleigh OM. On the pressure developed in a liquid during the collapse of a spherical cavity. Phil Mag. 1917;34:94–98.
Tomita Y, Shima A. Mechanism of impulsive pressure generation and damage pit formation by bubble collapse. J Fluid Mech. 1986;13:535–564.
Wu ZJ, Wang Y, Hwang NH. Occluder closing behavior: a key factor in mechanical heart valve cavitation. J Heart Valve Dis. 1994;3(suppl 1):25–34