An elderly female was admitted under the care of the orthopaedic team with a 2 week history of decreased mobility due to right knee pain. She had a past medical history of chronic atrial fibrillation, treated with amiodarone, and asthma which was well controlled on salbutamol inhalers. She was not on warfarin. Bony injury was ruled out clinically and radiologically and she was treated with simple analgesia. Whilst on the ward, she deteriorated acutely after complaining of shortness of breath. A cardiac arrest call was put out.
On arrival of the cardiac arrest team, she had a cardiac output. On examination, she was hypotensive (BP 70/50 mmHg) with a heart rate of 55 bpm. She was markedly cyanosed with a respiratory rate of 30 breaths per minute with oxygen saturation of 75% on high flow oxygen through a reservoir bag. Her Glasgow Coma Score was 7 (E1V2M4). There was no evidence of calf swelling or tenderness. Arterial blood gas analysis revealed marked type 1 respiratory failure – pH 7.2, pO2 5.4kPa, pCO2 7.8kPa, HCO3 19mmol/l and lactate 4mmol/l .
She was rapidly intubated, and resuscitated with a total of four litres of crystalloids and colloids. Invasive blood pressure monitoring was established. A clinical diagnosis of acute pulmonary embolus was made. She remained unstable despite resuscitation, requiring frequent boluses of vasopressors and adrenaline thus being too unstable to be transferred for a CT pulmonary angiogram. A bedside echocardiogram showed a markedly dilated right heart with elevated right heart pressures. There was paradoxical movement of the interventricular septum. Left ventricular function was also slightly impaired.
It was decided to thrombolyse the patient. As alteplase was being readied, the patient arrested. The initial rhythm was pulseless electrical activity with a rate of 40 beats per minute. She was resuscitated as per Advanced Life Support (ALS) guidelines and received adrenaline and atropine intravenously. After two cycles of cardio-pulmonary resuscitation (CPR) and the administration of thrombolysis, she regained cardiac output but remained hypotensive and hypoxic. An adrenaline infusion was commenced through a peripheral line. Despite this, she arrested six further times with increasing inotropic support requirement. After two hours from the initial cardiac arrest call, the decision was made to stop resuscitation.
Post-mortem results confirmed the presence of a large pulmonary embolus as well as bilateral deep venous thromboses (DVTs).
What is the evidence for the use of thrombolysis in pulmonary embolism?
The use of thrombolysis in acute pulmonary embolus remains controversial. Thrombolytic therapy accelerates clot lysis and is associated with improvements in perfusion scans, angiographic and haemodynamic parameters when compared to anticoagulation alone1. Thrombolytic therapy may improve pulmonary arterial blood pressure, right ventricular function and pulmonary perfusion. Despite this, thrombolysis is not without risks, the most serious being haemorrhage.
Goldhaber et al2, as part of the International Cooperative Pulmonary Embolism Registry, looked at 108 patients who had persistent hypotension due to PE. When patients with haemodynamic compromise were given thrombolytic therapy, there was no statistically significant improvement in 90-day mortality compared to those who weren’t thrombolysed.
Konstantides et al.3 compared thrombolysis in patients with haemodynamically stable (right ventricular strain on electrocardiogram or echocardiography) PE with heparin. There was an overall low rate of mortality in the 256 patients studied but the thrombolysis group showed significant improvements in terms of lower requirements for treatment escalation (re-thrombolysis, intubation or use of inotropes).
Firket et al4 showed that patients with confirmed or highly suspected pulmonary embolus who subsequently arrested, return of spontaneous circulation (ROSC) was achieved significantly earlier if thrombolysed. However, there are several flaws with their retrospective study. Only 60% of the 104 patients treated with thrombolysis studied had a confirmed diagnosis of PE on CT, transthoracic echocardiography or at post-mortem. Although they advocated the use of thrombolysis, therapy did not increase the likelihood of ROSC i.e. the majority of patients did not get a return of circulation. There was marked variation in the timing and dose of thrombolytic agent administered.
The British Thoracic Society guidelines for the treatment of suspected acute pulmonary embolism only recommend the use of alteplase as first line therapy in the setting of a massive PE5. They define a massive PE as one which causes circulatory collapse and cite the result of the meta-analysis by Thabut et al.6 comparing the use of thrombolytic therapy with heparin compared to heparin alone in patients with acute pulmonary embolus.
Thabut et al.6 looked at nine trials (461 patients) and found that thrombolytic therapy had no statistically significant effect on mortality but had a much higher incidence of major haemorrhage. One of the main criticisms of the included trials is that there was a lack of consistency in the degree of severity which prompted initiation of thrombolysis. Furthermore, there is only a single randomised controlled trial which looked at thrombolytic therapy in patients with confirmed massive pulmonary embolus7. The trial was stopped after the first 8 patients (of the intended 40) as all 4 patients who received thrombolysis survived and all 4 who didn’t, died.
Dong et al.8, as part of a Cochrane review, looked at eight trials involving 679 adult patients that compared thrombolytic therapy with placebo, heparin or surgical intervention in patients with acute PE. Thrombolytics did not show any benefit over heparin in terms of mortality and recurrence of blood clots. Again, all the patients were in stable condition unlike the patient in this case discussion. They concluded that there was limited evidence to suggest thrombolysis was superior to heparin and that further studies which compared treatment in haemodynamically stable and unstable patients with PE were required.
The European Society of Cardiology published their guidelines on the management of acute pulmonary embolism in 20089. The use of thrombolytic therapy was considered first-line treatment in patients with high-risk PE presenting with cardiogenic shock and/or persistent arterial hypotension. Their recommendation is based upon sub-group analysis of a meta-analysis performed by Wan10. His analysis of five trials showed that in patients with massive PE, the incidence of recurrent PE or death were reduced with thrombolysis (odds ratio 0.61 and 0.47 respectively).
There is insufficient evidence to recommend the administration of thrombolytic therapy to patients with haemodynamically stable pulmonary embolism. PEs present with a wide spectrum of severity which makes interpretation of clinical trials results difficult. This is further compounded by the variation in type, dose and timing of thrombolytic therapy. This patient suffered a cardiac arrest due to a massive pulmonary embolus. She was thromobolysed as per Resuscitation Council (UK) guidelines and received prolonged CPR. Despite the recommendations, there is a lack of clear mortality benefit in randomised controlled trials, involving thrombolytics and their use.
- Dalla-Volta S, Palla A, Santolicandro A et al. PAIMS2: alteplase combined with heparin versus heparin alone in massive pulmonary embolism: a randomised controlled trial. J Thromb Thrombolysis. 1995; 2: 227-229.
- Goldhaber Sz, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999; 353: 1386-1389.
- Konstantinides S et al. Association between thrombolytic therapy and the prognosis of haemodynamically stable patients with major pulmonary embolism: results of a multicentre registry. Circulation 1997; 96: 882-888.
- Fikret E et al. Impact of Rescue-Thrombolysis during Cardiopulmonary Resuscitation in Patients with Pulmonary Embolism. PLoS ONE 2009; 4(12): e8323.
- BTS Standards of Care Committee Pulmonary Embolism Guideline Developmet Group. BTS Guidelines for the management of suspected acute pulmonary emnolism. Thorax 2003; 58: 470-484.
- Thabut G, Thabut D, Myers RP et al. Thrombolytic therapy of pulmonary embolism: a meta-analysis. J Am Coll Cardiol 2002; 40: 1660.
- Jerjes-Sanchez C, Ramirez-Rivera A, Garcia M de L, Arriaga-Nava R, Valencia S, Rosado-Buzzo A, Pierzo JA, Rosas E. Streptokinase and heparin versus heparin alone in massive pulmonary embolism: a randomized controlled trial. J Thromb and Thrombolys. 1995;2:227-229.
- Dong B, Jirong Y, Liu G et al. Thrombolytic therapy for pulmonary embolism. Cochrane Databse Syst Rev 2009; CD004437.
- Torbicki A et al. Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2008; 29: 2276-2315.
- Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomised controlled trials. Circulation 2004; 110: 744 – 749.