John Y. C. Tsang

Plasma levels of endothelin-1, big endothelin-1 and thromboxane following acute pulmonary air embolism

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.

Biphasic release of immunoreactive endothelins following acute pulmonary thromboembolism in pigs.

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.

Role of the endothelin system in secondary pulmonary hypertension related to air embolism: lessons learned from testing four classes of endothelin blockers in a rat model.

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 PaO2 (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 (ETA-Ra) (Atrasentan, ABT-627), endothelin-B receptor antagonist (ETB-Ra) (A-192621) or mixed endothelin-A/endothelin-B receptor antagonist (ETA/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 ≥ ETA/B-Ra ≫ ETA-Ra = ETB-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 ETA-Ra > ETA/B-Ra ≥ ETB-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 ETARa, was completely normalized by ETB-Ra, but was further reduced by either ETA/B-Ra or ECEi. The basal mean arterial blood pressure in control rats was unaffected by ETA-Ra, was elevated by ETB-Ra, but was depressed by ETA/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.

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.

Proinflammatory Cytokines Are Not Released in the Circulation Following Acute Pulmonary Thromboembolism in Pigs

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- f (TNF- f ), interleukin 1 g (IL-1 g ), 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 (PaO 2 from 390 - 85 to 256 - 89 mm Hg while the FiO 2 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- f , IL-1 g , 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- f , IL-1 g , or IL-8. We conclude that these cytokines have minimal impact on the systemic circulation during APTE.

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.

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.

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.

Effects of a selective endothelin A receptor antagonist, ABT-627, in healthy normotensive anaesthetized rats developing acute pulmonary air embolism.

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 ET(A) receptor (ET(A)-R) antagonist in a rat model of APAE over 3 h. APAE rats developed a higher right ventricular systolic pressure (RVSP), lower mean arterial blood pressure (MABP), and had lower PaO(2). At 3 h, 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 10-25 min) of MABP without affecting the subsequent lowering of MABP, and improved oxygen saturation in APAE rats. These results show that ET(A)-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.

Delayed diaphragmatic herniation masquerading as a complicated parapneumonic effusion

Injury to the diaphragm following blunt or penetrating thoracoabdominal 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 patients case included the patients hobby of weightlifting, a persistently deviated mediastinum despite drainage of the pleural effusion and deceptive pleural fluid biochemical indices.