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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.

We studied the spatial distribution of the abnormal ventilation-perfusion (V̇a/Q̇) units in a porcine model of acute pulmonary thromboembolism (APTE), using the fluorescent microsphere (FMS) technique. Four piglets (∼22 kg) were anesthetized and ventilated with room air in the prone position. Each received ∼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 V̇a and blood flow (Q̇) at five time points ( t = −30, −5, 30, 60, 120 min) were mapped by FMS of 10 distinct colors, i.e., aerosolization of 1-μm FMS for labeling V̇a and intravenous injection of 15-μm FMS for labeling Q̇. Our results showed that, at t = 30 min following APTE, mean V̇a/Q̇ (V̇a/Q̇ = 2.48 ± 1.12) and V̇a/Q̇ heterogeneity (log SD V̇a/Q̇ = 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 (V̇a/Q̇ = 0) remained minimal. Cluster analyses showed that the low V̇a/Q̇ units were mainly seen in the least embolized regions, whereas the high V̇a/Q̇ 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 Q̇, whereas V̇a remained relatively unchanged. We concluded that the hypoxemia seen after APTE could be explained by the mechanical diversion of Q̇ to the less embolized regions because of the vascular obstruction by clots elsewhere. These low V̇a/Q̇ units created by high flow, rather than low V̇a, accounted for most of the resultant hypoxemia.

A rat model of acute pulmonary air embolism (APAE) was developed. These animals had a higher right ventricular systolic pressure (RVSP) (+ 69% at 15-minute peak, and 21-34% at 30-180 minutes), as well as a reduced mean arterial blood pressure (10-20% at 60-180 minutes), heart rate (20-26% at 60-180 minutes) and PaO 2 (9-11% at 30-180 minutes) compared with control rats. The role of the endothelin (ET) system, known to be involved in pulmonary hypertension of various etiologies, was investigated by evaluating the effect of the four classes of ET blockers: ET-converting enzyme inhibitor (ECEi) (CGS 35066), selective endothelin-A receptor antagonist (ET A -Ra) (Atrasentan, ABT-627), endothelin-B receptor antagonist (ET B -Ra) (A-192621) or mixed endothelin-A/endothelin-B receptor antagonist (ET A / B -Ra) (A-182086) in this animal model. All four were effective, to various degrees, at reducing the APAE-induced rise in RVSP. The relative efficacy of those compounds in reducing the acute elevation (15 minutes) of RVSP was ECEi ≥ ET A / B -Ra >> ET A -Ra = ET B -Ra. The sustained elevation (30-180 minutes) of RVSP was totally abolished by ECEi and attenuated by other ET blockers with a relative efficacy of ET A -Ra > ET A / B -Ra > ET B -Ra. ET receptor antagonists did not affect right ventricular basal tone (control rats) whereas ECEi reduced it by up to 12% after 2 hours. The APAE reduction in mean arterial blood pressure was unaffected by ETA-Ra, was completely normalized by ET B -Ra, but was further reduced by either ET A / B -Ra or ECEi. The basal mean arterial blood pressure in control rats was unaffected by ET A -Ra, was elevated by ET B -Ra, but was depressed by ET A / B -Ra and ECEi. All ET blockers maintained normal oxygen saturation in APAE. These results support a role for ETs in rat APAE, since ET blockers can attenuate the cardiopulmonary deterioration and blood gas exchange. However, modulation of the central hemodynamic profile is more complex and may limit the usefulness of some ET blockers.

Acute pulmonary air embolism (APAE) was induced in nine piglets by repeated intravenous bolus injection of room air into a large bore central venous catheter at time=0 min so that the mean pulmonary artery pressure (MPAP) was maintained at two times the baseline value for 4 h. Another five animals served as controls. At time=0, 30, 60, 120, 240 min, circulating arterial plasma levels of endothelin-1 (ET-1), its precursor big ET-1, and thromboxane (Tx), were measured by RIA and EIA, respectively, along with hemodynamics and blood gases. The data showed that following APAE, there was a rapid increase in MPAP and a persistent decrease in Pa O 2 , while the mean arterial blood pressure and cardiac output remained comparable. Plasma levels of ET-1, big ET-1 and Tx were also increased steadily in these first 4 h. These results showed that during APAE, the resulted changes in the pulmonary vascular and airway tones mediated by these potent mediators could explain the observed pulmonary hypertension and the deterioration of gas exchange.

Acute pulmonary air embolism (APAE) injures the vascular endothelium in the lung and results in pulmonary hypertension (PH). Endothelins (ETs), a family of potent vasoactive peptides, are known to be associated with PH of various aetiologies. We evaluated the effects of ABT-627, a selective ETA receptor (ETA-R) antagonist in a rat model of APAE over 3h. APAE rats developed a higher right ventricular systolic pressure (RVSP), lower mean arterial blood pressure (MABP), and had lower PaO2. At 3h, arterial plasma levels of ET-1 were increased. ABT-627-treated controls showed no effects. However, ABT-627 significantly lowered RVSP during APAE, abolished the short recovery phase (within 10–25min) of MABP without affecting the subsequent lowering of MABP, and improved oxygen saturation in APAE rats. These results show that ETA-R subtype is involved in the pathogenesis of APAE since a blockade of this receptor subtype attenuated the cardiopulmonary deterioration and improved blood gas exchanges in rats with this disease.

Previous investigators reported that gas exchange consistently worsened when cardiac output (Qt) was increased under normal and pathological conditions. The aim of the present paper is to offer an alternative explanation, besides the one previously proposed that was based on some attenuation of hypoxic pulmonary vasoconstriction. The new concept emphases the inherent heterogeneity of regional blood flow (Q), as well as the skewed relationship between ventilation perfusion ratio (V/Q) and arterial oxygen tension (PaO2). Namely, PaO2 is exquisitely sensitive to any change of V/Q ratio from 0 to 1, which is many times more than that from 1 to 100. As Qt is increased, the additional pulmonary flow is by no means uniformly distributed. Thus, either ventilation (V) remains stable or even becomes more variable, V/Q heterogeneity increases at increased Qt. The higher Q in most regions reduces their corresponding V/Q ratios from the previously normal value of about 0.8 to 1, precipitously into the hypoxic range towards true shunt (V/Q = 0) and increases the V/Q mismatch. In contrary, the simultaneously created higher V/Q units cannot mitigate these adverse changes because of the sigmoid shape of hemoglobin oxygen dissociation curve. By this mechanism, diseased lungs are more susceptible to hypoxemia when Qt is increased due to their pre-existing V/Q abnormalities.

By using the multiple-breath helium washout technique, ventilation heterogeneity (V˙H) after embolic injury in the lung can be quantitatively partitioned into the conductive and acinar components. Total V˙H, represented by the normalized slope of the phase III alveolar plateau, SnIII (total), was studied for 120 min in three groups of anesthetized and paralyzed mongrel dogs. Group 1 ( n = 3) received only normal saline and served as controls. Group 2 ( n = 4) received repeated infusions of polystyrene beads (250 μm) into the right atrium at 10, 40, 80, and 120 min. Group 3 ( n = 3) was similarly treated, except that the embolic beads used were 1,000 μm in diameter. The data show that, despite repeated embolic injury by polystyrene beads of different diameters, there was no significant increase in total V˙H. The acinar component of SnIII, which represents V˙H in the distal airways, accounts for over 90% of the totalV˙H. The conductive component of SnIII, which represents V˙H between larger conductive airways, remains relatively constant and a minor component. We conclude that pulmonary microembolism does not result in significant redistribution of ventilation.

The purpose of this investigation was to study the role of endothelins (ETs) in the pathogenesis of acute pulmonary thromboembolism (PTE). Eighteen piglets (20 +/- 3 kg) were anesthetized and ventilated with 100% oxygen, five of them then served as controls. Acute thromboembolic injury in the lung was induced by injecting 15-25 ml of preformed clots into the left lower lobar pulmonary artery during thoracotomy. Pulmonary arterial pressure (Ppa) increased by at least 2.5-fold from baseline. During the subsequent 8 h, seven blood samples were collected from the left atrium and assayed for immunoreactive ETs. The results showed that following PTE: (1) Ppa remained elevated but cardiac output remained constant throughout the experiments; (2) plasma level of immunoreactive ETs increased in the embolized group compared to controls and the profile of immunoreactive ET release suggested a biphasic response. We conclude that the release of these vasocontractile and bronchoconstrictive mediators after PTE may contribute to ventilation perfusion mismatching and account for the pulmonary hypertension and deterioration of gas exchange that are often seen clinically.

Injury to the diaphragm following blunt or penetrating thoraco-abdominal trauma is not uncommon. Recognition of this important complication of trauma continues to be a challenge because of the lack of specific clinical and plain radiographic features, the frequent presence of other serious injuries and the potential for delayed presentation. Delayed diaphragmatic herniation often presents with catastrophic bowel obstruction or strangulation. Early recognition of diaphragmatic injury is required to avoid this potentially lethal complication. The case of a 35-year-old man with a history of a knife wound to the left flank 15 years previously, who presented with unexplained acute hypoxemic respiratory failure and a unilateral exudative pleural effusion that was refractory to tube thoracostomy drainage, is reported. After admission to hospital, he developed gross dilation of his colon; emergency laparotomy revealed an incarcerated colonic herniation into the left hemithorax. Interesting clinical features of this patient's case included the patient's hobby of weightlifting, a persistently deviated mediastinum despite drainage of the pleural effusion and deceptive pleural fluid biochemical indices.

Tsang, John Y. C., Michael J. Emery, and Michael P. Hlastala. Ventilation inhomogeneity in oleic acid-induced pulmonary edema. J. Appl. Physiol.82(4): 1040–1045, 1997.—Oleic acid causes permeability pulmonary edema in the lung, resulting in impairment of gas-exchange and ventilation-perfusion heterogeneity and mismatch. Previous studies have shown that by using the multiple-breath helium washout (MBHW) technique, ventilation inhomogeneity (VI) can be quantitatively partitioned into two components, i.e., convective-dependent inhomogeneity (cdi) and diffusive-convective-dependent inhomogeneity (dcdi). Changes in VI, as represented by the normalized slope of the phase III alveolar plateau, were studied for 120 min in five anesthetized mongrel dogs that were ventilated under paralysis by a constant-flow linear motor ventilator. These animals received oleic acid (0.1 mg/kg) infusion into the right atrium at t = 0. MBHWs were done in duplicate for 18 breaths every 40 min afterward. Three other dogs that received only normal saline served as controls. The data show that, after oleic acid infusion, dcdi, which represents VI in peripheral airways, is responsible for the increasing total VI as lung water accumulates progressively over time. The cdi, which represents VI between larger conductive airways, remains relatively constant throughout. This observation can be explained by increases in the heterogeneity of tissue compliance in the periphery, distal airway closure, or by decreases in ventilation through collateral channels.

Previous studies reported that regional CO2tension might affect regional ventilation (V̇) 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 V̇ and perfusion (Q̇) at four different times (−5, 30, 60, 120 min) was mapped by fluorescent microspheres. Regional V̇ and Q̇ were examined postmortem by sectioning the air-dried lung into 900–1,000 samples of ∼2 cm3each. After the redistribution of regional Q̇ by APTE, but in the scenario assuming that no V̇ shift had yet occurred, CO2tension in different lung regions at 30 min post-APTE (PXCO2) was estimated from the V̇/Q̇ data and divided into four distinct clusters: i.e., PXCO2< 10 Torr; 10 < PXCO2< 25 Torr; 25 < PXCO2< 50 Torr; PXCO2> 50 Torr. Our data showed that the clusters in higher V̇/Q̇ regions (with a PXCO2< 25 Torr) received ∼35% less V̇ when measured within 30 min of APTE, whereas, in contrast, the lower V̇/Q̇ regions showed no statistically significant increases in their V̇. However, after 30 min, there was minimal further redistribution of V̇. We conclude that there are significant compensatory V̇ shifts out of regions of low CO2tension soon following APTE, and that these variations in regional CO2tension, which initiate CO2-dependent changes in airway resistance and lung parenchymal compliance, can lead to improved gas exchange.

Previous studies reported that the degree of hypoxemia following acute pulmonary thromboembolism (APTE) was highly variable and that its mechanism was mainly due to the creation of many high and low ventilation/perfusion (V/Q) units, as a result of the heterogeneous regional blood flow (Q) caused by embolic obstruction. We studied the effect of changing cardiac output (Qt) on gas exchange after APTE in 5 embolized piglets (23 ± 3 Kg), using Dobutamine intermittently at approximately 20 μg/kg/min for 120 minutes. The distribution of ventilation (V) and perfusion (Q) at various times was mapped using fluorescent microspheres in 941 ± 60 lung regions. After APTE, increase in Qt by Dobutamine improved venous oxygen tension (PvO2) but arterial PaO2 did not change consistently. On the other hand, cluster analysis showed that the V/Q ratio of most lung regions was lowered due to increases in Q at the same time. We concluded that the effect of changing cardiac output on gas exchange following APTE was affected by the simultaneous and varying balance between the changing V/Q mismatch and the concomitantly changing PvO2, which might explain the unpredictability of PaO2 in the clinical setting.

The effects of norepinephrine (NE) on gas exchange and regional blood flows (RBFs) during resuscitation of massive pulmonary embolism (PE) were studied in 10 anesthetized mongrel dogs. Acute PE was induced by infusing 2 to 3 g of polystyrene beads (100 to 130 μm) into the right atrium so that the cardiac output (Qt) was reduced to approximately half the baseline value. Prior to and after PE, the V A /Q distribution was estimated by the multiple inert gas elimination technique. The animals in group 1 (n = 6) were immediately resuscitated after PE by infusion of NE for 40 minutes in quantities sufficient to return Qt to pre-PE levels. Those in group 2 (n = 4) did not receive any intervention for the first 40 minutes after PE, but were similarly resuscitated by NE in the subsequent 20 minutes. Regional blood flows were marked by three radioactive 15-μm microspheres: prior to PE, immediately after PE, and 20 minutes after PE in both groups. The gas exchange data show that the RBF pattern after PE had a significant redistribution of flow to the upper lung zones. Norepinephrine infusion increased RBFs proportionally in all zones after PE without changing the pattern of flow already established after PE. The distribution of perfusion to shunt and V A /Q less than 0.1 and the distribution of ventilation to dead space and V A /Q greater than 10 increased immediately after PE and remained comparable after NE infusion. Thus, while NE infusion significantly increased systemic oxygen delivery it had minor effect on gas exchange heterogeneity following embolism.

We studied the roles of endothelins in determining ventilation (V̇a) and perfusion (Q̇) mismatch in a porcine model of acute pulmonary thromboembolism (APTE), using a nonspecific endothelin antagonist, tezosentan. Nine anesthetized piglets (∼23 kg) received autologous clots (∼20 g) via a central venous catheter at time = 0 min. The distribution of V̇a and Q̇ 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 V̇a/Q̇ was increased, as was V̇a/Q̇ heterogeneity (log SD V̇a/Q̇), 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 V̇a/Q̇ 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 V̇a/Q̇ regions.

Histological examination of acute lung injury associated with sepsis often revealed thromboembolic lesions in the pulmonary microcirculation. Several inflammatory mediators such as platelet activating factor, thromboxane, and endothelins have also been implicated in the pathogenesis of acute pulmonary thromboembolism (APTE). In the present study we examined the roles of three proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), and IL-8, in the early phase of APTE. APTE was induced in 13 anesthetized piglets (22+/-4 kg) by injecting thrombin-induced blood clots directly into the left lower lobar pulmonary artery. Five animals that received only warm sterile saline served as controls. Arterial plasma samples were collected regularly over 8 h so that cytokine levels could be measured later by enzyme-linked immunosorbent assay (ELISA). Administration of clots doubled the mean pulmonary arterial pressure (from 13+/-5 to 26+/-7 mm Hg) and caused significant decrease in arterial oxygen tension (PaO2 from 390+/-85 to 256+/-89 mm Hg while the FiO2 was maintained at 1.0). Mean arterial blood pressure and cardiac output remained comparable throughout the experiments after initial fluid resuscitation. Plasma levels of TNF-alpha, IL-1beta, and IL-8 were not significantly increased in the APTE group when compared with their baseline values or the control group. Our results thus show that APTE is associated with pulmonary hypertension and deterioration of gas exchange but not with the systemic release of TNF-alpha, IL-1beta, or IL-8. We conclude that these cytokines have minimal impact on the systemic circulation during APTE.

Previous reports have shown that neutrophils are retained in the lung after acute embolization and that these neutrophils play an important role in the subsequent formation of permeability pulmonary edema. The present study was designed to test the hypothesis that acute embolic injury results in microvascular damage in lung regions with the greater retention of neutrophils. Seventeen pigs (20 +/- 2 kg) were embolized by injecting polystyrene beads (250 microns; labeled with 131I) into the right atrium over 5 min. Five pigs, which received no embolic beads, served as controls. Neutrophils (89 +/- 5% pure), isolated on Ficoll-Histopaque gradient, were radiolabeled with 111In-oxine. Twenty minutes after embolization, the radiolabeled neutrophils were injected into the right atrium along with 85Sr-labeled microspheres to mark the initial neutrophil distribution within the lung as well as the regional pulmonary blood flow at the time of their delivery. The animals were killed 50 min after embolization, and the lungs were removed, frozen over liquid nitrogen, and cut into 60 samples. The data show that after embolization regional neutrophil retention was inversely related to the regional blood flow but was not affected by the embolic load in the same region. Regional extravascular lung water was increased in regions of higher neutrophil retention, but the regions with increased edema did not receive a greater embolic load. These results show that microvascular injury occurs in the lung regions with the greatest neutrophil retention and that this increased retention of neutrophils is unrelated to the extent of embolization.

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.