Abstract

Introduction and objectives: Hemodynamically unstable patients with acute pulmonary embolism (PE) are eligible for systemic thrombolysis (ST). However, catheter-directed therapy (CDT) and surgical thrombectomy (SUT) can also be considered with less clinical evidence. Limited information exists regarding the best reperfusion therapy in this setting. Our objective was to perform a descriptive analysis of different reperfusion therapies in acute pulmonary embolism and determine their safety and efficacy profile.

Methods: Retrospective analysis from a prospective single-centre registry of patients admitted with a diagnosis of PE from 2006 through 2021 who required reperfusion therapy. We analyzed the in-hospital outcomes and at 14-day follow up.

Results: A total of 50 out of 399 patients admitted with a diagnosis of PE received reperfusion therapies and were included in our analysis. Mean age, 64.5 (53-72), 46% female. This was the reperfusion strategy applied: ST (44%), CDT (42%) and SUT (14%). All patients had right ventricular dilatation and high troponin levels. The overall in-hospital mortality was 18%. Major and minor bleeding rates among the different reperfusion methods were 9.0% vs 4.7% vs 57.4%; P = .001), and 18.1% vs 9.5% vs 14.2%; P = NS), respectively. The 14-day follow-up showed that only CDT and SUT reduced the pulmonary artery systolic pressure while ST and CDT were associated with a reduced right ventricular diameter and an improved right ventricular function.

Conclusions: High mortality rates were found in this population with acute PE. No differences were seen regarding effectiveness seen among the different reperfusion strategies used. CDT and SUT may be considered as alternative reperfusion methods especially if ST is contraindicated.

Keywords: Pulmonary embolism. Systemic thrombolysis. Catheter-directed therapy. Reperfusion therapy. Surgical thrombectomy.

RESUMEN

Introducción y objetivos: Los pacientes con tromboembolia pulmonar (TEP) aguda hemodinámicamente inestables son candidatos para recibir trombolisis sistémica (TS); sin embargo, el tratamiento guiado por catéter (TGC) y la trombectomía quirúrgica (TQ) también se pueden considerar, aunque con menor nivel de evidencia. Existe información limitada respecto a cuál es el mejor método de reperfusión en esta población. El objetivo es realizar un análisis descriptivo de las distintas terapias de reperfusión en la TEP aguda y determinar su efectividad y seguridad

Métodos: Análisis retrospectivo de un registro prospectivo unicéntrico de pacientes ingresados con TEP aguda entre los años 2006 y 2021, que requirieron tratamiento de reperfusión. Analizamos la evolución intrahospitalaria y en el seguimiento a 14 días.

Resultados: De 399 pacientes con TEP, 50 recibieron tratamiento de reperfusión y fueron incluidos en el análisis. La edad media era de 64,5 años (rango: 53-72) y el 46% eran mujeres. Los métodos de reperfusión fueron TS en el 44%, TGC en el 42% y TQ en el 14%. Todos presentaron dilatación del ventrículo derecho y elevación de las troponinas. La mortalidad intrahospitalaria fue del 18%. Las tasas de sangrado mayor en los grupos de TS, TGC y TQ fueron del 9,0%, el 4,7% y el 57,4% (p = 0,001), y las de sangrado menor fueron del 18,1%, el 9,5% y el 14,2% (p no significativa), respectivamente. Durante el seguimiento a 14 días, solo el TGC y la TQ lograron una reducción de la presión sistólica en la arteria pulmonar, y con la TS y la TGC hubo una reducción de los diámetros del ventrículo derecho y una mejoría de su función.

Conclusiones: En esta población de pacientes con TEP aguda encontramos altas tasas de mortalidad intrahospitalaria. No se observaron diferencias en términos de efectividad entre los distintos tratamientos de reperfusión. El TGC y la TQ podrían considerarse métodos de reperfusión alternativos, en especial cuando la TS está contraindicada.

Palabras clave: Tromboembolia pulmonar. Tratamiento de reperfusión. Tratamiento guiado por catéter. Trombolisis sistémica. Trombectomía quirúrgica.

Abbreviations CGT: catheter-guided therapy. PASP: pulmonary artery systolic pressure. PTE: pulmonary thromboembolism. RV: right ventricle. ST: systemic thrombolysis. SUT: surgical thrombectomy.

INTRODUCTION

Acute pulmonary thromboembolism (PTE) is the third leading cause of cardiovascular mortality, and most deaths are due to acute right heart failure following the obstruction of flow into the pulmonary arteries. The in-hospital mortality rate in patients whose first sign at presentation is hemodynamic instability is 30%. However, it can be as high as 50% in some registries, and 10 times higher compared to stable patients.1

In the registries of patients with PTE there is a group of intermediate risk patients with a higher mortality rate compared to that recorded in clinical trials involving a wide spectrum of individuals including a subgroup with a high mortality rate and similar to that of patients with high-risk PTE. Identifying this high-risk population and selecting those patients who may benefit from some reperfusion method is tremendously challenging for the treating heart team.2-4 Similarly, PTE is associated with other complications at the follow-up like risk of recurrence of thromboembolic events and those associated with a reduced functional capacity or the eventual development of chronic thromboembolic pulmonary hypertension.5-6

There is consensus on the management of reperfusion in patients with high-risk PTE while in intermediate-risk patients, treatment is controversial and could only be indicated in patients with hemodynamic impairment on anticoagulant therapy.7-9 Currently, the reperfusion strategy recommended as the first option in this group of patients is systemic thrombolysis (ST) despite the risk of bleeding involved.7

Although evidence is scarce on this regard, in selected cases, catheter-guided therapy (CGT), and surgical thrombectomy (SUT) could be associated with a lower rate of hemorrhagic complications with similar efficacy.10-13

To this date, no studies have been conducted comparing such reperfusion strategies, so it is unknown which one of them is safer and more effective. The objective of this study is to conduct a descriptive analysis on the different reperfusion mechanisms in acute PTE and determine their effectiveness and safety profiles.

METHODS

A single-center, retrospective, observational cohort study was conducted with patients admitted with PTE who required reperfusion treatment. Data were collected from the prospective registry of a teaching hospital between 2006 and 2021. Reperfusion methods studied were ST, CGT, and SUT.

Patients received reperfusion treatment based on the heart team criterion, evidence, and national and international recommendations available at that time. Patients with overt shock due to right ventricular (RV) failure, and patients without shock with RV dilatation, myocardial damage, and clinical signs indicative of early instability despite parenteral anticoagulant treatment in therapeutic doses were considered eligible to receive reperfusion treatment. Added to this, to be considered eligible for reperfusion treatment, patients should also present with, at least, 2 of the following: persistent tachycardia with a heart rate > 110 bpm or < 60 bpm, systolic arterial pressure < 100 mmHg, elevated lactic acid levels, oxygen saturation < 90%, shock index (heart rate/systolic arterial pressure) > 1 or high thrombotic load (modified Miller score > 22). We should mention that patients with moderate-to-severe RV dysfunction or thrombus in transit were considered eligible for reperfusion treatment on an emergency basis.

ST was preferred in young patients with low risk of bleeding and without absolute or relative contraindications for the use of fibrinolytic agents. In patients with higher risk of bleeding (old age, malignant neoplasm, elevated RIETE or HAS-BLED scores), absolute or relative contraindications for systemic thrombolytic therapy or presence of central thrombi, CGT was considered more suitable. SUT was preferred for patients with suspected subacute PTE (symptoms of >15-day evolution, pulmonary artery systolic pressure [PASP] > 60 mmHg or RV hypertrophy), severe RV dysfunction requiring circulatory support or thrombus in transit.

Streptokinase was the fibrinolytic agent used between 2006 and 2010, and only alteplase has been used ever since. From 2008 CGT started being used as an alternative reperfusion method. Regarding the devices used for CGT, from 2008 through 2017, pigtail-type catheters for thrombus fragmentation and multipurpose catheters for manual thrombus aspiration were being used; the Penumbra System (Penumbra, United States) has been used since 2017, and since 2020 the Angio-Jet device (Boston Scientific, United States) has been available as well.

Data was collected from each patient’s baseline characteristics (age, sex, cardiovascular risk factors, past medical history, comorbidities), clinical status when acute PTE was diagnosed (arterial pressure, heart rate, hemodynamic stability, PESI score, thrombotic load), bleeding risk scores (HAS-BLED, RIETE), lab test parameters (ultra-sensitive cardiac T troponin, and lactic acid), and echocardiographic data on the RV size and function and PASP.

RV dilatation was assessed as a dichotomic variable and defined as normal with diastolic diameters < 41 mm, and dilated if ≥ 41 mm or else a RV/LV ratio > 0.9 as seen on the echocardiography or coronary computed tomography angiography.

RV function was also assessed as a dichotomic variable and defined as normal if the tricuspid annular plane systolic excursion was ≥ 16 mm and reduced if < 16 mm or in the presence of hypokinesia of the RV free wall as seen on the echocardiography.

PASP was assessed quantitatively by measuring the trans-tricuspid pressure gradient, and pressure to the right atrium derived from the inferior vena cava or its collapsibility as seen on the echocardiography.

Physician-investigators obtained this data from the patients’ electronic health records and stored it in an encrypted database authorized by the center research ethics committee.

The privacy of patients in the registry was guaranteed because names or initials were not stored in the database, and access to it was limited to the lead investigator only.

The study of the patients’ clinical progression while hospitalized included in-hospital mortality, the need for mechanical ventilation, major and minor bleeding according to the categorization established by the Bleeding Academic Research Consortium,14 and a composite of in-hospital mortality and major bleeding. The echocardiographic parameters studied before reperfusion and at 14 days were the RV function, the presence of RV dilatation, and the value of PASP.

The informed consent forms of all the patients were collected for the use of data with academic, statistical, and scientific purposes in the healthcare setting. The protocol was assessed and approved by our hospital Bioethics Research Committee (resolution no. 19-041).

Statistical analysis

This was a single-center, retrospective, observational, cohort study. For quantitative variable description, the mean ± standard deviation or median and interquartile range (IQR) 25-75 were used based on their distribution. Qualitative variables were expressed as frequency and percentage. Regarding the bivariate analysis of the 3 strategies the ANOVA technique with Bonferroni correction was used for continuous variables with equal variances while the Kruskal Wallis test was used for different variances. The chi-square test was used for dichotomic variables. Student t test and the Kruskal Wallis test were used for paired sample analysis based on distribution while the dichotomic variables were studied using McNemar test. P values < .05 were considered statistically significant. Analysis was conducted using the Stata/SE v13.0 statistical software package (StataCorp, United States).

RESULTS

A total of 50 patients out of the 399 with PTE received reperfusion treatment and were included in our analysis. No patient was excluded. The patients’ mean age was 64.5 years [53-72], and 46% were women. ST was indicated in 44% of the patients while CGT in 42%, and SUT in 14%. Three patients from the ST group required bailout CGT. The ST group (mean age, 53.5 years [50-68]) was younger compared to the CGT and SUT groups (69 [59-72] and 71 years [60-79]), respectively; P = .02. The remaining baseline characteristics were similar (table 1).


Table 1. Baseline characteristics of the population

Variable Overall (N = 50) ST (N = 22) CGT (N = 21) SUT (N = 7) P
Clinical characteristics
 Masculine sex, % 54 (27) 50 (11) 61.9 (13) 42.8 (3) .61
 Age, years (range) 64.5 (53-72) 53.5 (50-68) 69 (59-72) 71 (60-79) .022
 Dyslipidemia, % 36 (18) 36.6 (8) 42.8 (9) 14.2 (1) .4
 Current smoking, % 38 (19) 22.7 (5) 52.3 (11) 42.8 (3) .13
 Arterial hypertension, % 54 (27) 45.4 (10) 57.1 (12) 71.4 (5) .46
 Diabetes mellitus 18 (9) 22.7 (5) 19.5 (4) 0 (0) .40
 Ischemic heart disease, % 10 (5) 4.5 (1) 9.5 (2) 28.5 (2) .18
 Heart failure, % 4 (2) 0 (0) 4.7 (1) 14.2 (1) .24
 COPD, % 2 (1) 0 (0) 4.7 (1) 0 (0) .51
 Malignant neoplasm, % 26 (13) 18.1 (4) 38.1 (8) 14.2 (1) .25
 HAS BLEED > 4, % 10 (5) 9.0 (2) 4.76 (1) 28.5 (2) .19
 RIETE 1.5 (0-3) 0 (0-1.5) 1.5 (1-4) 3 (1-5) .08
 High risk ESC, % 14 (7) 13.6 (3) 19.0 (4) 0 (0) .46
 SAP, mmHg 120.5 (110-140) 121 (111-140) 118 (100-130) 135 (111-143) .94
 DAP, mmHg 78 (65-87) 80.5 (60-100) 76 (65-80) 91 (75-101) .60
 HR, bpm 110 (99-116) 110 (100-128) 110 (100-111) 105 (85-130) .44
 Absolute contraindication for ST, % 19 (4) 0 (0)
 Relative contraindication for ST, % 28 (6) 15 (1)
PESI
 Very high, % 28 (14) 13.6 (3) 52.3 (11) 0 (0)
 High, % 30 (15) 31.8 (7) 23.8 (5) 42.8 (3)
 Intermediate, % 22 (11) 18.1 (4) 19.0 (4) 42.8 (3)
 Low, % 16 (8) 31.8 (7) 0 (0) 14.2 (1)
 Very low, % 4 (2) 4.5 (1) 4.7 (1) 0 (0)
Echocardiographic parameters
 RV dysfunction, % 88.0 (44) 77.2 (17) 95.2 (20) 100 (7) .11
 RV dilatation, % 100 (50) 100 (22) 100 (21) 100 (7) NS
 PASP 55 (45-61.5) 45 (45-58) 56.5 (49-67.5) 60 (51-60) .17
PTE location
 Multiple-subsegmental, % 1.3 (5) 13.6 (3) 10 (2) 0 (0)
 Pulmonary artery trunk, % 14.2 (7) 9.0 (2) 5 (1) 57.1 (4)
 Both branches, % 57.1 (28) 59.0 (13) 65 (13) 28.5 (2)
 1 branch only, % 18.3 (9) 18.1 (4) 20 (4) 14.2 (1)
Laboratory parameters
 high sensitivity cardiac troponin T, pg/mL 48.5 (27.5-142) 31 (24-88) 64 (33-196) 88 (36-153) .02
 Lactic acid, mEq/L 2.1 (1.5-3) 2 (1.1-2.5) .63
Procedural data
 Procedural time, m 97.7 209.1
 Thrombus aspiration, % 95 (20)
 Thrombus fragmentation, % 52 (11)
 Local thrombolytic agents, % 38 (8)
Doses of thrombolytic agents
 Alteplase 100 mg (60%) 31.1 +- 11.9
 Streptokinase 2 000 000 (40%)

bpm, beats per minute; CGT, catheter-guided therapy; COPD, chronic obstructive pulmonary disease; DAP, diastolic arterial pressure; ESC, European Society of Cardiology; HR, heart rate; NS, non-significant; PASP, pulmonary artery systolic pressure: PTE, pulmonary thromboembolism; RV, right ventricle; SAP, systolic arterial pressure; ST, systemic thrombolysis; SUT, surgical thrombectomy.
Data are expressed as percentage or interquartile range 25-75.


All patients had RV dilatation and elevated cardiac T troponin levels (mean, 48.5 pg/mL). The group that received ST had higher mean troponin levels around 31 pg/mL [24-48], which was not as high compared to the CGT and SUT groups with 64pg/mL [33-196], and 88 pg/mL [36-153], respectively (P = .02). A total of 88% of the patients had RV dysfunction (ST, 77.2%; CGT, 95.2%; ST, 100%; non-significant P value). A total of 14% had high-risk PTE according to the ESC classification from 2019 (ST, 13.6%; CGT, 19%; SUT, 0%; non-significant P value). In 14.2% of the patients the pulmonary artery was compromised while in 75.4% of the patients 1 or the 2 main branches were compromised. The mean systolic arterial pressure was 120.5 mmHg, and the average heart rate 110 bpm with no inter-group differences being reported. A total of 58% of the population had high or very high PESI scores. PASP was high in all the patients for an average 55 mmHg [45-61.5] with no inter-group differences being reported (ST, 45 mmHg [45-58]; CGT, 56.5 mmHg [49-67,5]; SUT, 60mmHg [51-60]). Lactic acid levels were 2.1 mmol/L on average with no inter-group differences being reported (ST, 2 mmol/L [1.1-2.5]; CGT, 2.5 mmol/L [1.5-7.0]; SUT, 2.1 mmol/L [2-2.5]).

Alteplase was used in 60% of the patients from the ST group (mean dose, 100 mg) while streptokinase was used in the remaining 40% (mean dose, 2.0 million IU).

Within the CGT group, thrombus aspiration was performed in 95% of the patients, thrombus fragmentation in 52%, and local thrombolytic agents were used in 38%. Regarding the type of catheter used for CGT, we should mention that between 2008 and 2016 pigtail-type catheters were used for thrombus fragmentation and multipurpose catheters for thrombus aspiration in 10 patients; between 2017 and 2020 Penumbra catheters were used in 10 patients, and from 2020 to 2021 the Angio-jet catheters was used in 1 patient. Mean procedural time was 97.7 minutes and the fibrinolytic agent used in CGT was alteplase in 100% (mean dose, 31.1 mg ± 11.9 mg).

A total of 47% of the patients from the CGT group had absolute or relative contraindications to receive ST vs 15% of the patients from the SUT group. Similarly, the SUT mean procedural time was 209.1 minutes.

The mean length of stay was 10 days [7-18], which was longer for SUT (22 days [15-34]) compared to the other 2 groups (ST, 8.5 [7-15]; CGT, 10 days [6.5-15]; P = .02).

A total of 40% of the population required mechanical ventilation that was more widely used in the SUT group (100%) compared to the other 2 groups (ST, 18.1%; CGT, 42.8%; P = .0002).

Minor bleeding occurred in 14% of the population with no inter-group differences being reported while major bleeding occurred in 14% of the population, more often in the SUT group (57.4%) compared to the other 2 groups (ST, 9%,; CGT, 4,7%; P = .001). The only intracranial bleeding even reported occurred in 1 patient who received ST; the major bleeding events occurred in the SUT group were due to transfusion need and low hemoglobin count without need for reintervention. The only major bleeding event occurred in the CGT group was due to transfusion need after the intervention.

The in-hospital mortality rate was 18% (ST, 9%; CGT, 28.5%; SUT, 14.2%; non-significant P value), and except for 1 death due to cancer occurred in the CGT group, all deaths reported were due to cardiogenic shock following right ventricular failure. The rate of occurrence of the composite “in-hospital mortality and major bleeding” (table 2) was 28% (ST, 13.6%; CGT, 33.3%%; SUT, 57.4%; non-significant P value).


Table 2. In-hospital clinical outcomes

Variables Overall (N = 50) ST (N = 22) CGT (N = 21) SUT (N = 7) P
Length of stay, days (range) 10 (7-18) 8.5 (7-15) 10 (6.5-15) 22 (15-34) .02
Ventilatory support, % 40 (20) 18.1 (4) 42.8 (9) 100 (7) .0002
Minor bleeding (BARC < 3), % 14 (7) 18.1 (4) 9.5 (2) 14.2 (1) .72
Major bleeding (BARC ≥ 3), % 14.0 (7) 9 (2) 4.7 (1) 57.4 (4) .001
In-hospital mortality, % 18 (9) 9.0 (2) 28.5 (6) 14.2 (1) .25
Composite of in-hospital mortality and major bleeding, % 28.0 (14) 13.6 (3) 33.3 (7) 57.1 (4) .064

BARC, Bleeding Academic Research Consortium; CGT, catheter-guided therapy; ST, systemic thrombolysis; SUT, surgical thrombectomy.
Data are expressed as percentages or interquartile range 25-75.


A total of 42% of the patients were lost to follow-up after 14 days, which limits the validity of the findings reported after hospital discharge. In the population that was able to complete the study, normal RV diameters were reported in 70% of the patients from the ST group (P = .002), 75% of the patients from the CGT group (P = .002) and 40% of the patients from the SUT group (non-significant P value). Also, normal RVs were reported in 92% of the patients from the ST group (P = .004), 92% of the patients from the CGT group (P = .001), and 20% of the patients from the SUT group (non-significant P) as shown on figure 1.


Figure 1. Presence of RV dilatation and dysfunction after reperfusion. CGT, catheter-guided therapy; NS, non-significant; RV, right ventricle; ST, systemic thrombolysis; SUT, surgical thrombectomy.


A significant reduction of PASP was reported after reperfusion therapy both in the CGT group and in the SUT group (table 3).


Table 3. Values of pulmonary artery systolic pressure at admission and at 14 days

Strategy PASP at admission (mmHg) PASP at 14 days (mmHg) Difference (mmHg) P
ST (N = 11) 46.8 ±18.7 36.7 ± 23.7 10.0 ± 15.1 .051
CGT (N = 12) 58.83 ± 12.6 31.3 ± 10.89 27.5 ± 15.2 .0001
SUT (N = 5) 56.2 ±-9.47 35 ± 7.9 21.2 ± 15.3 .036

CGT, catheter-guided therapy; PASP, pulmonary artery systolic pressure; ST, systemic thrombolysis; SUT, surgical thrombectomy.
Interquartile range 25-75.

DISCUSSION

Our registry included a population of patients with acute PTE who required reperfusion treatment and whose in-hospital mortality rate was 18%, which is indicative that it was a population with high morbidity and mortality rates compared to the one seen in randomized clinical trials.15-20 One of the reasons that explains this phenomenon is that, unlike registries, randomized clinical trials often include younger, less severe, and less complex patients with fewer comorbidities.

Although the current clinical guidelines recommend ST as the first reperfusion treatment, in our population, only 44% of the patients received ST, the remaining 42% received CGT, and 14% SUT. The high rate of reperfusion with CGT reported in our registry is consistent with that reported by other high-volume centers in the United States where it is used in nearly 11% to 29% of intermediate-high or very high-risk PTEs. In such registries there is a clear tendency towards a wider use of CGT replacing ST that was used in 5.6% of the patients only.21-23 This phenomenon occurs in the context of low compliance to the ST recommendations made in this population. An example of this is the CONAREC XX registry where almost half of the patients with hemodynamic instability did not receive ST although it was the first option recommended by the clinical practice guidelines.24 The reasons behind this are still unclear. However, the risk of major bleeding reported, including intracranial bleeding, associated with the use of systemic thrombolytic agents could partially explain it. It is well known that registries include patients who are often left out of the clinical trials like the elderly, patients with active cancers, postoperative patients, and critically ill patients who often have a higher risk of bleeding, and contraindications for the use of fibrinolytic agents as our study confirmed where almost half of the patients from the CGT group had some contraindication for the use fibrinolytic agents.

One of the theoretical benefits of CGT or SUT over ST is the possible lower rate of severe or fatal bleeding. In a meta-analysis that only included prospective studies of a total of 566 patients treated with CGT, the rate of major bleeding was 5.8% (33 patients), similar to that of our registry.25 Although these rates are lower compared to those seen on trials on ST (rate of major bleeding, 11.5%; intracranial hemorrhage, 2% to 3%), no studies have been published to this date comparing CGT and ST.26-28

Although in our registry no statistically significant differences were seen regarding the rates of major bleeding between CGT and ST, we should mention that the population of patients treated with CGT was 10 years older, and almost half of them had contraindications for systemic fibrinolytic agents. This suggests that the population with the highest risk of bleeding could benefit from this reperfusion strategy. Also, no intracranial bleeding was reported in patients who received CGT. Although SUT was not associated with more major bleeding events, these were due to transfusion needs and a low hemoglobin count without further need for a new intervention; also, the low number of cases reported in this group does not allow us to draw any definitive conclusions on this matter.

Currently, there is no solid evidence demonstrating the benefit of CGT in the in-hospital “hard” clinical endpoints like in-hospital mortality and hemodynamic instability or in long-term results like PTE recurrence, development of chronic thromboembolic pulmonary hypertension, and improved quality of life.

When in-hospital mortality was compared among the different reperfusion treatments, no statistically significant differences were seen (ST, 9%; CGT, 28.5%; SUT, 14.2%; non-significant P value). However, patients from the CGT and SUT groups were older, had a higher risk of bleeding, and elevated troponin levels, which means that they were higher-risk patients. This is indicative that these strategies could be particularly beneficial in this population. We should mention that comparisons between groups and conclusions have a limited value, mainly because of the usual selection bias found in the registries, and the small number of patients and events included (possible beta error).

To this date, the evidence on the efficacy of CGT to treat acute PTE is based on surrogate endpoints like the RV/LV ratio, PASP, and the thrombotic load using Miller score.16-19 The use of CGT in patients with PTE would revert RV dilatation more rapidly compared to anticoagulation alone.23 Based on the scientific evidence available, we can see that both ST and CGT reduced the RV size and function significantly, an essential endpoint since the leading cause of death in patients with acute PTE is shock due to RV failure. Also, reperfusion treatments could be useful to reduce PASP at the follow-up, and eventually reduce the risk of chronic thromboembolic pulmonary hypertension. Still, no definitive conclusions can be drawn because of the patients lost, and the lack of long-term follow-up. More multicenter, prospective registries with long follow-ups are needed to strengthen the evidence available and determine whether reperfusion in the management of patients with acute PTE could have implications in the rate of chronic thromboembolic pulmonary hypertension, which sits at around 4% in most registries.

In our own opinion and considering the current evidence available, ST is still the first option in patients with acute PTE who require reperfusion treatment while CGT and SUT should be indicated in the presence of contraindications for systemic thrombolytic agents. It is essential to define whether invasive strategies could be an alternative to ST in patients with high risk of bleeding. It seems obvious that randomized clinical trials with control groups are needed to compare the different reperfusion strategies available to treat acute PTE that should include “hard” endpoints within their efficacy and safety endpoints always bearing in mind that these results don’t look anything like the real world.

However, there are numerous limitations that should be dealt with when facing this type of studies in the real world. That’s why the evidence collected from ideally multicenter prospective registries with clear inclusion and exclusion criteria and standard and reproducible reperfusion techniques would be highly valuable.29

Limitations

As it occurs in other registries, our study was observational and the indication for reperfusion and the method used were left to the heart team and were backed by the international recommendations effective at the time. The significant selection and inclusion bias and the low number of patients included in our study limits group comparison. Also, there was a considerable number of patients who were lost to follow-up, which limits even more the conclusions of the elements studied after hospital discharge.

Similarly, we should mention that the extended period of patient recruitment of the registry is associated with significant changes within the same reperfusion strategy (type and dose of fibrinolytic agents administered, catheters used, and coadjuvant therapy). The results obtained may not be generalized to other less complex centers, use of other fibrinolytic agents or less experience in the use of CGT, and SUT.

CONCLUSIONS

In this population of patients with acute PTE we found high rates of in-hospital mortality. Although the study has several limitations and biases regarding patient selection, no differences were seen regarding effectiveness among the different reperfusion treatments used. Both ST and CGT reduced the RV diameter significantly and improved the RV function after reperfusion with similar rates of bleeding. CGT and SUT could be considered alternative reperfusion methods in selected cases, and especially when ST is contraindicated or there is a high risk of bleeding.

FUNDING

None whatsoever.

AUTHORS’ CONTRIBUTIONS

M. Iwanowski, J. A. Bilbao, and J. M. Bononino: study design, data curation, analysis and interpretation of data, draft of the manuscript, and final approval of the latest version of the manuscript. H. E. Fernandez, and S. J. Baratta: study design, critical review of the manuscript, final approval of the latest version of the manuscript. R. E. Melchiori: study design, analysis and interpretation of data, draft of the manuscript, final approval of the latest version of the manuscript. N. A. Torres: study design, data curation, draft of the manuscript. R. A. Costantini, J. C. Santucci, and G. N. Vaccarino: critical review of the manuscript, and final approval of the latest version of the manuscript. S. N. Márquez Herrero, P. M. Rubio, E. M. Spaini, G. M. García Juárez, and M. Bivort Haiek: data curation, analysis and interpretation of data, and draft of the manuscript.

CONFLICTS OF INTEREST

None reported.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Patients with acute PTE and hemodynamic instability require reperfusion treatment because they are associated with high mortality and morbidity rates.
  • CGT is associated with significant improvements in surrogate endpoints. However no significant reductions have been reported regarding the mortality rate.
  • No randomized clinical trials have been conducted comparing ST, CGT, and SUT

WHAT DOES THIS STUDY ADD?

  • Real-world patients who require reperfusion treatment have high mortality and morbidity rates that are higher compared to those seen in randomized clinical trials.
  • No significant differences were found regarding the effectiveness of the different reperfusion treatments studied. Both CGT and ST reduce the RV size significantly and improve the RV function after reperfusion.
  • Our study provides information on the feasibility, effectiveness, and safety of the different reperfusion methods available in an Argentinian teaching hospital where evidence is even more limited.

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6. Kahn SR, Comerota AJ, Cushman M, et al. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2014;130:1636-1661.

7. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41:543-603.

8. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic Therapy for VTE Disease. CHEST Guideline and Expert Panel Report. Chest. 2016; 149:315-352.

9. Ubaldini J, Bilbao J, Bonorino J, et al. Consenso de Enfermedad Tromboembólica Aguda. Rev Argent Cardiol. 2016;84:74-91.

10. Giri J, Sista AK, Weinberg I, et al. Interventional Therapies for Acute Pulmonary Embolism: Current Status and Principles for the Development of Novel Evidence. A Scientific Statement from the American Heart Association. Circulation. 2019;140:e774-e801.

11. Qi Min W, Liang Wan C, Dao Zhong C, et al. Clinical outcomes of acute pulmonary embolectomy as the first-line treatment for massive and submassive pulmonary embolism: a single-centre study in China. J Cardiothorac Surg. 2020;15:321-327.

12. Lehnert P, Moller CH, Mortensen J, et al. Surgical embolectomy compared to thrombolysis in acute pulmonary embolism: morbidity and mortality. Eur J Cardio-Thorac Surg. 2017;2:354-361.

13. Kalra R, Bajaj NS, Arora P, et al. Surgical embolectomy for acute pulmonary embolism: systematic review and comprehensive meta-analyses. Ann Thorac Surg. 2017;103:982-990.

14. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: A consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123:2736-2747.

15. Kasper W, Konstantinides S, Geibel A, et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol. 1997;30:1165-1171.

16. Piazza G, Hohlfelder B, Jaff MR, et al. SEATTLE II Investigators. A prospective, single-arm, multicenter trial of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and submassive pulmonary embolism: the SEATTLE II study. JACC Cardiovasc Interv. 2015;8:1382-1392.

17. Kucher N, Boekstegers P, Müller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129:479-486.

18. Tapson VF, Sterling K, Jones N, et al. A Randomized Trial of the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Intermediate-Risk Pulmonary Embolism: the OPTALYSE PE trial. JACC Cardiovasc Interv. 2018;11:1401-1410.

19. Tu T, Toma C, Tapson VF, et al. FLARE Investigators. A prospective, single-arm, multicenter trial of catheter-directed mechanical thrombectomy for intermediate-risk acute pulmonary embolism: the FLARE study. JACC Cardiovasc Interv. 2019;12:859-869.

20. Kuo WT, Banerjee A, Kim PS, et al. Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): initial results from a prospective multicenter registry. Chest. 2015;148:667-673.

21. Kabrhel C, Rosovsky R, Channick R, et al. A multidisciplinary pulmonary embolism response team: initial 30-month experience with a novel approach to delivery of care to patients with submassive and massive pulmonary embolism. Chest. 2016;150:384-393.

22. Sista AK, Friedman OA, Dou E, et al. A pulmonary embolism response team’s initial 20 month experience treating 87 patients with submassive and massive pulmonary embolism. Vasc Med. 2018;23:65-71.

23. Reza N, Dudzinski DM. Pulmonary embolism response teams. Curr Treat Options Cardiovasc Med. 2015;17:387.

24. Cigalini I, Igolnikof D, Scatularo C, et al. Tromboembolismo pulmonar agudo en la Argentina. Registro CONAREC XX. Rev Argent Cardiol. 2019;87:137-145.

25. Kuo WT, Gould MK, Louie JD, Rosenberg JK, Sze DY, Hofmann LV. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol. 2009;20:1431-1440.

26. Meyer G, Vicaut E, Danays T, et al., for the PEITHO investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014; 370:1402-1411.

27. Fiumara K, Kucher N, Fanikos J, Goldhaber SZ. Predictors of major hemorrhage following fibrinolysis for acute pulmonary embolism. Am J Cardiol. 2006;97:127-129.

28. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014;311:2414-2421.

29. Piazza G. Trailblazing in pulmonary embolism research: the importance of extending beyond randomized controlled trials. Eur Heart J Acute Cardiovasc Care. 2021;10:237-239.

* Corresponding author:

E-mail address: mateo_iwanowski@hotmail.com (M. Iwanowski).

Abstract

Introduction and objectives: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes an infectious disease that can present as adult respiratory distress syndrome (ARDS). Without an effective drug therapy, extracorporeal membrane oxygenation (ECMO) is essential when invasive mechanical ventilation fails in severe cases. Our study carried out a systematic review of the studies published in 2020 to analyze the mortality of patients with ARDS due to SARS-CoV-2 who required ECMO.

Methods: A systematic review was conducted on Medline combining keywords on SARS-CoV-2 and ECMO. All studies published during 2020 with positive cases of SARS-CoV-2 treated with ECMO were included, whether observational studies or case series. However, due to the heterogeneity in the methodology of the studies, a proper statistical analysis could not be carried out, which ended up limiting our findings.

Results: Our research identified 41 publications during this period including 2007 cases of patients with severe SARS-CoV-2 infection who required invasive support with ECMO. Among these, 985 (49%) improved clinically and were decannulated or discharged from the hospital, while 660 (32.8%) died despite invasive mechanical support. Only 357 patients (17.7%) still needed ventilation support with ECMO at the time of publication of these studies without describing the final clinical outcome.

Conclusions: ECMO therapy could be useful in patients with ARDS due to SARS-CoV-2 according to the recommendations established in the clinical guidelines and based on the availability of financial resources during the pandemic. Conducting a randomized clinical trial comparing the use of ECMO with conventional invasive ventilatory therapy would provide more evidence on this regard and, consequently, more data on the management of severe SARS-CoV-2 infection.

Keywords: COVID-19. ECMO. SARS-CoV-2. Extracorporeal membrane oxygenation. Mortality. ARDS.

RESUMEN

Introducción y objetivos: El coronavirus del síndrome respiratorio agudo grave de tipo 2 (SARS-CoV-2) genera una enfermedad infecciosa que puede presentarse como síndrome de distrés respiratorio del adulto (SDRA). Sin un tratamiento farmacológico eficaz, el oxigenador extracorpóreo de membrana (ECMO) es fundamental cuando en los casos graves fracasa la ventilación mecánica invasiva. Presentamos una revisión sistemática de los trabajos publicados en el año 2020 para analizar la mortalidad de pacientes con SDRA por SARS-CoV-2 que precisaban ECMO.

Métodos: Se realizó una revisión sistemática en Medline combinando palabras clave sobre SARS-CoV-2 y ECMO. Se incluyeron todos los estudios publicados durante el año 2020 que registraran casos positivos de SARS-CoV-2 tratados con ECMO, ya fueran estudios observacionales o series de casos. Sin embargo, debido a la heterogeneidad en la metodología de los trabajos, no se pudo llevar a cabo un análisis estadístico adecuado, lo cual limita los hallazgos.

Resultados: La búsqueda identificó 41 publicaciones y se recogieron 2.007 casos de pacientes con infección grave por SARS-CoV 2 que precisaron soporte invasivo con ECMO. De estos, 985 (49%) mejoraron clínicamente y fueron descanulados o dados de alta del hospital, y 660 (32,8%) fallecieron a pesar del soporte invasivo. Solo 357 (17,7%) pacientes aún persistían con necesidad de asistencia ventilatoria con ECMO en el momento de la publicación de los estudios, sin que se describa la evolución clínica final.

Conclusiones: El tratamiento con ECMO podría ser útil en pacientes con SDRA por SARS-CoV-2, según las directrices de las guías clínicas y en función de la disponibilidad de los recursos económicos durante la pandemia. La realización de un ensayo clínico aleatorizado que compare el uso de ECMO con el tratamiento convencional ventilatorio invasivo arrojaría mayor evidencia, con el fin de aportar más datos sobre el tratamiento de la infección grave por SARS-CoV-2.

Palabras clave: COVID-19. ECMO. SARS-CoV-2. Oxigenador extracorpóreo de membrana. Mortalidad. SDRA.

Abbreviations SARS-CoV-2: severe acute respiratory syndrome coronavirus type 2. COVID-19: coronavirus disease-2019. ARDS: acute respiratory distress syndrome. ECMO: extracorporeal membrane oxygenation.

INTRODUCTION

In 2020, the World Health Organization (WHO) declared a public health emergency of international concern on a new strain of coronavirus different from the severe acute respiratory syndrome (SARS-CoV) and the Middle East respiratory syndrome (MERS-CoV) with which it shares some similar characteristics.1 This new strain known as severe acute respiratory syndrome type 2 (SARS-CoV-2) causes an infectious disease called COVID-19 (coronavirus disease-2019) by the WHO.1 The first case ever reported occurred in Wuhan, China, in December 2019.1 Since then, the number of contagions and deaths attributed to COVID-19 has been growing with unprecedented numbers. Until January 2021, a total of 91,492,398 and 2,252,164 cases of COVID-19 had been diagnosed worldwide and Spain, respectively.2 A total of 1,979,507 deaths due to this virus have been confirmed across the world. In Spain 19 516 cases have required ICU admission, and 53 314 deaths have been reported.2

Clinical signs are varied and go from upper respiratory tract infections to severe respiratory distress. It is possible that the intensity of the clinical response is associated with the level of expression of proinflammatory cytokines.3 As a matter of fact, the cases that end up in an intensive care unit show overexpression of cytokines, mainly IL-2, IL-7, IL-10, granulocyte-colony stimulating factor (G-CSF), interferon gamma-induced protein 10 (IP-10), macrophage inflammatory protein-1 alpha (MIP-1α), and tumor necrosis factor alpha TNFα.3 This mechanism contributes to the development of acute respiratory distress syndrome (ARDS). Patients who develop ARDS and survive have high chances of dying due to pulmonary fibrosis in the future.4 An autopsy study of patients dead due to ARDS conducted in 2013 found that the prevalence of pulmonary fibrosis with a 1 to 3 weeks clinical course was 24%. However, when the duration of ARDS was > 3 weeks, prevalence went up to 63%.5 As a matter of fact, ARDS survivors showed reticular patterns in the computed tomography scan in up to 85% of the cases.4 This reticular pattern is often found on a CT scan in the acute phase of patients with COVD-19.1

Although the lung is the organ most commonly affected in severe cases, SARS-CoV-2 infections can damage other organs and progress to multiorgan failure. Several drugs have been used during this pandemic, but none has improved survival to this date.6 The management of ARDS in severe cases of COVID-19 includes invasive mechanical ventilation, muscle relaxation, and prone positioning.1 When these measures fail, and for the lack of an effective drug therapy, the Extracorporeal Life Support Organization guidelines suggest the use of extracorporeal membrane oxygenation (ECMO).7

The use of ECMO has proven beneficial to treat ARDS due to other viral infections. During the 2009 pandemic caused by the H1N1 influenza virus, mortality went down 21% in Australia and New Zealand in patients treated with ECMO after developing ARDS.8 These data were similar to those obtained in the United Kingdom during this same pandemic (mortality rate dropped 23% in patients on ECMO vs 52% in patients without it).9 Also, refractory respiratory distress due to MERS-CoV studied in 2014-2015 in Saudi confirmed a lower in-hospital mortality rate in the group of patients treated with ECMO.10

Therefore, the main objective of our study was to conduct a systematic review of mortality in patients with severe SARS-CoV-2 infection who required invasive support with ECMO after developing ARDS refractory to conventional therapy.

METHODS

A systematic review was conducted following the criteria established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.11 A combination of the following keywords was used in Medline: «COVID-19», «ECMO», «SARS-CoV-2», «extracorporeal membrane oxygenator/ extracorporeal membrane oxygenation», «mortality», and «ARDS». Inclusion criteria were studies from 2020, whether observational studies or case series, that analyzed the mortality of patients with ARDS and SARS-CoV-2 infection treated with ECMO. Exclusion criteria were publications on ECMO and COVID-19 that would not include additional patients eligible for this research, with the objective of focusing on ECMO related complications, that proved its benefits compared to other therapies, with authors reporting on isolated case reports including children, pregnant and postpartum women with COVID-19 who required ECMO. However, due to the heterogeneous methodology of the studies included a proper statistical analysis could not be conducted. The study was conducted in observance of the Declaration of Helsinki regarding ethical principles on medical research with human beings. This study was approved by the Complejo Hospitalario Universitario ethics committee of the Canary Islands, Spain.

RESULTS

After combining the keywords, the search identified 573 publications. A total of 271 were ruled out for being duplicated or irrelevant. After reviewing the abstracts of the remaining 302 articles, 145 were excluded for not including any additional cases of patients who needed mechanical support or ECMO or for being reviews on ECMO and COVID-19. Out of the 157 studies that described cases with ECMO, 116 were discarded based on the exclusion criteria. Finally, a total of 41 publications were analyzed (figure 1) with a total of 2007 cases of patients with severe SARS-CoV-2 infections who required ECMO support with a mean age of 54 years (72% of whom were predominantly men) (table 1). Venovenous or veno-venovenous ECMO (VV-ECMO or VVV-ECMO) was administered to 1545 patients due to refractory hypoxemia yet despite prone positioning or ARDS. Venoarterial or veno-arteriovenous ECMO (VA-ECMO or VAV-ECMO) was administered to 84 patients due to cardiogenic shock. Of these, 985 (49%) patients improved clinically and were ECMO decannulated or released from the hospital. On the contrary, 660 patients (32.8%) died despite invasive mechanical support with ECMO. Finally, since 357 patients (17.7%) still needed ECMO support by the time these studies were being published, the final clinical outcome remains unknown.

Figure 1. Flowchart depicting the search for articles on extracorporeal membrane oxygenation (ECMO) and COVID-19.

Table 1. Registry of the studies available, number of patients on extracorporeal membrane oxygenation (ECMO), and number of patients released from the hospital, deceased, and still on ECMO by the time this study was being published

Study Journal Patients with COVID-19 Mean age, years (range) Sex masculine/feminine Total Patients on ECMO Patients on VV- or VVV/VA- or VAV-ECMO Patients decannulated or released from the hospital (%) Dead patients (%) Patients still on ECMO (%)
Total 6636 54 (44-71) 1448/457 2007 1545/84 985 (49%) 660 (32.8%) 357 (17.7%)
Ahmadi ZH et al.34 J Card Surg 7 46 6/1 7 7/0 2 5 0
Akhtar W et al.35 Indian J Thorac Cardiovasc Surg 18 47 16/2 18 15/3 14 4 0
Alnababteh M et al.36 Perfusion 59 44 8/5 13 13/0 7 6 0
Barbaro RP et al.24 Lancet 1035 49 764/269 1035 978/57 599 380 56
Charlton M et al.37 J Infect 34 46 27/7 34 NA 18 16 0
Cousin N et al.38 ASAIO J 30 57 24/6 30 30/0 14 16 0
Falcoz PE et al.39 Am J Respir Crit Care Med 377 56 16/1 17 16/1 11 6 0
Guo Z et al.40 J Cardiothorac Vasc Anesth 667 63 7/1 8 8/0 4 4 0
Hu H et al.41 Curr Med Sci 55 50 4/5 9 9/0 5 4 0
Huang S et al.42 J Clin Anesth 3 62 1/2 3 3/0 0 2 1
Huette P et al.43 Can J Anaesth 12 NA NA 12 NA 8 4 0
Jacobs JP et al.44 ASAIO J 32 52 22/10 32 26/5b 5 10 17
Kon ZN et al.45 Ann Thorac Surg 1900 40 23/4 27 27/0 11 1 15
Le Breton C et al.46 J Crit Care 13 58 10/3 13 13/0 11 2 0
Li J et al.47 Am J Med Sci 74 71 NA 2 NA 0 2 0
Loforte A et al.48 ASAIO J 4 49 4/0 4 4/0 1 2 1
Marullo AG et al.31 Minerva Cardioangiol 333 52 285/48 333 150/9b,c 54 57 222c
Miike S et al.49 J Infect Chemother 14 58 2/1 3 NA 2 1 0
Mustafa AK et al.50 JAMA Surg 40 48 30/10 40 NA 29 6 5
Osho AA et al.51 Ann Surg 6 47 5/1 6 6/0 5 1 0
Riera J et al.52 Crit Care Explor 19 50 16/3 19 19/0 13 4 2
Rieg S et al.53 PLoS One 213 65 NA 23 NA 9 14 0
Ruan Q et al.19 Intensive Care Med 150 67 NA 7 NA 0 7 0
Santos-Martínez S et al.54 REC Interv Cardiol 14 48 11/3 14 12/2 8 4 0
Schmidt M et al.30 Lancet Respir Med 492 49 61/22 83 81/2 52 30 1
Schroeder I et al.55 Anaesthesist 70 66 5/2 7 NA 1 6 0
Shen C et al.56 JAMA 5 36-65 1/0 1 NA 1 0 0
Sromicki et al.57 Circ J 9 59 6/3 9 7/2 7 2 0
Sultan I et al.32 J Card Surg 10 31-62a 7/3 10 10/0 2 1 7
Wu C et al.58 JAMA Intern Med 201 51 NA 1 NA 0 1 0
Xu Y et al.59 Front Med (Lausanne) 45 56 NA 10 NA 6 2 2
Xuan W et al.60 J Clin Anesth 5 61 NA 5 4/1b 2 3 0
Yang X et al.61 Crit Care Med 21 58 12/9 21 NA 9 12 0
Yang X et al.62 Lancet Respir Med 52 59 NA 6 NA 0 5 1
Yang Y et al.63 Card Fail Rev 7 45 3/4 7 6/1b 6 1 0
Yankah CA et al.64 Thorac Cardiovasc Surg 42 51 30/12 42 42/0 17 7 18
Yao K et al.65 J Infect Chemother 101 60 NA 11 NA 9 2 0
Zayat R et al.66 Artif Organs 17 57 11/6 17 16/1 9 8 0
Zeng Y et al.67 Critical Care 12 51 11/1 12 NA 3 5 4
Zhang G et al.13 J Clin Virol 221 55 NA 10 NA 2 3 5
Zhang J et al.68 ERJ Open Res 43 46 20/13 43 43/0 29 14 0
Zhou F et al.69 Lancet 191 56 NA 3 NA 0 3 0

COVID-19, coronavirus disease-2019; ECMO, extracorporeal membrane oxygenation; NA, not available; VA, venoarterial; VAV, veno-arteriovenous; VV, venovenous; VVV, veno-venovenous.

aStudy age range.

bIndication for VA- or VAV-ECMO not available.

cIncomplete data.

DISCUSSION

We present a systematic review of publications on patients with severe SAR-CoV-2 infections treated with ECMO during 2020 since the beginning of the COVID-19 pandemic. This study includes one of the largest series of patients requiring ECMO due to severe SARS-CoV-2 infection published on the medical literature to this date.

The main clinical presentation of COVID-19 is a mild infection with dry cough and fever as the most common symptoms; the overall rate of ARDS is 3.4%.12 However, after studying series of patients who develop pneumonia and require hospitalization, the rate of ARDS can be up to 17% to 21%.13,14 The systemic inflammatory response of patients ith COVID-19 can affect, to a greater or lower extent, the pulmonary epithelium and endothelium.15 However, the endothelium seems less affected by SARS-CoV-2, which produces fewer alveolar exudates, thus contributing to the production of dry cough. On the other hand, in patients with severe COVID-19 ARDS does not show the reduction of compliance that a standard ARDS would cause, suggestive that other mechanisms are responsible for severe hypoxemia.15 This milder endothelial aggression can contribute to a small viral affectation of distal organs.15

Myocardial damage is present in 7.2% to 20% of the cases15-18 and kidney injuries in 2.9% to 15% depending on the sources.15 Myocardial damage can be associated with higher in-hospital mortality16-18 and should tip us off to discard cardiogenic shock due to fulminant myocarditis in case of hemodynamic instability after severe SARS-CoV-2 infection19. Myocardial damage is multifactorial and could be the result of the virus direct cardiotoxicity on cardiomyocytes.16 This possibility may be associated with the compatibility that exists between the virus and the angiotensin-II receptor, present in over 7.5% of cardiomyocytes. We should not forget the systemic inflammatory response following the infection that can cause the direct inflammation and suppression of myocardial contractility.16 Similarly, the fewer visits to the emergency room due to acute coronary syndrome reported and the drop in the activity of the infarction code during the pandemic have both increased the rate of cardiogenic shock of ischemic origin.20 This has reduced the healthcare activity provided during the pandemic with fewer coronary interventions being performed. This serious complication may have increased the need for ventricular assist devices, particularly ECMO, in the context of a lower availability of this device due to being used by patients with severe SARS-CoV-2 infection.

To fight severe COVID-19 cases due to ARDS refractory to protective invasive mechanical ventilation, muscle relaxation, and prone positioning or cardiogenic shock refractory to inotropic and vasopressor support, VV-ECMO or VA-ECMO are available options according to the guidelines recently published by the Extracorporeal Life Support Organization (ELSO).7 The problem with this therapy is that it is an expensive and limited resource. Therefore, during this health crisis, it should be used in young populations with high mortality rates and fewer comorbidities.7 Kidney disease is not an absolute contraindication and it should not be used in patients on invasive mechanical ventilation for more than 7 days because of the worse outcomes reported.7 For all these reasons, thorough assessments prior to indicating the most appropriate ECMO support is needed in patients with severe SARS-CoV-2 infection.21 The best time to implant this device is when protective invasive mechanical ventilation and prone positioning fail, and as long as the patient does not develop septic shock or multiorgan failure.22 After implantation, it is recommended to assess the blood concentrations of IL-6 and lymphocytes because if the numbers of these markers do not improve with this therapy, these patients’ prognosis is often less promising.23

The search conducted found higher mortality rates in patients who received ECMO due to ARDS after severe SARS-CoV-2 infection compared to those who developed the disease caused by the H1N1 influenza virus in the United Kingdom during the pandemic of 2009: 32.8% vs 23%,9 respectively. These findings are consistent with those from the registry conducted by Barbaro et al., one of the largest registries ever published, of 1035 patients with a 39% in-hospital mortality rate.24 On the other hand, during the MERS-CoV pandemic of 2015, the mortality of the group that received ECMO therapy was analyzed (64% compared to 100% in the group without this device).10 However, due to the lack of clinical trials in the medical literature with control groups of treatment without ECMO for the management of SARS-CoV-2-induced ARDS, we still should not say that its use is beneficial. Also, the high pressure exerted on the health centers at the beginning of the pandemic may have contributed to the worse results reported like the ones published by Ruan et al.19 compared to other series that studied mortality with ECMO in these patients when this pressure on the healthcare system had probably gone down.24,30

During the first few months of 2020, 2 meta-analyses of patients with SARS-CoV-2-induced ARDS treated with ECMO were conducted. The first one included 4 Chinese studies and proved the poor benefits of this therapy in 17 patients since only 1 managed to survive.25 The other meta-analysis includes 6 series of 17 patients in total. Fourteen of these patients died and mortality rate was close to 82.3%.26 The limitation of these studies is the small number of patients included for analysis and both recommended conducting new studies.

There are reviews already currently available on the medical literature. However, one of them only includes 274 patients who required ECMO, meaning that mortality could not be properly analyzed since 45.6% of the patients remained hospitalized by the time the studies included were being published.27 A different review of 479 patients from 25 studies showed a 19.83% mortality rate. However, the authors claim that it is just an estimate since some of the studies did not report on the mortality rate of the subjects.28 Finally, Melhuish et al.29 grouped 331 cases from 10 different studies and 4 database registries and estimated a 46% mortality rate. A common limitation of these studies is that none of them includes the registry conducted by Barbaro et al.24 the largest published to this date. Our review widens and consolidates these findings after including the 3 largest series published to this date of 83, 333, and 1035 patients.24,30,31 Although we found a higher mortality rate compared to the H1N1 pandemic of 2009,8,9 ECMO support in these patients may be acceptable for the lack of another therapeutic option. However, every case should be treated individually; patients over 60 and with associated comorbidities like cardiovascular disease and diabetes have a higher mortality risk.17,28,31

Due to the complexity of ECMO support, the need for the proper learning curve and clinical experience, the results of this therapy can be biased. From 2003 through 2019, the number of centers that used this device across the world quadrupled, and the number of devices implanted has multiplied by a factor of 6.32 This is so to such an extent that during an unexpected pandemic when resources need to be immediately restructured, the results obtained by the studies within the first few months of 2020 should be interpreted with caution. For example, during the pandemic of 2009, much more ECMO systems were used, which may have generated higher chances of recovery compared to the current limitation of resources available for the implantation of this device. This means that mortality results may be different too.1

Finally, we should mention that despite the fact that patients survive with the invasive support provided by ECMO, the chances of experiencing pulmonary fibrosis in the future are non-negligible with the corresponding higher mortality rate.5 Further studies are needed to identify patients with greater chances of developing this complication; also, antithrombotic therapy may be useful for the management of SARS-CoV-2 infections causing parenchymal pulmonary fibrosis.5

Limitations

The first limitation of our study is that unpublished multicenter registers on scientific journals were excluded.33 Also, patients treated with ECMO from studies focused on analyzing ECMO related complications and isolated case reports were excluded. The characteristics of patients from each study or the methodologies used have not been compared because they were different.

CONCLUSIONS

We believe that invasive support with ECMO may be useful for certain patients based on the recommendations established by the clinical guidelines and the availability of resources despite the dissimilar results obtained. A randomized clinical trial comparing the use of ECMO to conventional invasive mechanical ventilation would bring further evidence on this regard.

FUNDING

This study received no funding whatsoever.

AUTHORS’ CONTRIBUTIONS

N. Báez-Ferrer was involved in the reference search, data analysis, and writing of this manuscript. A. Bompart-Cairós, and D. López-Rial both participated in the reference search. P. Abreu-González, and D. Hernández-Vaquero participated in the review and writing of this manuscript. A. Domínguez-Rodríguez conducted the manuscript final review.

CONFLICTS OF INTEREST

None reported.

WHAT IS KNOWN ABOUT THE TOPIC?

  • ARDS can be the clinical presentation of SARS-CoV-2 infection.
  • Multiple drug therapies fail during the management of this entity. The use of ECMO is especially important in patients who are refractory to mechanical ventilation, muscle relaxation, and prone positioning.
  • Since the beginning of the COVID-19 pandemic and all across 2020 several articles of patients with severe SARS-CoV-2 infection manifested as ARDS have been published. These articles have analyzed the mortality rate associated with ECMO therapy. However, to this date, no randomized clinical trial has assessed the clinical benefit of ECMO in these patients.

WHAT DOES THIS STUDY ADD?

  • We presented the results of a systematic review of the studies published in 2020 during the COVID-19 pandemic to analyze the mortality rate of patients with SARS-CoV-2-induced ARDS requiring ECMO.
  • A total of 41 publications were identified during 2020, and 2007 cases of patients with severe SARS-CoV-2 infection who required invasive support with ECMO were collected.
  • Of all the cases collected, a mortality rate associated with ECMO in patients with severe SARS-CoV-2 was found to be 32.8%; 660 patients died despite therapy with invasive mechanical support.
  • ECMO therapy may be useful in patients with SARS-CoV-2-induced ARDS. However, it would be interesting to conduct a randomized clinical trial to compare the use of ECMO to conventional invasive ventilation therapy during this pandemic.

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* Corresponding author: Servicio de Cardiología, Hospital Universitario de Canarias, Ofra s/n, La Cuesta, 38320, Tenerife, Spain.

E-mail address: nestor.baez@hotmail.com (N. Báez-Ferrer).

ABSTRACT

Introduction and objectives: Recipients of a heart transplant need to receive serial endomyocardial biopsies (EMB) to discard rejection, a procedure that is usually performed through the femoral or jugular vein. Over the last few years, we have developed a technique to perform EMBs using the brachial venous access that we have implemented as the preferential access route. In this article, we describe the technique and the initial clinical experience of 2 different centers.

Methods: Between 2004 and 2016, we developed and implemented a brachial venous access technique. We registered the main clinical and procedural variables of all the brachial biopsies performed in both centers and compared them with a retrospective series of femoral and jugular procedures.

Results: Brachial EMBs were successfully performed 544 of the time with no major complications. The number of brachial procedures per patient rose from 1 to 14. Over the same period of time 1054 femoral and 686 jugular procedures were performed. The total procedural time was similar with different access routes (mean for brachial/femoral/jugular access: 28/26/29 min., P = .31) while fluoroscopy time was shorter in jugular procedures (mean 5/5/3 min. respectively; P < .001). The brachial procedure was recalled as the least painful procedure of all compared to the jugular or femoral ones (2/8/9 score on a scale from 1 to 10; P = .001) with an overall patient preference towards the brachial access.

Conclusions: The venous brachial access route is a good alternative to the central venous one to perform EMBs and is the route of choice in our centers. Also, it has high feasibility and safety and brings additional comfort to patients.

Keywords: Endomyocardial biopsy. Heart transplant. Brachial access.

RESUMEN

Introducción y objetivos: Los pacientes receptores de un trasplante cardiaco necesitan someterse a biopsias endomiocárdicas (BEM) para descartar el rechazo, procedimiento que habitualmente se realiza por acceso venoso yugular o femoral. En los últimos años hemos desarrollado una técnica de biopsia por vía braquial, que hemos implementado como acceso preferente. En este artículo describimos la técnica y la experiencia clínica inicial de 2 centros empleando el acceso braquial.

Métodos: Entre 2004 y 2016 desarrollamos e implementamos la técnica de biopsia por vía venosa braquial. Se registraron las principales variables clínicas y del procedimiento de todas las BEM realizadas por vía braquial en ambos centros, y se compararon las características con los procedimientos realizados por vía femoral y yugular.

Resultados: Se realizó la BEM por vía braquial en 544 casos, sin complicaciones mayores. El número de procedimientos braquiales por paciente varió entre 1 y 14. En el mismo periodo se realizaron 1.054 BEM femorales y 686 yugulares. La duración total del procedimiento fue similar por los distintos accesos (mediana braquial/femoral/yugular: 28/26/29 min; p = 0,31), con un menor tiempo de escopia por vía yugular (mediana 5/5/3 min, respectivamente; p < 0,001). Los procedimientos realizados por vía braquial se valoraron como menos dolorosos que los realizados por vía yugular o femoral (2/8/9 en la escala de dolor EVA de 1-10, respectivamente; p = 0,001), y fue la vía de elección por parte de los pacientes.

Conclusiones: La BEM por vía venosa braquial es una buena alternativa a la punción venosa central y la vía de elección en nuestros centros, con altas factibilidad y seguridad, y mayor comodidad para el paciente.

Palabras clave: Biopsia endomiocárdica. Trasplante cardiaco. Acceso braquial.

Abbreviations: EMB: endomyocardial biopsy. RHC: right heart catheterization. RV: right ventricle.

INTRODUCTION

Endomyocardial biopsy (EMB) is an invasive procedure usually performed using central venous access to obtain samples of the interventricular septum from the right ventricle (RV).1,2 Its main indication is for heart transplant recipients who need repeated EMBs to discard organ rejection despite immunosuppressive therapy.3 Less frequently, the EMB is also used as a diagnostic tool with certain heart diseases like myocarditis or suspected infiltrative disease,4 scenarios where the arterial femoral or radial approach may also be considered to access the left ventricle.5,6

EMBs are often performed through central venous access, femoral or jugular access;2-4 although it is a safe technique, it is associated with a risk of vascular or nerve damage that is inherent to jugular or femoral punctures.7

The forearm veins may be a good alternative access route to perform EMBs with the potential advantage of increased vascular safety and more comfort to the patient (figure 1). Basilic and cephalic veins are superficial veins that converge at the subclavian vein, superior cava vein, and ultimately right heart. However, the use of this access route known by the generic term “brachial” to perform EMBs is rare and, to this day, has been reported in one series only.8

Figure 1. Schematic representation of the anatomy of the superficial veins of the arm, forearm and surrounding structures.

In our centers we have developed a new technique to perform EMBs through the brachial vein that we have been using since 2004. The main objective of this manuscript is to describe our technique to perform EMBs through brachial venous access, and the feasibility, safety, and efficacy reported by 2 different centers; our secondary objective was to compare the performance of the brachial route to that of conventional femoral and jugular access routes.

METHODS

Brachial biopsy technique

We have spent over 12 years modifying our technique in 2 different centers since we first described it,9 and have used different catheters and forceps to overcome the main difficulty we have encountered: the lack of devices specifically developed for this purpose. What follows is a description of the approach that has become predominant in our clinical practice.

After the identification of a large brachial vein, preferably the basilic vein over the cephalic one, we prepare a sterile field and puncture the vein with a regular venous catheter (18 gauge or larger) to allow the insertion of the sheath and guidewire. This first step used to be performed by our nursing team. When a vein was not readily visible or palpable, the physician in charge would perform an ultrasound-guided puncture to select the highest caliber vein. Similarly, when the standard puncture failed or if we knew of failed prior attempts or there were signs indicative that the veins had been punctured multiple times like bruising and scarring we used ultrasound guidance. The addition of ultrasound guidance has been gradual since 2015, and it has significantly increased the percentage of patients considered eligible to receive an EMB through brachial access. Once punctured, the vein is wired using a standard 0.035 in J wire, local anesthetics are administered, and a 7 Fr sheath is inserted. Afterwards, a long 0.035 in J wire is advanced and over the wire, a 7 Fr multipurpose guide catheter is positioned towards the right ventricle of the interventricular septum using fluoroscopy guidance. When the J wire could not be advanced easily often due to a venous valve or an occluded or spastic vein, a hydrophilic guidewire or a coronary 0.014 in guidewire was used.

Regarding the biopsy, we used a long forceps (104 cm; Cordis, Johnson & Johnson, United States) that comes in 2 different sizes: 5.5 Fr (142 cases) and 7 Fr (402 cases). Since the guide catheter is longer compared to the biopsy forceps we made it shorter by cutting the proximal 5 cm to 10 cm. To prevent bleeding or air embolism during manipulation, a 7 Fr femoral sheath can be used to seal the proximal end of the catheter. To facilitate the advance of the forceps through the tricuspid valve and prevent it from acquiring caudal orientation we shaped its distal end with a curve. Once the delivery catheter was in place we inserted the forceps, checked the septal orientation with fluoroscopy, and took 3-6 samples as usual. Figure 2 shows the main steps of this technique. The procedure was considered successful when an adequate sample was obtained and no major complications occurred. The inability to advance the J wire or the guide catheter that would eventually lead to change the access route was considered a failure.

Figure 2. Step-by-step procedure of a brachial endomyocardial biopsy. A: a basilic or cephalic vein is identified and punctured with an 18-gauge venous catheter. B: the vein is wired for the insertion of a 7 F sheath. C: a multipurpose 7 Fr guide catheter is advanced over a J wire and the proximal 5 cm-to-10 cm are cut. D: the catheter is inserted into the right ventricle, and its septal orientation is checked through fluoroscopy before inserting the forceps.

After the procedure and only if the patient needed right heart catheterization it was performed through the same vein. If the patient needed an additional coronary angiography, the arterial access route, preferably radial, was canalized. Finally, we extracted both the catheter and the sheath and left a gentle elastic compression for 2 hours. No bed rest was required after the EMB procedure.

Data collection and analysis

We retrospectively collected the demographics, main procedural characteristics, and immediate and 48 h complications of all consecutive patients admitted to our catheterization laboratory to receive EMB from August 2004 through April 2016. Major complications were defined as death, major bleeding, pneumothorax, stroke, and cardiac tamponade. We compared the characteristics of brachial procedures to those of a series of biopsies performed through the jugular or femoral access route. We retrospectively contacted a sample of patients who had received the procedure through 2 different venous routes (brachial and central venous access) and asked them to rate the pain experienced during the procedure on a scale from 1 to 10. Also, to state their preferred venous access for the future.

Statistical analysis was performed using R 3.2.3. Data were expressed as mean ± standard deviation, median (interquartile range) or number (percentage). Inter-group differences were studied using the unpaired Student t test, the Wilcoxon rank sum test, Kruskal-Wallis test or the chi-square test as appropriate.

RESULTS

Brachial biopsy population

Between August 2004 and April 2016 we performed a total of 544 brachial EMBs in 118 patients. Mean age of the cohort was 52 ± 13 years; 12% of the patients were female. The reason for the biopsy was post-transplant follow-up in 525 procedures (96.5%) and cardiomyopathy assessment in the remaining patients. The veins used for the procedure were the basilic (90%) and the cephalic (10%) veins; the right arm was more commonly used (74%). The number of brachial procedures per patient rose from 1 to 14 (mean of 5 [1-10]). In 71 cases (13% of the procedures) right heart catheterization (RHC) was performed too, and in 82 cases (15%) a coronary angio­graphy was performed. In these procedures most of the coronary angiographies were performed through the radial or ulnar arteries (92%). Fifty-seven-point-four percent of the cases were outpatient procedures. No major complications were reported.

The brachial approach failed in 33 cases, always due to the impossibility to wire the vein or advance the catheter so we had to change the access route. Success rate for brachial EMBs was 94%. The percentage of ultrasound-guided procedures varied between both centers; we found that after its routine use in 1 center the brachial approach success rate has gone up up to 98.4% since 2015.

Venous access comparison

A total of 2284 biopsies were included in the registry from August 2004 through April 2016: 1054 femoral, 686 jugular, and 544 brachial. The main reason to perform this procedure was heart transplant in the 3 cohorts (P < .001). The patients’ clinical characteristics were similar except for brachial procedures that were less common in women (13% vs 26%, P < .001). Most of the patients were outpatient cases in all the groups (61% of the total procedures) who did not require hospitalization. The main clinical characteristics are shown on table 1.

Table 1. Demographics and baseline characteristics of jugular, femoral and brachial patients

Jugular (n = 686) Femoral (n = 1054) Brachial (n = 544) P
Age (years) 51 ± 13 52 ± 14 52 ± 13 .38
Women 175 (25.5) 257 (24.4) 66 (12.1) < .001
Hypertension 275 (46.6) 444 (48.8) 253 (52.7) .14
Hyperlipidemia 218 (36.8) 384 (42.6) 195 (40.9) .08
Diabetes 152 (31.1) 269 (31.8) 137 (34.7) .49
Reason for biopsy < .001
 Heart transplant 677 (98.7) 989 (93.8) 525 (96.5)
 Cardiomyopathy 9 (1.3) 65 (6.2) 19 (3.5)
Patient destination .017
 Outpatient 414 (60.3) 666 (63.2) 312 (57.3)
 Inpatient 253 (36.9) 336 (31.9) 206 (37.9)
 Nonspecific 19 (2.8) 52 (4.9) 26 (4.8)

Data are expressed as no. (%) and mean ± standard deviation.

Success rate was 96.7% for jugular procedures, 99.8% for femoral procedures, and 93.9% for brachial procedures. Crossover to a different access route was required in 33 brachial cases (19 to femoral and 14 to jugular), 2 femoral cases, and 22 jugular cases (P < .001). Patients in whom the brachial access failed were similar to the remaining patients of the cohort: 12% were women with a mean age of 56 years [46-62] and 94% were heart transplant recipients. Seventeen (51.6%) out of the 33 failed procedures occurred during the early experience (between 2004 and 2007). Procedural characteristics are shown on table 2.

Table 2. Procedural characteristics

Jugular (n = 686) Femoral (n = 1054) Brachial (n = 544) P
Systolic BP (mmHg) 148 ± 25 147 ± 24 140 ± 24 .01
Diastolic BP (mmHg) 79 ± 14 82 ± 14 77 ± 13 .03
Procedural success 664 (96.7) 1052 (99.8) 511 (93.9) < .001
Crossover 22 2 33 < .001
 Brachial to femoral 19
 Brachial to jugular 14
 Femoral to jugular 2
 Jugular femoral 22

BP, blood pressure.

Data are expressed as no. (%) and mean ± standard deviation.

We compared total procedural and fluoroscopy times among different venous routes. Total procedural time for biopsy alone was similar among the groups (mean for brachial/femoral/jugular: 28/26/29 min., P = .31); however, fluoroscopy time was the shortest of them all in jugular procedures (mean 5/5/3 min., respectively; P < .001). Additional RHC or coronary angiography were performed less frequently in the jugular cohort (P < .001 in both cases).

Together with RHC, the total procedural time was longer in the brachial route compared to the central one (P = .004); however, fluoroscopy time was longer in the femoral cohort compared to both the brachial (P = .003) and the jugular (P < .001) cohorts.

When the EMB was combined with coronary angiography, procedural times were again longer in the brachial group (brachial/femoral/jugular: 66/59/61 min., P = 0.02), but they were only statistically significant with femoral times (P = .022); also, longer fluoroscopy times were required in the brachial compared to jugular access (P = .002), but not in the femoral access (P = .6). Table 3 and figure 3 show the total and fluoroscopy times per procedure alone and combined with RHC or angiography. When we compared our experience with brachial EMBs half way and then over the last half we saw a reduction in the total procedural time (30 min. vs 28 min., P = .366) and total fluoroscopy time (6.6 min. vs 6.0 min., P = .031).

Table 3. Procedure and fluoroscopy times grouped by access and procedures

Jugular (n = 686) Femoral (n = 1054) Brachial (n = 544) P
EMB only
 Number of cases 596 (86.9) 738 (70) 394 (72.4) < .001
 Procedural time 29 [20-40] 26 [20-37] 28 [19-40] .31
 Fluoroscopy time 3 [2-5] 5 [3-8] 5 [3-7] < .001
EMB + RHC
 Number of cases 46 (6.7) 131 (12.4) 69 (12.7) < .001
 Procedural time 43.5 [32.75-63.5] 43.5 [37-54.75] 51 [45-63.5] .004
 Fluoroscopy time 3 [2-5.5] 11 [7.75-15.25] 7 [6-11] < .001
EMB + CA
 Number of cases 44 (6.4) 185 (17.6) 81 (14.9) < .001
 Procedural time 61 [52-77.5] 59 [46-70] 66 [53-87] .019
 Fluoroscopy time 8 [7-18] 12 [8-17] 14 [10-19] .003

Data are expressed as median [interquartile range] and no. (%).

CA, coronary angiography; EMB, endomyocardial biopsy; RHC, right heart catheterization.

Figure 3. Comparison between the total procedural time (top charts) and fluoroscopy time (bottom charts) according to the different access routes. Inter-group comparisons were conducted using the Kruskal-Wallis and pairwise Wilcoxon tests. RHC, right heart catheterization; NS, not significant.

No major complications occurred at the 48-hour follow-up although 9 minor complications were reported: 2 vein dissections and 3 phebitis all in the brachial procedures, and 4 hematomas, 1 in the brachial access and 3 in the jugular one. Bed rest after femoral access extended for 2 hours. However, it was not required after brachial or jugular access, which facilitated shorter recovery time.

We contacted 19 patients who received repeated procedures (64 total) through 2 or 3 different access routes. They all said that the brachial route was less painful compared to the femoral and jugular ones (2/10 vs 9/10 and 8/10, respectively; P < .001). When asked about their personal preference regarding future procedures, the brachial access was the preferred access route in all the patients. Figure 4 shows the pain and discomfort reported for each access route.

Figure 4. Pain and discomfort perceived during the procedures in patients treated through 2 different access locations (brachial and other). Chart A shows the average numeric pain score for each route from 0 (no pain) to 10 (maximum pain). Chart B shows the distribution of the pain score for the brachial access (green) vs femoral and jugular accesses combined (gray). Differences are statistically significant (Wilcoxon signed-rank test; P = .001).

DISCUSSION

We report the experience of 2 Spanish centers performing EMBs through the brachial veins and the largest series described so far. We showed that it is a feasible and safe alternative that can be used in most patients on a routine basis. Also, we found that in these patients this access route was less painful and uncomfortable compared to the jugular and femoral ones. They also chose it for future prospective procedures.

Experience with the brachial approach

The forearm approach to access the right heart has already been described as a feasible and safe procedure to perform hemodynamic studies in patients with heart failure.9 Since patients with a heart transplant need to receive repeated EMBs as part of rejection monitoring, it is important to use a technique that brings both safety and comfort and avoids central venous punctures to minimize EMB risks.10 For this reason, we decided to describe this new peripheral venous access and compared it to the other 2 approaches often used in our centers.

Brachial vein is a good-sized vessel capable of accommodating 7 Fr sheaths. Its superficial location facilitates easy punctures that can be improved using ultrasound-guidance in cases of suboptimal palpation. Because of its straighter path, the basilic vein was mainly used in both traditional and ultrasound-guided accesses. The cephalic vein, although a plausible access too, connects to the subclavian with a pronounced angle that can stop the advance and rotation of the catheters. The technique described here facilitated the performance of EMBs in all but 33 cases where the guidewire or the catheter could not be advanced. We should mention that ultrasound guidance was not recorded on a routine basis and that half of the failures occurred within the first 3 years of using this approach; we think that both the learning curve and ultrasound guidance are major contributors to access failure.

In the absence of specific materials we decided to adapt the ones available in our catheterization laboratories to meet our purposes. Although we did not observe any complications from cutting the catheter (air embolism, bleeding) having better suited devices would have made the procedures safer and easier.

Peripheral versus central venous access

In this manuscript we reported the differences in procedural and fluoroscopy times among brachial, femoral, and jugular access routes. The brachial route did not seem to increase significantly the total procedural time except for when the biopsy was combined with RHC or angiography. Brachial fluoroscopy time was similar to femoral fluoroscopy time although both were longer compared to the jugular one. These differences remained even when the EMB was combined with the RHC or angiography and are consistent with those previously described in the only other series reported so far.8 The longer total procedural time of brachial procedures may be explained by the longer it took to puncture and wire the peripheral vein; conversely, the femoral vein allows faster punctures, but a more difficult positioning of the catheters–especially the Swan-Ganz–which may explain why fluoroscopy time was longer when using the femoral access in cases that combined EMB plus RHC. Although we did not study operator radiation exposure directly, we think that the radiation the operator may be exposed to is lower in the brachial approach compared to the jugular one. That is so because the former allows keeping further distance away from the X-ray source and use of radioprotective screens, which is something uncomfortable with jugular procedures where the operator is straddling on the C-arm. We should mention that we found a tendency towards shorter total and fluoroscopy times in procedures performed by more experienced operators.

Although previous reports of RHC revealed more complications in the access site in patients treated with transfemoral procedures,11 we could not confirm these findings in patients who received EMB. No major complications occurred in any of the groups either. However, rare minor complications were reported more frequently in the brachial access group. Minor complications in other central locations–such as accidental arterial punctures, small hematomas or nerve damage–maybe were underestimated since data were recorded retrospectively and therefore with reporting bias; considering the location of the jugular and femoral access, we still believe that the risk of complications is real.12,13 Probably, over the next few years ultrasound-guided punctures of central veins will become widely used, which should contribute to increase the safety and comfort of all vascular access routes.

Women had a lower probability of undergoing brachial procedures compared to males. This may be associated with the smaller size of their brachial veins, which may have discouraged the operators from attempting this route.

Regarding the degree of discomfort, patients with brachial access reported significantly lower pain measured through numeric rating scales. Regarding pain and comfort patients with a history of 2 different venous approaches (brachial and another one) preferred the brachial access compared to the femoral or jugular one. Although this cohort was small, these data are consistent with those reported by Harwani et al,8 where the overall preference was brachial approach. This added to the fact that no bed rest is required, makes the brachial access a good choice for subjects in the outpatient setting mainly.

Limitations

This is a retrospective, observational study from 2 tertiary centers and has certain inherent limitations in the comparison of the different routes mainly. One of the main limitations is the retrospective collection of femoral and jugular procedures, which may have underestimated the real prevalence of vascular complications. In our opinion, brachial access may be safer, but this still needs to be confirmed in prospective series of cases. Also, we have to acknowledge that the use of ultrasound-guidance, the reasons for changing the access route or the need for special material (hyrophilic guidewires, contrast injection) were not recorded on a routine basis. Another major limitation is the small number of patients asked to compare their experience with the different accesses; the small size of the cohort led to lower statistical consistency. Finally, the procedures were performed with equipment not specifically designed for these purposes, so it was not the ideal equipment to use. This may indeed have held our technique back. Also, we believe that the development of a low-profile catheter specifically designed for brachial EMBs may contribute to easier and shorter procedures in the future.

CONCLUSION

EMBs obtained from the arm are highly feasible and safe compared to the standard jugular or femoral access. The arm brings extra comfort to the patients and may become the route of choice in experienced centers.

FUNDING

The study did not receive any specific funding. M. Tamargo has been receiving a grant from IISGM (Ayuda Intramural PostMIR del Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain) since 2019. F. Díez-Delhoyo received funds from 2016 to 2019 from Contrato i-PFIS (Doctorados IIS-Empresa en Ciencias y Tecnologías de la Salud, Instituto de Salud Carlos III, Ministry of Economy, Industry and Competitivity, Spain). J. García-Carreño has been receiving funds from Contrato Instituto de Investigación Sanitaria Gregorio Marañón-IISGM, Madrid, Spain since 2019.

L. Grigorian has been receiving funds from Contrato CIBERCV with the project Retos Colaboración — RTC- 2016-4611-1, Madrid, Spain since 2016.

CONFLICTS OF INTEREST

The authors have declared no conflicts of interest whatsoever.

MAIN POINTS

WHAT IS KNOWN ABOUT THE TOPIC?

  • EMB is still the gold standard for rejection monitoring purposes and histological confirmation of myocarditis.
  • It is usually performed through a central vein, which is associated with the potential risk of major complications.
  • Previous evidence shows that right heart catheterization can be performed through a brachial vein. Still, evidence is scarce regarding the possibility of performing EMBs through this vein.

WHAT DOES THIS STUDY ADD?

  • EMB performed through a peripheral vein is a feasible and safe option.
  • Basilic and cephalic veins can easily be used to obtain endomyocardial samples using the material available in any catheterization laboratory with results comparable to the femoral or jugular vessels.
  • The brachial approach seems less painful and should be considered for patients undergoing EMBs.

References

1. Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease:A Scientific Statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. Eur Heart J. 2007;28:3076-3093.

2. AM, Maleszewski JJ, Rihal CS. Current Status of Endomyocardial Biopsy. Mayo Clin Proc. 2011;86:1095-1102.

3. Kern MJ. Endomyocardial biopsy in cardiac transplant recipients using the femoral venous approach. Am J Cardiol. 1991;67(4):324.

4. Esplugas E, Jara F, SabatéX, et al. Right ventricular endomyocardial biopsy. Description of the percutaneous femoral vein technic. Rev Esp Cardiol. 1987;40:410-414.

5. Schäufele TG, Spittler R, Karagianni A, et al. Transradial left ventricular endomyocardial biopsy:assessment of safety and efficacy. Clin Res Cardiol. 2015;104:773-781.

6. García-Izquierdo Jaén E, Oteo Domínguez JF, Jiménez Blanco M, et al. Diagnostic yield and safety profile of endomyocardial biopsy in the nontransplant setting at a Spanish referral center.REC:interventional cardiology. REC Interv Cardiol. 2019;2:99-107.

7. Practice Guidelines for Central Venous Access:A Report by the American Society of Anesthesiologists Task Force on Central Venous Access. Anesthesiology. 2012;116:539-573.

8. Harwani N, Chukwu E, Alvarez M, Thohan V. Comparison of Brachial Vein Versus Internal Jugular Vein Approach for Access to the Right Side of the Heart With or Without Myocardial Biopsy. Am J Cardiol. 2015;116:740-743.

9. Bielsa I, España J, Perez Quesada J, Pacheco A. Biopsia cardiaca y cateterismo derecho a través de la vena basílica. Metas Enf. 2006;9:22-26.

10. D'Amario D, Burzotta F, Leone AM, et al. Feasibility and Safety of Right and Left Heart Catheterization Via an Antecubital Fossa Vein and the Radial Artery in Patients With Heart Failure. J Inv Cardiol. 2017;29:301-308.

11. Imamura T, Kinugawa K, Nitta D, et al. Is the Internal Jugular Vein ornFemoral Vein a Better Approach Site for Endomyocardial Biopsy in Heart Transplant Recipients?Int Heart J. 2015;56:67-72.

12. Yang C-H, Guo GB-F, Yip H-K, et al. Bilateral Cardiac Catheterizations. Int Heart J. 2006;47:21-27.

13. Speiser B, Pearson K, Xie H, Shroff AR, Vidovich MI. Compared to femoral venous access, upper extremity right heart catheterization reduces time to ambulation:A single center experience:Arm Access for RHC and Ambulation Times. Catheter Cardiovasc Int. 2017;89:658-664.

14. Bennett MK, Gilotra NA, Harrington C, et al. Evaluation of the Role of Endomyocardial Biopsy in 851 Patients With Unexplained Heart Failure From 2000-2009. Circ:Heart Failure. 2013;6:676-684.

Corresponding author: Departamento de Cardiología, Hospital General Universitario Gregorio Marañón, Dr. Esquerdo 46, 28007 Madrid, Spain.


E-mail address: enrique.gutierrez@salud.madrid.org (E. Gutiérrez Ibañes)

ABSTRACT

Introduction and objectives: Endomyocardial biopsy (EMB) is an established diagnostic tool in myocardial disease. However, this technique may carry major complications. We present the diagnostic and safety results of our experience in EMB in the non-transplant setting. We also present the results after the implementation of a technical and safety protocol developed at our center.

Methods: We retrospectively analyzed the data of all EMBs conducted in non-transplant patients from September 2004 through July 2018. We compared the diagnostic yield and rate of major complications of EMB in two different periods: before and after implementing the protocol.

Results: We included 204 EMBs performed in 190 patients. The most frequent indications were the evaluation of ventricular dysfunction or suspected myocarditis (51.5%) and the evaluation of restrictive cardiomyopathy or suspected infiltrative disease (44.6%). One hundred and seventy-two EMBs were performed in the right cardiac chambers (84.3%) and 30 EMBs in the left cardiac chambers (14.7%). The specimens were taken from both ventricles on 2 cases only. Definite diagnosis was reached in 52% of the cases. After the implementation of the protocol, the diagnostic yield significantly improved (42.5% vs 58.1%; P = .030) and the rate of major complications decreased (from 7.5% to 3.2%; P = .167), with a statistically significant lower rate of cardiac perforation (6.3% vs 0.8%; P = .025).

Conclusions: The EMB is a diagnostic tool with a great potential in patients with suspected cardiomyopathy. Our experience shows that a technical and safety protocol can help decrease the rate of complications and improve the diagnostic yield of EMB.

Keywords: Endomyocardial biopsy. EMB. Cardiomyopathy. Myocarditis. Amyloidosis. Electroanatomical map.

RESUMEN

Introducción y objetivos: La biopsia endomiocárdica (BEM) es una técnica diagnóstica fundamental en el diagnóstico de distintas miocardiopatías, pero no está exenta de posibles complicaciones. Se presentan los resultados en términos de rentabilidad diagnóstica y seguridad de la serie de BEM realizadas en corazón no trasplantado en nuestro hospital, así como las consecuencias de la implementación de un protocol de actuación y seguridad en BEM desarrollado en nuestro centro.

Métodos: Se revisaron de forma retrospectiva todas las BEM en corazón no trasplantado realizadas desde septiembre de 2004 hasta julio de 2018. Se comparó la rentabilidad diagnóstica y seguridad en dos etapas: antes y después de la puesta en marcha del protocolo.

Resultados: Se incluyeron 204 BEM realizadas en 190 pacientes. La indicación más frecuente fue el estudio de disfunción ventricular o sospecha de miocarditis (51,5%), seguida de estudio de miocardiopatía restrictiva o infiltrativa (44,6%). Se realizaron 172 BEM en cavidades derechas (84,3%) y 30 en cavidades izquierdas (14,7%); solo en 2 de los procedimientos se tomaron muestras de ambos ventrículos. La BEM permitió el diagnóstico definitivo en el 52% de los casos. Tras la implementación del protocolo se observó una mejoría en la rentabilidad diagnóstica (42,5 frente a 58,1%; p = 0,030) y una disminución en la tasa de complicaciones mayores (del 7,5% al 3,2%; p = 0,167), con una reducción estadísticamente significativa en la tasa de perforaciones cardiacas (6,3 frente a 0,8%; p = 0,025).

Conclusiones: La BEM es una técnica con un gran potencial diagnóstico en pacientes con sospecha de miocardiopatía. Aunque puede presentar complicaciones potencialmente graves, la puesta en marcha de un protocol de actuación y seguridad se asocia a una reducción en la tasa de complicaciones y a una mejoría en la rentabilidad diagnóstica.

Palabras clave: Biopsia endomiocárdica. BEM. Miocardiopatías. Miocarditis. Amiloidosis. Mapa electroanatómico.

Abbreviations: EMB: endomyocardial biopsy.

INTRODUCTION

Endomyocardial biopsy (EMB) is a key diagnostic tool to monitor rejection in individuals with a heart transplant1 and also for the diagnosis of different cardiomyopathies.2-4 Since this technique was born over a century ago,5,6 several important advances have been made to improve its diagnostic yield and minimize the risk of complications for the patient. However, EMB-induced major complications, though rare, can be serious.7

Our goal was to present the results in terms of diagnostic yield and safety of an EMB series in non-transplanted hearts conducted at our hospital, a national reference center in the diagnosis and management of cardiomyopathies with a huge experience in heart transplants and, consequently, in the monitoring of rejection through EMB in cardiac transplants. Also, we aimed to describe the consequences that implementing a plan of action and safety has on the rate of complications and diagnostic yield of this technique.

METHODS

All EMB procedures conducted in non-transplanted hearts were retrospectively included from September 2004 through July 2018. The demographical and physiological data, relevant echocardiographic parameters (left ventricular ejection fraction and interventricular septum maximum thickness) and times associated with the procedure were all studied.

The main indications for conducting an EMB in a non-transplanted heart were taken into consideration according to the recom- mendations published by the American Heart Association/European Society of Cardiology back in 2007.2,3 In an attempt to facilitate the analysis of data, the indication for the procedure was coded into 4 categories: 1) study of unexplained ventricular dysfunction or suspicion of myocarditis; 2) suspicion of infiltrating disease or restrictive cardiomyopathy; 3) study of ventricular arrhythmias and 4) cardiac tumors. All the histopathological studies extracted from all specimens were reviewed in all the cases (both before and after the protocol) by the same highly-experienced anatomical pathologist in the study of EMBs. The specimens were not reviewed retrospectively in this study again. Instead, the initial 2-stage diagnosis was maintained.

Also, the rate of major complications such as the ones shown in formerly published studies was taken into consideration: mortality, perforation with cardiac tamponade, sustained ventricular arrhythmias with hemodynamic instability, complete atrioventricu- lar block requiring pacemaker, stroke, acute myocardial infarction and appearance of severe valve regurgitation.8-10 The main characteristics of the procedures conducted before and after implementing a plan of action and safety were compared including the rate of major complications and diagnostic yield of the EMB in both periods of time.

Plan of action and safety

Back in February 2013, a plan for action and safety was implemented at our center in an attempt to improve the safety of EMBs and diagnose early whatever complications that may arise. These are the landmarks of this plan:

  • Designation of a coordination group for the EMB program in the non-transplant setting including hemodynamic cardiologists, specialists in cardiomyopathies and advanced heart failure, and pathologists.

  • Planning the procedure together with the cardiologist who prescribed the test taking the indication and characteristics of the patient into consideration to be able to determine the location of the EMB and the access route. The location of the EMB (right ventricle, left ventricle or both) is basically determined by the gadolinium enhancement pattern on the cardiac magnetic resonance imaging. In highly selected cases with patchy uptake pattern or a prior negative EMB, the electroanatomic mapping-guided EMB is preferred.

  • Delivery of the informed consent document by the prescribing cardiologist and explanation to the patient of all potential benefits and risks involved in this procedure.

  • Management of perioperative antiaggregant and antiplatelet drugs by the prescribing cardiologist.

    • – Antiaggregant action: most EMBs can be conducted without the need to withdraw antiaggregant drugs with acetylsalicylic acid. However, if withdrawal is required, it should occur 7 days in advance. For patients treated with clopidogrel and ticagrelor, it should occur 5 days in advance and for those treated with prasugrel, withdrawal should occur 7 days in advance.

    • – Antiplatelet action: each patient’s thromboembolic risk is taken into consideration. In patients on dicumarinic treatment, bridge therapy is implemented only in those with high thromboembolic risk, being the drug withdrawn 5 days prior to the procedure and treatment with low molecular weight heparin prescribed 3 days prior to the procedure. In patients on direct-acting anticoagulants, the drug is withdrawn between 24 and 72 hours in advance depending on renal clearance. Bridge therapy is not required.

    • – The moment when antiaggregant or antiplatelet drugs are reintroduced is always determined taking into consideration each patient’s individual hemorrhagic and thromboembolic risk.

  • Conducting or otherwise supervising the procedure should always be the sole responsibility of the interventional cardiologist with the most experience in performing EMBs in non-transplant settings.

  • Conducting a transthoracic echocardiography prior to the procedure in order to confirm the lack of pericardial effusion, define cardiac anatomy (size of the interventricular septum and cavities, location of papillary muscles, etc.), and determine the presence and degree of possible valve regurgitation.

  • The pericardiocentesis working team should be prepared before starting the procedure.

  • Monitorization of vital signs and electrocardiogram during the entire procedure.

  • Acquisition of at least 3 good quality specimens from every previously projected location, and confirmation of the position of the bioptome using x-ray imaging and contrast injection before every take.

  • Transportation of the specimens preserved in formaldehyde at 4% or a specific preservation medium as per the pathologist instructions.

  • Conducting the transthoracic echocardiography immediately after performing the last biopsy or on suspicion of complications during the procedure and monitoring the presence or increase of pericardial effusion or other mechanical complications such as valvular regurgitation. At times (ie, on suspicion of inflammatory or infiltrative cardiomyopathy with segmental damage based on prior imaging modalities), it may be useful to perform an electrocardiogram during the procedure in order to be more precise on the location of the specific segment to be biopsized.

  • Hemodynamic and electrocardiogram monitoring for at least 6-8 hours at the diagnostics hemodynamics unit in day-hospital care or, in the case of patients already hospitalized, at the intensive care unit, paying special attention to the appearance of any possible complications of vascular access.

  • In the presence of pericardial effusion following the EMB and clinical or echocardiographic data of cardiac tamponade, a pericardiocentesis for drainage purposes should be attempted at the cath. lab. In most cases, a drainage catheter is inserted and then removed when the amount of drainage fluid is nearly nonexistent and the pericardial effusion has been resolved. In the presence of progressive effusion or hemodynamic instability despite the pericardiocentesis procedure, urgent surgery is indicated to drain the pericardial effusion and repair cardiac perforation.

Description of the procedure

The description of the procedure is shown at in the supplementary data and in the figure 1.

Figure 1. A: Material used to perform EMBs at our center. On the right side, the bioptome (black arrow) and the sheath and the 7-Fr multipurpose catheter (blue arrow) used in right-side EMBs. On the left side, the Endojaw biopsy forceps (red arrow) and 2 of the sheathless systems used for radial access in left-side EMBs: the JR4 7.5-Fr 100-cm-long guidewire catheter (green arrow) and the 7-Fr Railway access system (yellow arrow). B: the latter system described is shown while mounted on a multipurpose catheter at exchange port level. C: open EMB forceps directed towards the left ventricular posterolateral wall for specimen acquisition purposes (left anterior oblique 30° and cranial 15°). D: clockwise rotation in the same projection to direct the guidewire catheter towards the septum using an IV contrast to verify its position.

Statistical analysis

Qualitative variables are expressed as percentages and continuous variables as mean ± standard deviation as the measure of dispersion. The chi-square test was used to compare qualitative variables ant the Student t-test was used for independent sample comparison purposes.

The statistical software package SPSS 21 (SPSS, Inc.; Chicago, Illinois, United States) was used for statistical analysis purposes. P values < .05 were considered statistically significant.

RESULTS

From September 2004 through July 2018, 204 EMBs were performed in the non-transplant setting in 190 patients (12 with 2 EMBs and 1 with 3 EMBs). After implementing the aforemen- tioned plan, all EMBs were performed under the direct supervision of an experienced interventional cardiologist or by the cardiologist himself. A total of 172 EMBs were performed in right cavities (84.3%) and 30 in left cavities (14.7%), whereas in only 2 procedures specimens were taken from both ventricles. When it comes to right-side EMBs, the most widely used vascular access was the femoral vein (88.4%) followed by the cephalic or the basilic vein (9.9%) and the right internal jugular vein (1.7%). In the case of left-side EMBs, over half of them were performed through the radial artery (56.7%) and the rest (43.3%) through the femoral artery. One of the cases of biventricular EMB required femoral vein puncture and transseptal access, and another one, arterial and femoral vein puncture separately. In 47.5% of the cases, the EMB was performed in isolation and in the remaining cases in association with another procedure (right catheterization, coronary angiography, and even intra-aortic balloon pump counterpulsation implantation in one patient). Also, it should be mentioned that three of the procedures were electroanatomic mapping-guided EMBs.

Procedural characteristics and diagnostic yield

Table 1 shows the main procedural characteristics by comparing both stages: before and after the implementation of the plan of action and safety. Overall, a definitive anatomopathological diagnosis was achieved in 52.0% of the cases. It is important to stress out that even though the indications were not significantly different in one stage compared to the other, the diagnostic yield improved significantly after the implementation of the plan (42.5% vs 58.1%; P = .030), basically to the detriment of a greater diagnostic yield in cases of ventricular dysfunction or suspicion of myocarditis (28.2% vs 53.0%; P = .013). Also, there was a significant increase in the number of specimens obtained and the number of left-side EMBs. There was a significant reduction in procedural time with no differences in the x-ray imaging time, although it is true that this difference may have been related with the fact that the isolated EMB (without an associated procedure) was less common before than after the implementation of the plan (33.8% vs 56.5%; P = .004).

Although it never reached statistical significance (P = .083), diagnostic yield was different for each and every indication. It was greater in cases of suspicion of restrictive or infiltrative cardiomyopathy and cardiac tumors. Table 2 shows the anatomical pathology diagnosis in each and every indication.

The left-side and biventricular EMB diagnostic yield was similar compared to the right-side EMB diagnostic yield (56.3% vs 51.2%; P = .384). It should be mentioned that, in left-side EMBs, the most common indication was the study of ventricular dysfunction or suspicion of myocarditis (70% of the cases). However, this indication was less common in right-side EMBs (48.9% of the cases).

All electroanatomic mapping-guided EMBs were performed after the implementation of the plan. The definitive anatomopatho- logical diagnosis was achieved in 2 of the 3 EMBs (one case of myocarditis and one case of enteroviral cardiomyopathy). Also, specific therapy was prescribed in both cases.

Table 1. Baseline characteristics and EMB procedural characteristics. Overall and comparisons before and after the implementation of the plan of action and safety

Total (n = 204) Before the implementation (n = 80) After the implementation (n = 124) P
Main characteristics
 Age (years) 52.1 ± 17.1 50.4 ± 16.5 53.2 ± 17.4 .252
 Males (%) 60.3 55.0 63.7 .214
 LVEF (%) 44.2 ± 17.2 48.1 ± 18.9 42.5 ± 16.2 .060
 IVS (mm) 12.8 ± 4.5 12.7 ± 4.5 12.8 ± 4.5 .927
 BSA (m2) 1.83 ± 0.21 1.81 ± 0.23 1.84 ± 0.20 .632
 Number of valid specimens 3.6 ± 1.4 3.0 ± 1.2 4.0 ± 1.4 < .001
 Duration of the procedure (min) 43.3 ± 19.9 47.8 ± 22.5 41.1 ± 18.2 .038
 X-ray imaging time (min) 12.1 ± 7.1 12.6 ± 6.3 11.9 ± 7.6 .516
Indications .698
 Study of unexplained ventricular dysfunction or myocarditis 105 (51.5%) 39 (48.8%) 66 (53.2%)
 RCM or suspicion of infiltrative cardiomyopathy 91 (44.6%) 36 (45.0%) 55 (44.4%)
 Ventricular arrhythmias 5 (2.5%) 3 (3.7%) 2 (1.6%)
 Tumors 3 (1.4%) 2 (2.5%) 1 (0.8%)
Location of the EMB .003
 Right ventricle only 172 (84.3%) 76 (95.0%) 96 (77.4%)
 Left ventricle only 30 (14.7%) 4 (5.0%) 26 (21.0%)
 Biventricular 2 (1.0%) 0 2 (1.6%)
52.0 42.5 58.1 .030

BSA, body surface area; EMB, endomyocardial biopsy; IVS, interventricular septum; LVEF, left ventricular ejection fraction; RCM, restrictive cardiomyopathy.

Safety and major complications

In our series, there were 10 major complications that amounted to a 4.9% overall rate. No patient died. All complications occurred while performing the EMB in the right cavities, except for two cases of transient ischemic attack that occurred while performing two left-side EMBs. Table 3 shows all major complications and their progression.

Figure 2 shows the main major complications that took place in our series before and after the implementation of the plan of action and safety. It is important to say that after the implementation of this plan the major complications were cut in half (from 7.5% to 3.2%), although this difference was not statistically significant (P = .167). This decrease was due to less cases of cardiac perforation with only one case being reported after the implementation of the plan (6.3% before vs 0.8% after the implementation of the plan; P = .025).

Figure 2. Major complications associated with the EMB before and after the implementation of the plan of action and safety. EMB, endomyocardial biopsy. TIA, transient ischemic attack.

DISCUSSION

Even though over the last few years we have not had any significant advances in the non-invasive diagnosis of acute rejection in heart transplant recipients11,12 or in the non-invasive diagnosis of different cardiomyopathies,13-16 the EMB is still the gold standard procedure to achieve a definitive diagnosis in these situations. The findings of the EMB can also have relevant prognostic implications. However, the diagnostic yield of this technique is not absolute and varies from one series published to the next (table 4).8,9,17-24 In our series it was impossible to achieve a definitive anatomopathological diagnosis in little over half the cases. It is interesting to see how the diagnostic yield of our series improved significantly after the implementation of the plan basically to the detriment of an improved diagnostic yield in cases of ventricular dysfunction or on suspicion of myocarditis. The advances made in immunohistochemical techniques and genomic detection methods, the planning of all cases by choosing the most suitable approach for each patient (based on the type of cardiomyopathy suspected), the experience accumulated, and the acquisition of a larger amount of specimens in every procedure are some of the reasons that would justify such a change.

The EMB rates from series published by high-volume centers indicate rates of major complications below 1% (table 4). In our series, the rate of complications is higher. The fact that the most common indication in our center was for the study of ventricular dysfunction could explain this, since this group of patients has a higher risk of complications.25 It is important to emphasize here that the implementation of the plan, added to the role played by the learning curve in this technique23,24 have cut the occurrence of major complications at our center in half revealing a rate of perforations below 1%. We believe that our results show a more realistic situation of EMBs currently performed in our setting. Therefore, we believe that this type of procedure should not be trivialized and should be performed at centers with enough experience and under the supervision and rules from a clear-cut plan of action of safety.

Table 2. Diagnostic yield in each and every EMB indication

Indication for EMB Diagnostic yield Definitive anatomopathological diagnosis
Study of unexplained ventricular dysfunction or suspicion of myocarditis (n = 105) Total: 43.8%
Before the implementation: 28.2%
After the implementation: 53.0% (P = .013)
Myocarditis: 37 (35.2%)
HCM: 4 (3.8%)
Amyloidosis: 2 (1.9%)
Cobalt toxicity: 2 (1.9%)
Mitochondrial cardiomyopathy: 1 (1.0%)
Undiagnosed: 61 (58.1%)
Suspicion of RCM or infiltration (n = 91) Total: 61.5%
Before the implementation: 58.3%
After the implementation: 63.6%
(P = .611)
Amyloidosis: 44 (48.4%)
HCM: 7 (7.7%)
EMF: 2 (2.2%)
Sarcoidosis: 1 (1.1%)
Myocarditis: 1 (1.1%)
Fabry: 1 (1.1%)
Undiagnosed: 35 (38.5%)
Ventricular arrhythmias (n = 5) Total: 40.0% MCH: 1 (20.0%)
Myocarditis: 1 (20.0%)
Undiagnosed: 3 (60.0%)
Cardiac tumors (n = 3) Total: 66.7% Angiosarcoma: 2 (66.7%)
Undiagnosed: 1 (33.3%)

EMB, endomyocardial biopsy; EMF, endomyocardial fibrosis; HCM, hypertrophic cardiomyopathy.

The overall diagnostic yield of the entire series is shown here as well as the comparison between the 2 stages (before and after the implementation of the plan of action and safety) in the 2 main indications. The definitive anatomopathological diagnosis of each indication is expressed as absolute numbers and percentages using brackets.

Table 3. Summary of major complications in chronological order of appearance

Patient Date of the procedure Age (years) Sex Indication for the EMB Location Final diagnosis Complication Treatment
1 June 2017 66 Female Study of ventricular dysfunction or suspicion of myocarditis RV Undiagnosed Perforation with cardiac tamponade Pericardiocentesis
2 November 2016 40 Male Study of ventricular dysfunction or suspicion of myocarditis LV Lymphocytic myocarditis TIA Did not need
3 June 2016 35 Male Suspicion of RCM or infiltrative cardiomyopathy Biventricular (RV) Sarcoidosis SMVT during right-side EMB with hemodynamic instability Electrical cardioversion
4 May 2015 71 Male Suspicion of RCM or infiltrative cardiomyopathy RV Amyloidosis Ventricular arrhythmia leading to asystole Transcutaneous cardiac pacing and IV atropine
5 January 2013 49 Female Study of ventricular dysfunction or suspicion of myocarditis RV Undiagnosed Perforation with cardiac tamponade Pericardiocentesis
6 October 2012 55 Female Study of ventricular dysfunction or suspicion of myocarditis RV Undiagnosed Perforation with cardiac tamponade Surgery
7 October 2011 82 Male Suspicion of RCM or infiltrative cardiomyopathy RV Amyloidosis Severe pericardial effusion with no signs of hemodynamic compromise Delayed surgery (due to persistent pericardial effusion at follow-up)
8 July 2011 67 Male Suspicion of RCM or infiltrative cardiomyopathy LV Amyloidosis TIA Did not need
9 June 2008 51 Male Study of ventricular dysfunction or suspicion of myocarditis RV Undiagnosed Perforation with cardiac tamponade Pericardiocentesis
10 May 2007 37 Male Study of ventricular dysfunction or suspicion of myocarditis RV Lymphocytic myocarditis Perforation with cardiac tamponade and cardiorespiratory arrest Surgery

EMB, endomyocardial biopsy; IV, intravenous; LV, left ventricle; RCM, restrictive cardiomyopathy; RV, right ventricle; SMVT, sustained monomorphic ventricular tachycardia; TIA, transient ischemic attack.

Table 4. Diagnostic yield and major complications in the main EMB series in the non-transplant setting published to date

Author (year) Number of EMBs Location/vascular access Average number of specimens/EMBs Diagnostic yield Major complications
Deckers et al.17(1992) 546 RV/jugular (96.2%); femoral (1.3%); subclavian (0.5%). 6 ± 2 Not indicated 0.5% perforations
0.4% mortality
Felker et al.18 (1999)a 1278 RV/jugular Not published 16% 0.9%
Bennet et al.19(2013) 851 RV/not indicated 5.6 25.5% 0.9%
Hiramitsu et al.20(1998)b 19 964 RV (84.3%); LV (56.7%); RA (6.0%) 2.6 in RV
2.8 in LV
2.2 in RA
Not indicated 0.7% perforations
0.05% mortality
Holzmann et al.8 (2008)c 3048 RV/femoral 8.2 ± 0.8 (retrospective);
10.1 ± 0.6 (prospective)
Not indicated 0.12% in retrospective series
0% in prospective series
Yilmaz et al.9 (2010) 755 RV (17.1%); LV (35.1%); BiV (47.3%)/femoral 5.6 ± 1.5 in RV;
5.8 ± 1.5 in LV;
8.4 ± 3.5 BiV
BiV 79.3% vs UniV 67.3% 1.1% (BiV 0.56% vs UniV 1.51%)
Fiorelli et al.21 (2012) 1783 RV/jugular + 5 cases LV Not indicated Not indicated 0.8%
0.2% mortality
Jang et al.22 (2013) 228 RV/femoral 5.6 ± 2.3 Not indicated 1.3%
Chimenti et al.23 (2013) 4221 RV (15.9%); LV (27.3%); BiV (56.8%)/femoral 4.2 ± 1.6 in RV;
4.5 ± 1.2 in LV;
8.7 ± 1.6 BiV
LV 96.3% vs RV 71.4% in BiV EMBs 0.39% (LV 0.33% vs RV 0.5%)
Isogai et al.24 (2015)d 9167 Not indicated Not indicated Not indicated 0.9%

BiV, biventricular; EMB, endomyocardial biopsy; LV, left ventricle; RA, right atrium; RV, right ventricle; UniV, univentricular.
aComplications studied in 323 patients only.
bData published from one multicenter survey including 134 Japanese hospitals. The percentages of the EMB locations are the ones provided by each center. The vascular access used by the different centers varied, mostly venous access and through the femoral artery.
cSeries of 3048 EMBs in 2415 patients (2505 EMBs analyzed retrospectively and 543 prospectively with systematic data mining) for the study of ventricular dysfunction.
dMulticenter study including data from 491 Japanese hospitals. The table disregards the EMBs performed in the transplant setting. The rate of major complications includes one composite variable of pericardiocentesis, surgery or temporary pacing.

In some series, the acquisition of specimens from both ventricles has improved the procedural diagnostic yield without increasing the rate of complications reported.9,23 Our experience on this regard is still limited, but still we could confirm that left-side EMBs were more widely accepted after the implementation of the plan. In Spain this approach has been used until recently for the diagnosis of cardiomyopathies. The difference in the diagnostic criteria used in other left ventricle and biventricular EMB series makes it difficult to draw any comparisons with our own results. We would like to highlight that, in our experience, the left-side EMB is a safe technique (with only one complication reported since the implementation of the protocol) with a diagnostic yield similar to the one of right-side EMBs. This statement is even more valuable if we think that main the indication for left-side EMBs was the suspicion of myocarditis where traditionally the EMB has a limited diagnostic yield.26 In sum, we strongly believe that this is a useful approach that can provide with valuable information in these cases.

Over the last few years, the use of radial access to acquire left-side EMBs has been gradually replaced by the femoral access in our series. There is evidence on the medical literature of its feasibility and safety27-31 with a growing interest in its implementation in the clinical practice since this technique has been perfected with thinner catheters and bioptomes, and sheathless catheters specially designed for this access. The risk of complications is potentially lower. Also, same as it happens with coronary interventions through radial access,32 this technique allows to reduce hospital stays and discharge patients just after a few hours under hospital observation.

Performing electroanatomic mapping-guided EMBs is a promising strategy to improve the diagnostic yield of this procedure. Ever since Corrado et al.33 described for the first time the correlation between areas of low voltage and fibrofatty replacement in patients with arrhythmogenic right ventricular dysplasia, several studies have validated and confirmed the safety of this combined approach for the diagnosis of several cardiomyopathies.34 Our own experience with these cases is still limited. Nevertheless, we believe this is a promising technique for the diagnosis of cardiomyopathies with patchy distribution such as myocarditis or cardiac sarcoidosis. Also, it allows us to optimize the acquisition of specimens, reduce its number, and direct the bioptome towards transition areas instead of areas of greater necrosis where the risk of perforation is higher.

Limitations

Our study has several limitations. In the first place, this was a retrospective study with all the biases associated with a study of this nature when it comes to obtaining relevant data. Secondly, this study included the experience of a single center, which is why results are not easy to generalize. On the other hand, and since this is a reference center on the management of cardiomyopathies in advanced functional class and amyloidosis, it is possible that patients were overrepresented in our series.

CONCLUSIONS

In our own experience, the EMB is a technique with an attractive diagnostic potential in patients with suspected cardiomyopathy. However, we should not forget that this procedure can also lead to potentially serious complications. This study shows that the implementation of a plan of action and safety allows to minimize the appearance of complications and improve the diagnostic yield of EMBs.

CONFLICTS OF INTEREST

None declared.

WHAT IS KNOWN ABOUT THE TOPIC?

  • The EMB is a key tool for the diagnosis of several cardiomyopathies.
  • Yet despite its huge diagnostic potential, this procedure can lead to serious complications.
  • The large series of EMBs published so far show rates of complications that are usually low (< 1%) and variable data of diagnostic yield.

WHAT DOES THIS STUDY ADD?

  • The results of safety and diagnostic yield of an EMB series in the non-transplant setting performed at our center in a great variety of clinical contexts were presented here. This is the largest Spanish series ever published to this date.
  • We describe the technical characteristics of the EMB technique, and the details of the plan of action and safety approved by our center to perform EMBs.
  • We proved, for the very first time, that the implementation of a plan of action and safety generates lower rates of major complications and improves the diagnostic yield of EMBs.

SUPPLEMENTARY DATA

REFERENCES

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4. Caforio ALP, Adler Y, Agostini C, et al. Diagnosis and management of myocardial involvement in systemic immune-mediated diseases:a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Disease. Eur Heart J. 2017;38:2649-2662.

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9. Yilmaz A, Kindermann I, Kindermann M, et al. Comparative evaluation of left and right ventricular endomyocardial biopsy:differences in complication rate and diagnostic performance. Circulation. 2010;122:900-909.

10. Sławek S, Araszkiewicz A, Gaczkowska A, et al. Endomyocardial biopsy via the femoral access —still safe and valuable diagnostic tool. BMC Cardiovasc Disord. 2016;16:222.

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19. Bennett MK, Gilotra NA, Harrington C, et al. Evaluation of the role of endomyocardial biopsy in 851 patients with unexplained heart failure from 2000-2009. Circ Heart Fail. 2013;6:676-684.

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21. Fiorelli AI, Benvenuti L, Aielo V, et al. Comparative analysis of the complications of 5347 endomyocardial biopsies applied to patients after heart transplantation and with cardiomyopathies:a single-center study. Transplant Proc. 2012;44:2473-2478.

22. Jang SY, Cho Y, Song JH, et al. Complication Rate of Transfemoral Endomyocardial Biopsy with Fluoroscopic and Two-dimensional Echocardiographic Guidance:A 10-Year Experience of 228 Consecutive Procedures. J Korean Med Sci. 2013;28:1323-1328.

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34. Vaidya VR, Abudan AA, Vasudevan K, et al. The efficacy and safety of electroanatomic mapping-guided endomyocardial biopsy:a systematic review. J Interv Card Electrophysiol. 2018;53:63-71.

Corresponding author: Servicio de Cardiología, Hospital Universitario Puerta de Hierro, Manuel de Falla 1, 28222 Majadahonda, Madrid, Spain.
E-mail address: usegij@gmail.com (J.F. Oteo Domínguez).

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