ICU Physiology in 1000 Words: Pulmonary Embolism & Right Ventricular Ischemia
Commonly, we are sold that acute pulmonary thromboembolism [PE] burns the right ventricular [RV] candle at both ends. This is because perfusion of the right coronary artery [RCA] is mediated by both its upstream mean arterial pressure [MAP] and downstream right ventricular end-diastolic pressure [RVEDP]. Given that a PE may decrease the former and increase the latter, perfusion of the RCA is particularly precarious in the face of an acute, substantial RV outflow obstruction. Additionally, unlike the left coronary artery, the RCA is perfused during both systole and diastole; as a consequence, high RV cavity pressure can especially impair normal RCA systolic perfusion  likely by congesting the Thebesian vessels .
Yet, the immediate effects of PE upon the human RV are more-or-less a mystery; studying patients who present minutes-to-hours after a PE undoubtedly represents a selection bias . Another blatant confound is underlying cardiopulmonary co-morbidities [3-5]. So when we encounter the ubiquitous claim of RV ischemia and/or infarction [RVI] contributing to the pathophysiology of PE [6-9], we may rightfully wonder if RVI is a pure and inevitable consequence of PE? To better clarify this question and avoid the aforementioned confounds, this brief post will – unless otherwise stated – consider animal models of PE and human studies with subjects free from cardiopulmonary disease.
Pressure-volume loops and oxygen demand
The normal human mean pulmonary arterial pressure [mPAP] is 14 mmHg at rest . Pulmonary emboli obstructing 25-30% of the pulmonary vasculature increased the mPAP moderately – to roughly 20-30 mmHg or 1.5-to-2 times normal – in healthy adults ; at this level of obstruction, RV size usually grew . Remarkably, however, stroke volume [SV] was preserved or elevated with this PE severity . How?
The investigators found that increased cardiac output was strongly, negatively associated with the partial pressure of arterial oxygen [PaO2]. Given that hypoxemia is a strong adrenergic stimulus, sympathetic tone likely maintained SV by two general mechanisms:
Increasing end-diastolic volume [EDV] secondary to augmented venous return [6, 11]
Lowering end-systolic volume [ESV] by enhancing RV contractility [see figure 1]
Figure 1: Effects of PE on RV pressure-volume [PV] loop. A - shows baseline and B - shows the effect of PE [increased Ea, arterial elastance - slope of purple line]. Without concomitant increase in RV contractility or end-systolic pressure volume relationship [ESPVR], end-systolic volume would rise to ESVB1 [purple]; with rise in ESPVR, ESV falls ESV B2 in blue and stroke volume [SV] is preserved. EDPVR is end-diastolic pressure volume relationship, EDV is end-diastolic volume. Total work is proportional to myocardial oxygen demand and represents sum of areas of blue and red shade.As seen in the figure, PE produces ‘uncoupling’ between RV function and the pulmonary artery [PA]; this topic was considered previously for the left ventricle. The increase in ‘pulmonary vascular resistance’ or – more accurately – impedance  secondary to PE can be graphically modeled as an increased pulmonary arterial elastance [Ea]. Visibly, a pure rise in Ea pulls ESV up with it – to the detriment of SV – and RV-PA uncoupling has commenced. Yet, as above, enhanced RV contractility [i.e. ESPVR - see figure 1B] pushes ESV back down; if this is coupled with increased venous return to raise EDV [not shown in figure], then one can see how SV is preserved or even increased! Yet this new, compensated state has increased total RV work [i.e. the total shaded area] which is directly proportional to myocardial oxygen demand .
Given that RV work – and therefore oxygen demand – rises with acute PE, one might expect RCA flow to grow in tandem. Measurements of RCA flow in more severe cases of RV outflow obstruction will enlighten – described next.
Oxygen demand & right coronary flow
Interestingly, in healthy adults following a very large acute PE [i.e. > 50% by angiography] an mPAP above 40 mmHg was never observed; indeed, ‘severe’ pulmonary hypertension was graded as a value between 30 and 40 mmHg [3, 5] or about 2-to-3 times normal. At this level, RVEDP was essentially always elevated . What can we say about RCA perfusion here? Does the elevated RVEDP impair RCA flow?
In a series of interesting animal studies, mPAP was increased to the aforementioned levels [i.e. 2-3 times normal] and then to the point of RV failure [defined as decreasing SV in the face of rising RVEDP] [8, 14, 15]. Absolute RCA flow, flow-demand ratios and biopsies for evidence of biochemical ischemia were obtained. At all levels of mPAP and even during RV failure when RVEDP was elevated, total RCA flow increased. Further, when the pericardium was intact, there was no biochemical evidence of RCA ischemia, even during RV failure! Interestingly, the oxygen supply – demand ratio did progressively fall with worsening RV outflow impedance. This was measured as the ratio of RCA flow to RV tension-time index . Thus, as predicted by the pressure-volume loops, demand was rising and even outpaced supply despite the absence of biochemical ischemia.
Importantly, a more recent porcine study replicated the aforementioned . Similar degrees of mPAP were achieved with no biochemical or histopathological evidence for RV ischemia, even after many hours. Notably, serum troponin levels rose, but on histopathology, myocardial necrosis was limited to islands around adrenergic nerve terminals – suggesting that cell death was not secondary to oxygen debt, but rather adrenergic toxicity !
In aggregate, the animal studies in which frank RV ischemia was observed – almost ubiquitously – required not simply a fall in SV, but also decreased MAP [1, 9, 18, 19].
As stated at the outset, the reasoning above is restricted to animal models and relatively healthy humans. Obviously, patients treated for PE frequently have cardiopulmonary co-morbidities including RCA obstruction. Indeed, even in animal models, RV dysfunction occurred sooner when RCA flow was compromised  and case series of humans with RV infarction secondary to PE do exist, even in those without RCA obstruction. Nevertheless, hypotension and cardiac arrest often muddy the precipitating force behind RV myocardial injury .
In totality, and most simply, the above highlight the importance of hypotension in acute PE. It may be that the primum movens of RV ischemia is decreased MAP . This also explains why hypotension is a better prognosticator than angiographic obstruction  and why therapies that boost MAP such as balloon occlusion of the aorta , intra-arterial injection of blood [i.e. to raise MAP!] [see ref. 11 in ] and norepinephrine  have salutary effects on the RV in acute PE .
Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he also the creator and author of a free hemodynamic curriculum at heart-lung.org
Brooks H, Kirk ES, Vokonas PS et al: Performance of the right ventricle under stress: relation to right coronary flow. The Journal of clinical investigation 1971, 50(10):2176-2183.
Spotnitz HM, Berman MA, Epstein SE: Pathophysiology and experimental treatment of acute pulmonary embolism. American heart journal 1971, 82(4):511-520.
Sharma G, McIntyre K, Sharma S et al: Clinical and hemodynamic correlates in pulmonary embolism. Clinics in chest medicine 1984, 5(3):421-437.
McIntyre KM, Sasahara AA: Determinants of right ventricular function and hemodynamics after pulmonary embolism. Chest 1974, 65(5):534-543.
McIntyre KM, Sasahara AA: The hemodynamic response to pulmonary embolism in patients without prior cardiopulmonary disease. The American journal of cardiology 1971, 28(3):288-294.
Wood KE: Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest 2002, 121(3):877-905.
Prewitt RM: Hemodynamic management in pulmonary embolism and acute hypoxemic respiratory failure. Critical care medicine 1990, 18(1 Pt 2):S61-69.
Calvin Jr JE: Acute right heart failure: pathophysiology, recognition, and pharmacological management. Journal of cardiothoracic and vascular anesthesia 1991, 5(5):507-513.
Lualdi JC, Goldhaber SZ: Right ventricular dysfunction after acute pulmonary embolism: pathophysiologic factors, detection, and therapeutic implications. American heart journal 1995, 130(6):1276-1282.
Douschan P, Kovacs G, Avian A et al: Mild elevation of pulmonary arterial pressure as a predictor of mortality. American journal of respiratory and critical care medicine 2018, 197(4):509-516.
Eckstein J, Horsley A: Effects of hypoxia on peripheral venous tone in man. The Journal of laboratory and clinical medicine 1960, 56:847-853.
Tedford RJ: Determinants of right ventricular afterload (2013 Grover Conference series). Pulmonary circulation 2014, 4(2):211-219.
Walley KR: Left ventricular function: time-varying elastance and left ventricular aortic coupling. Critical care 2016, 20(1):270.
Calvin JE: Right ventricular afterload mismatch during acute pulmonary hypertension and its treatment with dobutamine: A pressure segment length analysis in a canine model. Journal of Critical Care 1989, 4(4):239-250.
Calvin J, Quinn B: Right ventricular pressure overload during acute lung injury: Cardiac mechanics and the pathophysiology of right ventricular systolic dysfunction. Journal of Critical Care 1989, 4(4):251-265.
Schmitto JD, Doerge H, Post H et al: Progressive right ventricular failure is not explained by myocardial ischemia in a pig model of right ventricular pressure overload. European Journal of Cardio-Thoracic Surgery 2009, 35(2):229-234.
Mühlfeld C, Coulibaly M, Dörge H et al: Ultrastructure of right ventricular myocardium subjected to acute pressure load. The Thoracic and cardiovascular surgeon 2004, 52(06):328-333.
Vlahakes GJ, Turley K, Hoffman J: The pathophysiology of failure in acute right ventricular hypertension: hemodynamic and biochemical correlations. Circulation 1981, 63(1):87-95.
Gold FL, Bache RJ: Transmural right ventricular blood flow during acute pulmonary artery hypertension in the sedated dog. Evidence for subendocardial ischemia despite residual vasodilator reserve. Circulation research 1982, 51(2):196-204.
Coma-Canella I, Gamallo C, Onsurbe PM et al: Acute right ventricular infarction secondary to massive pulmonary embolism. European heart journal 1988, 9(5):534-540.
Molloy WD, Lee K, Girling L et al: Treatment of shock in a canine model of pulmonary embolism. American Review of Respiratory Disease 1984, 130(5):870-874.