Massive atrial myxoma requiring emergency cardiopulmonary bypass in a patient with heparin resistance

Summary

Heparin exhibits complex pharmacology with a wide variation in individual response. Despite this, heparin is the most commonly used anticoagulant during cardiopulmonary bypass. Heparin resistance in the context of a patient with severe cardiovascular compromise presents a potentially life‐threatening challenge. A 31‐year‐old woman was listed for emergency excision of a massive left atrial myxoma. On induction of anaesthesia, she developed marked cardiovascular instability secondary to mitral inflow obstruction. An initial heparin dose of 600 units.kg^‐1 produced an activated clotting time of 360 s; however, immediate cardiopulmonary bypass was required. Heparin resistance remained problematic throughout the procedure, with an inadequate response to antithrombin three supplementation. Despite a total dose of 120,000 units of heparin, anticoagulation was fully reversed with 500 mg protamine and there was no subsequent re‐heparinisation. Heparin resistance, when coinciding with profound cardiovascular instability, requires a pragmatic response to expedite establishment of cardiopulmonary bypass whilst minimising potential harm. In this case, successful cardiopulmonary bypass was achieved with additional heparin boluses from an alternative batch administered both intravenously and via the bypass circuit. We therefore advocate consideration of this approach as one possible solution to achieving safe entry onto cardiopulmonary bypass in a crisis scenario.

Introduction

Cardiac myxoma is the commonest benign cardiac tumour and is a rare, but potentially life threatening diagnosis. Emergency surgery is indicated in the context of cardiovascular compromise, embolic risk and excessive tumour burden. Heparin is used worldwide as the drug of choice to establish the dense anticoagulation required for safe cardiopulmonary bypass [1] and is known to exhibit reduced clinical effects in some rare cases secondary to multiple aetiologies [2, 3, 4, 5].

We describe a case of a patient with congestive cardiac failure secondary to a massive left atrial myxoma requiring immediate surgical intervention. Severe heparin resistance was observed and led to difficulty instituting cardiopulmonary bypass. Cardiac myxoma and heparin resistance are both rare pathologies, with their co‐existence making this case challenging and extremely unusual. However, it is likely that heparin resistance is an under‐recognised phenomenon in cardiac anaesthesia [3]. Explore the physiology of heparin resistance and the evidence surrounding its management [2, 5].

Report

A 31‐year‐old woman who was previously fit and well presented to a district general hospital with increasing dyspnoea on exertion, palpitations and bilateral leg swelling. She had received two courses of antibiotics from her general practitioner for a possible upper respiratory tract infection, with no improvement. On admission, she was in congestive cardiac failure with marked peripheral and pulmonary oedema, a gallop rhythm and a palpable liver edge.

A transthoracic echocardiogram revealed a 7 cm left atrial myxoma attached to the interatrial septum and prolapsing through the mitral valve (Fig. 1). The left ventricle was non‐dilated, with severe global impairment and an ejection fraction of 30%. Severe pulmonary hypertension was noted with associated right ventricular failure. Continuous wave Doppler assessment demonstrated severe tricuspid regurgitation. A pre‐operative full blood count revealed a platelet count of 382 × 10⁹.l⁻¹.

Figure 1.

Mid‐oesophageal four‐chamber view of the heart demonstrating the right atrium (RA), right ventricle (RV), left atrium (LA), left ventricle (LV) and a 7.0 × 3.9 cm atrial myxoma arising from the interatrial septum, prolapsing through the mitral valve during diastole.

Emergency transfer from the district general hospital to the cardiothoracic centre was facilitated and the patient was rapidly moved to the operating theatre. Invasive central venous and arterial blood pressure monitoring were instituted. The central venous pressure was measured at 24 mmHg, with an arterial blood pressure of 141/75 mmHg and a sinus tachycardia of 125 beats per minute. The patient was pre‐oxygenated, during which time she was prepared and draped for surgery in order to facilitate urgent transfer onto cardiopulmonary bypass in the event of life‐threatening cardiovascular instability on anaesthetic induction. Anaesthesia was induced with 750 μg fentanyl (10 μg.kg⁻¹) and 20 mg propofol. Sixteen milligrams of vecuronium was administered to facilitate tracheal intubation with an 8.0 mm cuffed oral tracheal tube, after which lung protective ventilation was commenced. Anaesthesia was maintained with isoflurane. The sternotomy and transoesophageal echo examination were undertaken simultaneously, the latter demonstrating a 7.0 × 3.9 cm mass arising from the interatrial septum, prolapsing through the mitral valve during diastole. This mass almost completely occluded the mitral valve orifice and caused severe left atrial hypertension. The continuous wave Doppler trace demonstrated a jet of severe tricuspid regurgitation. A right ventricular systolic pressure of 49 mmHg was noted, which when combined with a right atrial pressure (measured from the central venous catheter) of 25 mmHg, gave an estimated pulmonary artery systolic pressure of 74 mmHg. During surgical dissection, the patient’s haemodynamic parameters deteriorated and the measured right ventricular systolic pressure equilibrated with systolic blood pressure, suggestive of complete cardiovascular collapse, which prompted emergent establishment of cardiopulmonary bypass.

An initial dose of 30,000 units heparin (600 units.kg⁻¹) produced an activated clotting time (ACT; MAX‐ACT Helena Laboratories, Mt Waverley, Australia) of 360 s. Given the observed cardiovascular instability, cardiopulmonary bypass was commenced with an additional 10,000 units heparin administered in the cardiopulmonary bypass circuit and a further empirical 30,000 units heparin given intravenously, drawn from a different batch. This increased her ACT to 480 s. Because heparin requirements remained high whilst on cardiopulmonary bypass, antithrombin three concentrate (1000 units) was administered, to no effect. The total heparin dose administered by the termination of cardiopulmonary bypass was 120,000 units. Restoration of baseline ACT, which was confirmed with kaolin‐K and kaolin‐K with heparinase assays for thrombo‐elastography (TEG; TEG 5000 Haemonetics S.A., Switzerland), was achieved with 500 mg protamine. An infusion of protamine was commenced at 25 mg.hour⁻¹ and continued for 6 hours, as per the institutional standard operating procedure. There was no heparin rebound on serial thrombo‐elastography.

Weaning from cardiopulmonary bypass was uncomplicated, undertaken with a bolus of calcium chloride, enoximone 5 μg.kg⁻¹.min⁻¹, noradrenaline 0.15 μg.kg⁻¹.min⁻¹ and adrenaline 0.05 μg.kg⁻¹.min⁻¹ to obtain functionally normal haemodynamics. The central venous pressure was 5 mmHg.

The patient was transferred to the intensive care unit where she made a rapid recovery, her trachea was extubated and she was weaned off of all cardiovascular support within 24 hours. Her recovery to discharge was uneventful.

Discussion

Heparin is the most widely used anticoagulant during cardiopulmonary bypass [1]. It is inexpensive, has a rapid onset of action and is readily reversible [2]. However, heparin pharmacology is complex, with a wide interindividual variability in pharmacokinetics and pharmacodynamics [2]. Heparin resistance in the context of cardiopulmonary bypass has been defined as an ACT < 480 s after 400 units.kg⁻¹ heparin [3]. The incidence of heparin resistance in this setting has been found to vary between 4% and 26% [3].

The aetiology of heparin resistance can be divided into antithrombin three‐dependent and ‐independent causes [2]. Antithrombin three‐dependent causes include reduced synthesis and accelerated clearance or consumption [2]. Antithrombin three‐independent causes include increased heparin binding and clearance, which is seen in both hepatic disease and splenomegaly [4]. Heparin binding occurs with a wide array of plasma proteins, including acute phase reactants, leading to heparin resistance associated with: inflammation; sepsis; malignancy; endothelial dysfunction; the puerperium; thrombocytosis and elevated platelet factor four titres [5]. Reduced antithrombin three titres have been shown to correlate with reduced heparin responsiveness, especially at plasma concentrations below 60% of normal, which may aid in risk prediction [5]. Normal antithrombin three titres may also avoid the inappropriate use of antithrombin concentrates. However, a poor correlation has been demonstrated between in vitro and in vivo heparin activity, likely due to inaccuracies in calculation of blood volume and the effect of exclusively in vivo pharmacokinetics [6]. Additionally, laboratory testing is not universally available and takes 30–60 minutes, making it impractical in an emergency.

The aetiology of this patient’s heparin resistance remains unclear. The lack of response to antithrombin and ease of reversal of anticoagulation with a relatively small dose of protamine suggest that there may have been increased heparin consumption as a consequence of the acute phase response.

There is a lack of consensus on a suitable target ACT for initiation of cardiopulmonary bypass [5]. A 2019 review of international centres showed variation in accepted ACTs [7], with the majority of clinicians targeting an ACT of either 400 s or 480 s to initiate cardiopulmonary bypass [7]. One study suggested that coagulation was activated with an ACT < 300 s and that 480 s should be targeted in order to incorporate a margin of safety [8]. Graylee et al. measured the coagulation activation in human subjects and stated that an ACT > 350 s is not associated with any greater inhibition of coagulation [9]. This is frequently interpreted as meaning that the ACT should not fall below 400–480 s and can result in larger doses of heparin being administered [9].

There is also a lack of consensus in the management of heparin resistance. Finley and Greenberg have proposed a pragmatic system beginning with antithrombin supplementation in those at risk of deficiency [2]. In those who are thought unlikely to be deficient, or who fail to respond to supplementation, they advise increasing heparin administration to a level of 4 units.ml⁻¹, or 300 units.kg⁻¹, beyond which ACT has previously been shown to cease to significantly increase. For patients who fail to respond to either measure, they suggest: accepting a lower ACT; giving further heparin boluses; using a fixed regimen with repeated heparin doses at set time intervals; administering antithrombin to supraphysiological plasma concentrations; or using an alternative anticoagulant. For the last strategy, direct thrombin inhibitors have been investigated, however, their use has been limited by a lack of available reversal agents.

Pre‐operative prediction of heparin resistance would be useful for those patients considered at risk of cardiovascular instability in order to appropriately prepare and limit the impact of potential hazards, but there are no validated risk prediction systems. Several factors linked with heparin resistance in the elective setting have been identified, including: antithrombin plasma concentrations < 60% of average; platelet concentrations > 300 × 10⁹.l⁻¹; age > 65 years; and pre‐operative heparin therapy [5]. However, the study reporting these risk‐factors excluded those requiring emergency surgery in whom an acute phase response is more likely and a higher index of suspicion may therefore be warranted.

Kawatsu et al. investigated heparin resistance in the elective and emergency setting [10]. Their data identified that an elevated platelet count and lower antithrombin three plasma concentrations were significantly associated with those at risk of heparin resistance, which corresponded with previous findings [5]. However, increased D‐dimer; creatinine and C‐reactive protein concentrations; chronic aortic dissection; chronic obstructive pulmonary disease; smoking; and elevated fibrinogen concentrations were also found to be independent predictors of heparin resistance [10].

There is little evidence for the management of heparin resistance in patients requiring cardiopulmonary bypass. In the elective setting, there should be a careful assessment of risk‐factors for heparin resistance and measurement of antithrombin three plasma concentration should be considered in selected cases. In emergency settings and patients at risk of cardiovascular collapse, a high index of suspicion should be maintained. When heparin resistance is recognised, a practical approach should be taken in order to manage the case and maintain patient safety, balancing the risks of cardiopulmonary bypass at a lower ACT against increased doses of anticoagulants and the prolongation of periods of cardiovascular instability. In this case, successful cardiopulmonary bypass was achieved with further heparin boluses administered via the cardiopulmonary bypass circuit and intravenously from an alternative batch. We therefore advocate consideration of this approach as one possible solution to achieving safe establishment of cardiopulmonary bypass in life threatening emergency clinical scenarios.