ICU Physiology in 1000 Words: Pulmonary Embolism & Right Ventricular Ischemia

Jon-Emile S. Kenny MD [@heart_lung]

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 [1] likely by congesting the Thebesian vessels [2].

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 [3].  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 [10].  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 [3]; at this level of obstruction, RV size usually grew [6].  Remarkably, however, stroke volume [SV] was preserved or elevated with this PE severity [5].  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:

1. Increasing end-diastolic volume [EDV] secondary to augmented venous return [6, 11]

2. 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 [12] 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 [13].

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 [5].  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 [8].  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 [16].  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 [17]!

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].

The Caveat

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 [1] 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 [20].

Clinical implication

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 [9].  This also explains why hypotension is a better prognosticator than angiographic obstruction [6] and why therapies that boost MAP such as balloon occlusion of the aorta [2], intra-arterial injection of blood [i.e. to raise MAP!] [see ref. 11 in [2]] and norepinephrine [21] have salutary effects on the RV in acute PE [1].

Please see other posts in this series,

JE

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

References

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