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Table of Contents
ORIGINAL ARTICLE  
Year : 2013  |  Volume : 16  |  Issue : 4  |  Page : 245-249
Influence of ethanol-induced pulmonary embolism on hemodynamics in pigs


1 Department of Pathophysiological and Therapeutic Science, Division of Radiology, Tottori University, 36-1 Nishicho, Yonago, Tottori 683-8504, Japan
2 Department of Radiology, Tottori Prefectural Kosei Hospital, 150 Higashishowa-Machi, Kurayoshi, Tottori 682-0804, Japan
3 Department of Radiology, San-in Rosai Hospital, 1-8-1 Kaikeshinden, Yonago, Tottori 683-8605, Japan
4 R and D Center, Terumo Corporation, 1900-1 Inokuchi, Nakaimachi, Ashigarakami-Gun, Kanagawa 259-0151, Japan
5 Department of Microbiology and Pathology, Organ Pathology, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago, Tottori 683-8504, Japan

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Date of Submission06-Dec-2012
Date of Acceptance28-Jun-2013
Date of Web Publication1-Oct-2013
 

   Abstract 

Aims and Objectives: Ethanol is widely used for the embolization treatment of vascular malformations, but it can also cause serious complications such us pulmonary hypertension, cardiopulmonary collapse and death. The complications are considered secondary to pulmonary vasospasm and ethanol-induced sludge embolism, etc., We studied the hemodynamic effects of intravenous absolute ethanol injection and ethanol sludge injection in pigs. Materials and Methods: A total of 5 pigs underwent intravenous injection of ex vivo generated ethanol-induced sludge in which residual ethanol was removed (Group S) and 4 pigs underwent intravenous injection of absolute ethanol (Group E). Hemodynamic parameters related to the pulmonary and systemic circulation were compared between the groups. Results: Transient pulmonary hypertension was observed in both groups and the hemodynamic changes were similar in both groups. Conclusions: Sludge can induce transient pulmonary hypertension or cardiopulmonary collapse, without ethanol and may be the mechanism by which ethanol induces its adverse hemodynamic effects.

Keywords: Cardiopulmonary collapse; Ethanol; Pulmonary hypertension

How to cite this article:
Yata S, Hashimoto M, Kaminou T, Ohuchi Y, Sugiura K, Adachi A, Kawai T, Endo M, Takasugi S, Yamamoto S, Matsumoto K, Kodani M, Ihaya T, Takahashi M, Ito H, Ogawa T. Influence of ethanol-induced pulmonary embolism on hemodynamics in pigs. Ann Card Anaesth 2013;16:245-9

How to cite this URL:
Yata S, Hashimoto M, Kaminou T, Ohuchi Y, Sugiura K, Adachi A, Kawai T, Endo M, Takasugi S, Yamamoto S, Matsumoto K, Kodani M, Ihaya T, Takahashi M, Ito H, Ogawa T. Influence of ethanol-induced pulmonary embolism on hemodynamics in pigs. Ann Card Anaesth [serial online] 2013 [cited 2020 Jan 29];16:245-9. Available from: http://www.annals.in/text.asp?2013/16/4/245/119164



   Introduction Top


Ethanol is widely used for embolization of vascular malformations, but it is associated with serious hemodynamic complications including pulmonary hypertension, cardiopulmonary collapse and death. [1],[2],[3] Pulmonary vasospasm is considered as one of the key factor of these adverse hemodynamic effects. Other factor like sludge emboli, which is produced by interaction of ethanol with blood has been also implicated. [4] The main pathophysiologic mechanism of this phenomenon is thought to be pulmonary vasospasm as pulmonary hypertension and cardiopulmonary collapse are usually transient in nature. [5] Previous animal experiments have demonstrated that air bubble embolism can also induce transient pulmonary hypertension. [6] We hypothesized that ethanol-induced sludge may play an important role in the pulmonary hypertension and cardiopulmonary collapse in the context of complications associated with ethanol embolotherapy. In order to explore this hypothesis, we studied the hemodynamic effects of ethanol-induced sludge embolism in pigs.


   Materials and Methods Top


In vivo experiments were performed after approval of all protocols by the Animal Care and Use Committee of Our Institution. Nine pigs (weighing 38.0 to 44.7 kg, mean weight, 42.1 kg) were studied. Animals were anesthetized with halothane, intubated and positioned. Two 4-French (4-Fr) catheters (Terumo, Tokyo, Japan) were inserted through the right femoral vein into the main pulmonary artery: One was used for continuous pulmonary arterial pressure (PAP) monitoring and the other was used for pulmonary angiography. Another 4-Fr catheter was placed in the left femoral artery for continuous arterial pressure (AP) monitoring. The right external jugular vein was exposed and a 4-Fr sheath (Radifocus Introducer, Terumo, Tokyo, Japan) was placed. Ethanol-induced sludge was administered in five animals (Group S) and absolute ethanol in four other animals (Group E) through the sheath. In all animals hemodynamics were allowed to stabilize before data collection. Thereafter, the changes in PAP and AP were recorded for comparison between two groups.

Preparation of sludge solution

Sludge solution was generated ex vivo. This solution was generated by mixing 10 ml of absolute ethanol with 25 ml of a venous blood sample. After centrifugation at 3,000 rpm for 5 min blood serum was discarded to remove the ethanol fraction and then 20 ml of normal saline was added. The final "sludge solution" was obtained by repeating this process 3 times [Figure 1].
Figure 1: Ethanol-induced sludge. Ethanol interacting with blood produces embolic debris, consisting of denatured protein and cellular fragments. We refer this embolic debris as "sludge." The sludge consists of very small particles

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Injection of absolute ethanol or sludge solution

Animals received repeated intravenous injections of 2 ml of the sludge solution (Group S) or absolute ethanol (Group E) until there was a > 5 mmHg elevation in the mean (M) PAP. At this point, injections were discontinued and the animals were allowed to recover until MPAP returned to the baseline +5 mmHg ("recovery time"). Pulmonary angiogram was performed just before the start of injections and again at the time of MPAP elevation and at MPAP stabilization. The pattern of hemodynamic changes was recorded. Examinations were performed 1 or more times in each animal [Table 1]. A total of eight experiments were conducted in each animal group. All pigs were euthanized with an injection of KCl and 5000 IU of heparin solution at the end of the experiments. The lungs of all the animals were explanted and subjected to microscopic examination.
Table 1: Number of examinations in each pig

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   Results Top


Hemodynamic changes

A similar pattern of hemodynamic changes was seen in both the animal groups. Pig #2 (Group E) and pig #6 (Group S) died due to severe cardiopulmonary collapse. [Figure 2] demonstrates hemodynamic changes in the two pigs that died during experiments. This consisted of an initial increase in PAP with a subsequent decrease in PAP until death. AP decreased as PAP increased and did not recover. The amount of absolute ethanol (Group E) or sludge solution (Group S) injected in these dead pigs was 12 and 10 ml, respectively. With the exception of these two pigs, PAP initially increased and then recovered within 30 min in both groups. The PAP recovery time for each survived pig is shown in [Table 2]. The mean recovery time was 703.4 ± 373.6 s in Group E and 660.1 ± 127.8 s in Group S. The AP decreased along with an increase in PAP and then rose and returned to baseline levels over 30 min [Figure 3]. [Figure 4] and [Figure 5] demonstrate the level the MPAP increased and the level the MAP went down after administration of absolute ethanol (Group E) or sludge solution (Group S) among the survived pigs. The average level the MPAP went up was 18.5 mmHg in Group E and 22.5 mmHg in Group S. The average level the MAP went down was −35.1 mmHg in Group E and −35.5 mmHg in Group S. The amount of absolute ethanol (Group E) or sludge solution (Group S) injected until MPAP went up by 5 mmHg was 4-8 mL (mean, 5.2 mL) and 8-14 mL (mean, 9.7 mL), respectively.
Figure 2: Changes in pulmonary arterial pressure (PAP) and arterial pressure (AP) after intermittent injection in pig #2 (a; Group E) and pig #6 (b; Group S). This consisted of an initial increase in PAP with a subsequent decrease in PAP until death. AP decreased as PAP increased and did not recover

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Figure 3: Changes in pulmonary arterial pressure (PAP) and arterial pressure (AP) after intermittent injection in pig #1 (a; Group E) and pig #8 (b; Group S). In both groups, PAP initially increased and then normalized within 10 min. Further, AP initially decreased as PAP increased, then increased suddenly and normalized within 10 min

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Figure 4: The figure shows the level the mean pulmonary arterial pressure (MPAP) went up after administration of absolute ethanol (Group E) or sludge solution (Group S) among the survived pigs. Dot demonstrates MPAP in each pig. The average level the MPAP went up was 18.5 mmHg in Group E and 22.5 mmHg in Group S

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Figure 5: The figure shows the level the mean arterial pressure (MAP) went down after administration of absolute ethanol (Group E) or sludge solution (Group S) among the survived pigs. Dot demonstrates MAP in each pig. The average level the MAP went down was − 35.1 mmHg in Group E and − 35.5 mmHg in Group S

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Table 2: Time (seconds) required for MPAP normalization ("recovery") in the two animal groups

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Pulmonary angiography

In both the animal groups, the peripheral pulmonary arteries were not visualized when the PAP increased, but the pulmonary angiogram normalized as PAP normalized [Figure 6].
Figure 6: Pulmonary angiography in pig #5 (Group S). In contrast to angiography (a) performed prior to ethanol injection, the peripheral pulmonary arteries in the bilateral lungs filed (b) were not visualized when the pulmonary arterial pressure (PAP) was increased. Pulmonary perfusion recovered (c) as PAP normalized. Similar findings were seen in Group E

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Microscopic evaluation

In both groups, microscopic examination of the lung specimens showed an amorphous sludge with aggregation of platelets scattered throughout the lumen of pulmonary arterioles, which was markedly different from normal thrombus [Figure 7]a. A similar amorphous sludge was also observed in the ex vivo specimens of sludge [Figure 7]b.
Figure 7: Microscopic features of sludge (H and E, × 400). (a) Microscopic evaluation of both groups showed amorphous sludge (black arrow) with aggregation of platelets scattered throughout the lumen of the pulmonary arterioles, which was markedly different from the appearance of normal thrombus (white arrow). (b) The same sludge was observed in the specimen of sludge made ex vivo

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   Discussion Top


Apparently, the ethanol-induced pulmonary hypertension and cardiopulmonary collapse arise from pulmonary vasospasm and scattered sludge. The hemodynamic changes in response to intravenous ethanol administration are usually transient in subjects that survive the initial insult. [5] Further, they can be reversed by vasodilator drugs in animal experiments. [7] Yakes et al., suggested [8] that ethanol-induced cardiopulmonary collapse results from a physiological sequence of events, beginning with a bolus of ethanol arriving at the pulmonary artery capillary bed and inducing precapillary spasm. This causes the PAPs to rise, which increases right ventricular afterload, decreases right ventricular contractility and decreases right ventricular cardiac output. This leads to decreased left heart filling, decreased left heart cardiac output, systemic hypotension and decreased coronary artery perfusion. If these changes are sufficiently severe, they lead to cardiac arrhythmia and cardiovascular collapse. There is experimental evidence documenting transient pulmonary hypertension induced by intravenous injection of ultrasound contrast agents containing microbubbles, [6] we hypothesize that such hemodynamic changes might also be caused by ethanol-induced sludge embolism. In the present study, the PAP and AP value varied, but the pattern of PAP and AP changes was similar in both groups. In surviving pigs, the initial elevation in PAP recovered within 30 min in both the animal groups. Even the injection of ethanol-induced sludge showed that the emboli alone could induce transient pulmonary hypertension and systemic hypotension. On pulmonary angiography, the peripheral pulmonary arteries were not visualized when the PAP was elevated, which indicate stagnation of pulmonary circulation, but could be visualized when the PAP normalized. Microscopic examination histologically confirmed sludge embolism. Sludge embolism as well as pulmonary vasospasm could induce transient hemodynamic changes and reversible findings of pulmonary angiography in a short period of time. Sludge arriving at the pulmonary artery bed leads to increased PAP, disturbance of pulmonary circulation, decreased AP, decreased cardiac output, decreased central venous pressure and subsequently decreased PAP. We also speculate that, with increasing time, the sludge redistribute into some pulmonary arterioles, while the remaining, unaffected pulmonary arterioles dilate and thereby act as collaterals. Subsequently, recovery of pulmonary circulation occurs, leading to recovery of AP. This may explain the transient nature of the increase in PAP and the reversibility in the abnormal pulmonary angiogram findings in response to sludge embolism. In addition, this distribution into the pulmonary arterioles may happen more easily in sludge embolism than with thromboembolic pulmonary embolism, because sludge emboli consist of very small particles. In pigs that died, these initial changes were of sufficient severity to result in cardiopulmonary collapse.

The fact that ethanol interacting with blood produces embolic debris consisting of denatured protein and cellular fragments (i.e., "sludge") is well-known. However, the amount of sludge produced depends on the blood flow, the concentration of ethanol interacting with the blood and the size of the vessel into which ethanol is injected. [9] Furthermore, response of the pigs against the ethanol may have variations from humans. Thus, it is not possible to know accurately how much sludge is produced after ethanol injection and to compare with the amount of sludge generated ex vivo. That is why, in this study, we selected a 5 mmHg elevation in the MPAP as a threshold for inducing pulmonary hypertension. In our earlier unpublished preliminary study, many pigs died of severe cardiopulmonary collapse when there was a >10 mmHg elevation in the MPAP on injecting sludge or absolute ethanol.

Concerning the clinical implications of our study, it appears that a slow and intermittent injection or a large amount of fluid transfusion can reduce the risk of hyperalcoholemia. However, the influence of micro-embolism may be cumulative. This may be the reason that there is a dose limit in ethanol injection therapy. [5] As a next step, it would be worth conducting an experiment to know if the intravenous capturing of the microparticles can reduce the risk of cardiopulmonary collapse.

In conclusion, transient pulmonary hypertension or cardiovascular collapse can occur in response to ethanol-induced sludge, even in the absence of ethanol. The ethanol-induced sludge plays an important role in the genesis of pulmonary hypertension or cardiopulmonary collapse during ethanol embolotherapy. Further studies are warranted for exploring ways to prevent these catastrophic complications by reduction of sludge.

 
   References Top

1.Yakes WF, Baker R. Cardiopulmonary collapse: Sequelae of ethanol embolotherapy [abstract]. Radiology 1993;189:145.  Back to cited text no. 1
    
2.Wong GA, Armstrong DC, Robertson JM. Cardiovascular collapse during ethanol sclerotherapy in a pediatric patient. Paediatr Anaesth 2006;16:343-6.  Back to cited text no. 2
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3.Rimon U, Garniek A, Galili Y, Golan G, Bensaid P, Morag B. Ethanol sclerotherapy of peripheral venous malformations. Eur J Radiol 2004;52:283-7.  Back to cited text no. 3
[PUBMED]    
4.Ko JS, Kim JA, Do YS, Kwon MA, Choi SJ, Gwak MS, et al. Prediction of the effect of injected ethanol on pulmonary arterial pressure during sclerotherapy of arteriovenous malformations: Relationship with dose of ethanol. J Vasc Interv Radiol 2009;20:39-45.  Back to cited text no. 4
[PUBMED]    
5.Yakes WF, Rossi P, Odink H. How I do it. Arteriovenous malformation management. Cardiovasc Intervent Radiol 1996;19:65-71.  Back to cited text no. 5
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6.Uchimoto R, Niwa K, Murayama C, Miyazawa T. General pharmacological profile of SH/TA-508, an ultrasound contrast agent (III). Jpn Pharmacol Ther 1997;25:2951-60.  Back to cited text no. 6
    
7.Kim JS, Nam MH, Do YS, Lee CJ, Kim CS, Sim WS, et al. Efficacy of milrinone versus nitroglycerin in controlling pulmonary arterial hypertension induced by intravenous injections of absolute ethanol in anesthetized dogs. J Vasc Interv Radiol 2010;21:882-7.  Back to cited text no. 7
[PUBMED]    
8.Yakes WF, Krauth L, Ecklund J, Swengle R, Dreisbach JN, Seibert CE, et al. Ethanol endovascular management of brain arteriovenous malformations: Initial results. Neurosurgery 1997;40:1145-52.  Back to cited text no. 8
[PUBMED]    
9.Ellman BA, Parkhill BJ, Marcus PB, Curry TS, Peters PC. Renal ablation with absolute ethanol. Mechanism of action. Invest Radiol 1984;19:416-23.  Back to cited text no. 9
[PUBMED]    

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Correspondence Address:
Shinsaku Yata
Division of Radiology, Department of Pathophysiological and Therapeutic Science, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago, Tottori 683-8504
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-9784.119164

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