Microbubbles (MB) of air pass into the patient during hemodialysis (HD) without inducing an alarm.1,2 Most MB are less than 10 µm.1 It is assumed by others that they shrink and collapse due to surface tension. Microbubbles that still reach the lungs are expected to be deposited in the lungs and adsorbed there.3 We found an increase in microembolic signals during HD that was present in the AV fistula and also in the carotid artery.2 This indicated that there either was an increase of embolies developed by the dialysis process itself or that MB of air can pass the lung barrier. The findings were more prevalent than could be expected by having an open foramen ovale.2
To explore if microembolic signals, found in patients on chronic HD, are due to clot formation or by air contamination, we investigated tissue from a patient on chronic HD after autopsy.
Materials and Methods
Autopsy was performed after informed consent was obtained from relatives (approved by the local Ethical Committee). Tissue was collected at autopsy from the patient and was immersion-fixed in 4% paraformaldehyde in 0.1 M Na phosphate, pH 7.4, and paraffin embedded. It was stained with hematoxylin/eosin and immunohistochemistry, using antibodies against C3, immunoglobulin G (IgG), IgM, and fibrinogen.
This study was on a 61 year-old man who suffered from diabetes mellitus from 30 years of age. Eighteen years later, he suffered from several thromboses. Thrombophilic investigation after his second thrombotic episode revealed no activated protein C resistance, no deficiencies of the coagulation inhibitors, antithrombin, protein C, or free protein S, but there were signs of hypofibrinolysis. After this, he was on lifelong treatment with dicumarol.
Due to diabetic nephropathy, HD was initiated at 56 years of age. Chronic HD was performed and as access a central dialysis catheter was used. Six years later, he died from cardiac arrest, 10 minutes after initiation of acute ultrafiltration due to pulmonary edema. No intracardial injections were given during resuscitation. He had been on a regular HD 2 days earlier.
Autopsy revealed a closed foramen ovale and pulmonary edema. Microscopic evaluation verified the presence of MB of air in the vessels of the lungs (Figure 1), the brain (Figure 2), and the heart. Anti-C3 and anti-IgG staining was negative around the MB while staining for antifibrinogen was positive (Figure 3).
We are the first to report findings of a patient on chronic HD with MB of air covered by fibrin in the lungs and also in the brain and heart, despite closed foramen ovale. This indicates that MB of air were present already before death and also that they may pass the pulmonary circulation and enter the left heart and be distributed throughout the body.
When an air embolus enters the blood, the coagulation system is activated as well as platelets that may form a clot around the air bubble.4 These effects prolong air reabsorption, aggravate hemodynamic effects, and cause marked thrombocytopenia5 and may also induce changes in fibrin polymerization.5
The impression was that MB were more frequent in the lung compared to the brain (not calculated).
The possibility that such air embolies may cause damage of tissue is evident when comparing with other areas of exposure, such as cardiopulmonary bypass.4 Thereby, in the lung extensive microscopic finding of pulmonary fibrosis was present (no history of chronic lung disease). Therefore, these changes may be part of a chronic exposure to air embolies. The lungs were edematous. However, according to others,4 edema may be part of the obstructive and inflammatory processes in the vessels besides fluid overload. This may impair oxygenation further and add on to increase workload for the heart, thereby resulting in cardiac arrest in some patients.
This case also shows that the MB of air are not directly adsorbed when they enter blood and are not eliminated once they arrive the lungs (half-life unknown). The possibility that MB may pass the lungs is in agreement with others who observed bubbles shrinking in lung arterioles until they eventually passed the capillaries.6
Besides a direct embolic effect, MB, through complement activation, may adhere to the endothelium and promote vessel damage such as atherosclerosis.7
Microbubbles are used as diagnostic tools (volumes limited to <8.5 ml; GE Healthcare, Stockholm, Sweden). These products are contraindicated among patients with either known hypersensitivity to the products or have fixed right-to-left, bidirectional cardiac shunts or transient right-to-left shunts. The products are in general not for intra-arterial injection. Pulmonary and cardiovascular problems have been noted.8
Parallels could be drawn with professional divers. Thorsen et al.8 found that after one dive such air bubbles cause adverse effect to lung capacity after deep saturation with chest symptoms with retrosternal discomfort or nonproductive cough. The transfer factor for carbon monoxide and maximum oxygen uptake was reduced after the dives.9
In conclusion, this case indicates that microembolies of air that enters the blood during HD are trapped into the lungs. In addition, the smallest bubbles pass the pulmonary capillaries and are dispersed throughout the whole body. We suggest that these embolies may contribute to organ impairment and the impaired prognoses found in HD patients. If these findings are confirmed, efforts are needed to reduce the extent of MB in the dialysis circuit.
We thank the Västerbotten County Council and the Department of Medicine, Norrland University Hospital, Umeå, Sweden, and Njurföreningen i Västerbotten, Sweden for financial support.
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