Gas exchange and pulmonary hypertension following acute pulmonary thromboembolism: has the emperor got some new clothes yet?

Patients present with a wide range of hypoxemia after acute pulmonary thromboembolism (APTE). Recent studies using fluorescent microspheres demonstrated that the scattering of regional blood flows after APTE, created by the embolic obstruction unique in each patient, significantly worsened regional ventilation/perfusion (V/Q) heterogeneity and explained the variability in gas exchange. Furthermore, earlier investigators suggested the roles of released vasoactive mediators in affecting pulmonary hypertension after APTE, but their quantification remained challenging. The latest study reported that mechanical obstruction by clots accounted for most of the increase in pulmonary vascular resistance, but that endothelin-mediated vasoconstriction also persisted at significant level during the early phase.

Estimation of endothelin-mediated vasoconstriction in acute pulmonary thromboembolism.

We aimed to investigate the role of endothelin-mediated vasoconstriction following acute pulmonary thromboembolism (APTE). Thirteen anesthetized piglets (~25 kg) were ventilated with 0 PEEP. Cardiac output (Qt) and wedge pressure (Pw) were measured by a Swan Ganz catheter, along with arterial and venous blood gases. APTE was induced by autologous blood clots (~0.8 g/kg, 12-16 pieces) via a jugular venous catheter at time = 0 minutes until the mean pulmonary arterial pressure (Ppa) was about 2.5 times the baseline at 30 minutes. Eight control animals (Group 1) received only normal saline afterward, while the remaining five (Group 2) received at time = 40-minute saline plus Tezosentan, a nonspecific endothelin antagonist. The drug was initially given as an intravenous bolus (10 mg/kg), followed by an infusion (2 mg/min) until the end of the experiment at 2 hours. Hemodynamic data were measured before APTE and then at 30-minute intervals. Pulmonary vascular resistance index (PVRI) was calculated as (Ppa-Pw)/CI, where CI was cardiac index or Qt/W (body weight). Fluorescent microspheres (FMS) were used to mark regional blood flows and ventilation for cluster analysis. PVRI acutely increased within minutes and remained high despite some recovery over time. With Tezosentan treatment, the results showed that endothelin-mediated vasoconstriction persisted significantly up to 2 hours and accounted for about 25% of the increase in PVRI while clot obstruction accounted for the remaining 75%. CI remained relatively constant throughout. Tezosentan also affected PVRI indirectly by mitigating the shift of regional blood flow back to the embolized areas over time, possibly by attenuating vasoconstriction in the nonembolized areas. We conclude that following APTE, although the increased PVRI is mostly due to mechanical embolic obstruction, secondary factors such as vasoconstriction and pattern of regional blood flow over time also play important roles.

The DNR Order: What Does it Mean?

As medical science continues to advance, patients nowadays with progressive cardiopulmonary diseases live to older ages. However, they too will eventually reach their unsustainable physiological limit and many die in poor health and discomfort prior to their demise. Regrettably many physicians have not kept pace in dealing with the inevitable end-of- life issues, along with modern technological developments. Without proper guidance, ill-informed patients often face unnecessary anxiety, receive futile resuscitation at the expense of their dignity and public cost which has and will become increasingly overwhelming according to our current demographic trends. In any health care reform, experts often suggest that difficult questions will have to be asked but the solutions are at least partly in the logistical details. From time to time, we see an isolated "Do Not Resuscitate" or DNR order in the chart, which is not always followed by thoughtful discussion on the boundary of care, either simultaneously or known to be followed up soon. This paper attempts to begin asking some of these difficult questions, point out the fallacies of this order and expose the weaknesses in the present state of entitlement by public demand if physicians retreats more from the discussion. The solution does not lie in asking the questions but in changing the practice pattern in real life on a continuous basis, hopefully to be eventually accepted by most, if not all.

Regional CO2 tension quantitatively mediates homeostatic redistribution of ventilation following acute pulmonary thromboembolism in pigs.

Previous studies reported that regional CO(2) tension might affect regional ventilation (V) following acute pulmonary thromboembolism (APTE). We investigated the pathophysiology and magnitude of these changes. Eight anesthetized and ventilated piglets received autologous clots at time = 0 min until mean pulmonary artery pressure was 2.5 times baseline. The distribution of V and perfusion (Q) at four different times (-5, 30, 60, 120 min) was mapped by fluorescent microspheres. Regional V and Q were examined postmortem by sectioning the air-dried lung into 900-1,000 samples of approximately 2 cm(3) each. After the redistribution of regional Q by APTE, but in the scenario assuming that no V shift had yet occurred, CO(2) tension in different lung regions at 30 min post-APTE (P(X)CO(2)) was estimated from the V/Q data and divided into four distinct clusters: i.e., P(X)CO(2) < 10 Torr; 10 < P(X)CO(2) < 25 Torr; 25 < P(X)CO(2) < 50 Torr; P(X)CO(2) > 50 Torr. Our data showed that the clusters in higher V/Q regions (with a P(X)CO(2) < 25 Torr) received approximately 35% less V when measured within 30 min of APTE, whereas, in contrast, the lower V/Q regions showed no statistically significant increases in their V. However, after 30 min, there was minimal further redistribution of V. We conclude that there are significant compensatory V shifts out of regions of low CO(2) tension soon following APTE, and that these variations in regional CO(2) tension, which initiate CO(2)-dependent changes in airway resistance and lung parenchymal compliance, can lead to improved gas exchange.

Endothelin receptor blockade does not improve hypoxemia following acute pulmonary thromboembolism.

We studied the roles of endothelins in determining ventilation (Va) and perfusion (Q) mismatch in a porcine model of acute pulmonary thromboembolism (APTE), using a nonspecific endothelin antagonist, tezosentan. Nine anesthetized piglets (approximately 23 kg) received autologous clots (approximately 20 g) via a central venous catheter at time = 0 min. The distribution of Va and Q at five different time points (-30, -5, 30, 60, 120 min) was mapped by fluorescent microspheres of 10 different colors. Five piglets (group 1) received tezosentan (courtesy of Actelion) starting at time = 40 min for 2 h, and four piglets (group 2) received only saline and served as control. Our results showed that, in all of the animals at 30 min following APTE but before tezosentan, the mean Va/Q was increased, as was Va/Q heterogeneity (log SD Va/Q), which represented a widening of its main peak. Afterwards, tezosentan attenuated the pulmonary hypertension in group 1 but also produced moderate systemic hypotension. However, it did not improve arterial PO2 or Va/Q mismatch. We concluded that endothelin antagonism had minimal impact on gas exchange following APTE and confirmed our earlier observation that the main mechanism for hypoxemia in APTE was due to the mechanical redistribution of pulmonary regional blood flow away from the embolized vessels, resulting in the creation of many divergent low and high Va/Q regions.

Spatial pattern of ventilation-perfusion mismatch following acute pulmonary thromboembolism in pigs.

We studied the spatial distribution of the abnormal ventilation-perfusion (Va/Q) units in a porcine model of acute pulmonary thromboembolism (APTE), using the fluorescent microsphere (FMS) technique. Four piglets ( approximately 22 kg) were anesthetized and ventilated with room air in the prone position. Each received approximately 20 g of preformed blood clots at time t = 0 min via a large-bore central venous catheter, until the mean pulmonary arterial pressure reached 2.5 times baseline. The distributions of regional Va and blood flow (Q) at five time points (t = -30, -5, 30, 60, 120 min) were mapped by FMS of 10 distinct colors, i.e., aerosolization of 1-mum FMS for labeling Va and intravenous injection of 15-mum FMS for labeling Q. Our results showed that, at t = 30 min following APTE, mean Va/Q (Va/Q = 2.48 +/- 1.12) and Va/Q heterogeneity (log SD Va/Q = 1.76 +/- 0.23) were significantly increased. There were also significant increases in physiological dead space (11.2 +/- 12.7% at 60 min), but the shunt fraction (Va/Q = 0) remained minimal. Cluster analyses showed that the low Va/Q units were mainly seen in the least embolized regions, whereas the high Va/Q units and dead space were found in the peripheral subpleural regions distal to the clots. At 60 and 120 min, there were modest recoveries in the hemodynamics and gas exchange toward baseline. Redistribution pattern was mostly seen in regional Q, whereas Va remained relatively unchanged. We concluded that the hypoxemia seen after APTE could be explained by the mechanical diversion of Q to the less embolized regions because of the vascular obstruction by clots elsewhere. These low Va/Q units created by high flow, rather than low Va, accounted for most of the resultant hypoxemia.