Respiratory complications of critical illness (Proceedings)

Respiratory dysfunction commonly occurs as a sequela of critical illness in dogs and cats. Early detection of pulmonary compromise allows early recognition of problems, aggressive management, and therefore increased survival. Apart from frequent and relatively benign complications such as fluid overload and atelectasis, other pulmonary complications in the critical patient reflect the lung response to inflammation as part of the Systemic Inflammatory Response Syndrome (SIRS), immunosuppression, and failure of lung defenses. The complications most commonly seen include the canine acute respiratory distress syndrome, bacterial pneumonia, and thromboembolic disease.

Canine acute respiratory distress syndrome

The canine acute respiratory distress syndrome (ARDS) is an acute, usually fatal, complication of a number of disease states, particularly sepsis. In sepsis, a diffuse inflammatory process is triggered by bacterial endotoxin, which results in activation of an avalanche of diverse inflammatory mediators, including a variety of cytokines, the complement and arachidonic acid cascades, and cells such as neutrophils and macrophages. This common pathway of inflammation can affect the function of any or all organ systems in the septic patient. Patients that develop respiratory failure due to ARDS are simply demonstrating a local pulmonary manifestation of SIRS. Alternatively, ARDS may be triggered by local pulmonary catastrophes such as severe aspiration pneumonia, pulmonary contusions or smoke inhalation, which can trigger an inflammatory response that may become generalized within the lung parenchyma. In either case, since the lung has only one way to respond to inflammatory damage, the clinical and histopathologic findings are very similar.

In dogs with ARDS, the initial stages of the syndrome begin as a diffuse exudative vascular leak syndrome, with infiltration of neutrophils and macrophages into the lung. These changes are accompanied by effusion of protein-rich fluid into the alveoli, and clinical evidence of progressive pulmonary edema. As ongoing inflammation is combined with early attempts at repair by the lung tissue, we begin to see proliferation of Type II pneumocytes, formation of hyaline membranes within alveoli due to organization of protein-rich fluid and cellular debris, deficiency of surfactant, and collapse and atelectasis of alveoli. Much later, these changes are followed by interstitial fibrosis as the lung attempts to repair the damaged tissue. The inflammatory changes in the lung may vary in severity, and are usually unevenly distributed, affecting ventral areas first. At times, the process is mild and then termed Acute Lung Injury (ALI). In more severely affected animals, the inflammation is profound, overwhelming, and leads to severe hypoxia (ARDS).

ARDS is recognized clinically by the development of pulmonary edema in an animal with a predisposing cause of an inflammatory response. Animals that have ARDS are in severe respiratory distress, and are usually cyanotic. Auscultation reveals harsh lung sounds that rapidly progress to crackles. Dogs may expectorate pink foam, and if intubated, sanguinous fluid may drain out of the endotracheal tube. Arterial blood gases usually reveal hypoxia and hypocarbia, and metabolic acidosis may be present. These animals usually have diffuse bilateral pulmonary alveolar infiltrates throughout all lung fields on thoracic radiographs.

Most dogs and cats with ARDS show little response to oxygen supplementation, and remain severely dyspneic. If placed on a ventilator, the lungs are found to have very poor compliance, and high peak airway pressures may be seen even if the tidal volume is small. Positive end expiratory pressure is usually required to achieve adequate oxygenation.

Few options are available for definitive management of ARDS and patient care is primarily aimed at treating the underlying cause and supporting oxygenation. In humans, there is a very high mortality rate, and even those who survive require positive pressure ventilation for several weeks. Obviously, this is beyond the capability of most veterinarians. Because of the variety of inflammatory cascades and cells that mediate the inflammatory response in ARDS, specific anti-inflammatory drugs such as corticosteroids are largely ineffective for treatment, and may cause immunosuppression that can exacerbate sepsis. Advances such as liquid ventilation, synthetic surfactant therapy, inhaled nitric oxide, and other new drugs, which have begun to be useful in human medicine, have not yet been evaluated in dogs with naturally occurring disease.

Pulmonary thromboembolism

Etiology

Recognition and awareness of pulmonary thromboembolism has increased dramatically in the last few years. Thrombi may develop as a result of a combination of 2 or more of the following processes: 1) hypercoagulability, 2) vascular endothelial damage, 3) abnormal blood flow patterns or blood stasis.

Vascular endothelial damage is an integral part of sepsis as a sequela of SIRS. Diffuse vascular damage occurs frequently as a consequence of a variety of inflammatory disorders such as sepsis, pancreatitis, or immune-mediated diseases such as autoimmune hemolytic anemia. In each of these situations, various inflammatory mediators are activated, all of which can lead to endothelial damage. Once endothelial damage has occurred, activation of the coagulation cascade follows, contributing to the development of thrombi. Endothelial damage also occurs locally due to intravenous catheters, and infusion of irritating substances. Stasis of blood is a feature of many critical illnesses. Any condition that leads to poor perfusion or shock may predispose to pooling of blood in the periphery or in the splanchnic vasculature. This is particularly true of sepsis states. Other disorders that may be accompanied by blood stasis include vascular obstructive diseases and heart failure.

Diagnosis

The diagnosis of pulmonary thromboembolism can be extremely challenging. Many animals with minor pulmonary showering by emboli may be completely asymptomatic, while those with major thromboembolic disease can develop profound respiratory distress and die acutely. Auscultation findings are very variable, ranging from normal, to harsh or even crackles.

Most clinically affected animals have significant hypoxia, which can be determined by clinical parameters, or by arterial blood gas analysis or pulse oximetry. Thoracic radiographs are variable, and often reveal normal to hyperlucent lung fields. Alternatively some animals with thromboembolism may have areas of alveolar disease or pleural effusion. Acute pulmonary thromboembolism is often accompanied by a sudden change in platelet count (usually a decrease), which presumably is caused by platelet consumption. Dogs with hypercoagulability diagnosed by thromboelastography are at risk for thrombosis, but may not definitively have excessive thrombus formation. The presence of active thrombolysis, documented by increases in D-dimers and/or Fibrin Degradation Products, is highly suggestive of active thrombosis.

Definitive diagnosis of pulmonary thromboembolism is made by selective angiography. Although selective angiography of the pulmonary artery can be performed using plain radiographs, it is invasive because of the need for catheter placement in the pulmonary artery. Instead, CT angiography, although more expensive, provides improved imaging of clots and is less invasive because the contrast medium can be injected through a peripheral vein. Thoracic CT also allows imaging of the lung parenchyma which can provide further diagnostic information. Unfortunately, CT is expensive and not always available, and does require anesthesia, which increases the risk in these hypoxic patients. Alternate imaging techniques are also possible. The finding of abnormal perfusion on scintigraphic ventilation/perfusion scanning is also strongly suggestive, but not diagnostic, of thromboembolic disease.

Treatment of pulmonary thromboembolism

Supportive care

If pulmonary thromboembolism is suspected, several potential therapies may be attempted. Aggressive supportive care, attention to tissue perfusion, oxygen supplementation, and treatment of the underlying disease remain priorities for management. The most important aspects of therapy are to ensure that the effects of all of the three elements of Virchow's triad are eliminated. Therefore, factors contributing to SIRS should be minimized (treat sepsis aggressively), drugs such as corticosteroids which increase hypercoagulability should be avoided, and any stasis of blood flow should be corrected if possible.

If the size of the embolus is not excessive, the animal's own fibrinolytic system should be able to eventually break it down, and recanalize obstructed vessels. The time required for resolution in critically ill animals may vary from just a few days, to 2-3 weeks. If the trigger factors can be eliminated, then there is hope that the embolism will not recur.

Specific therapy: thrombolysis

Options for specific therapy include either active thrombolysis or anticoagulants. "Clotbuster" drugs, such as tissue plasminogen activator, streptokinase, or urokinase actively break down clots within the circulation. These drugs are best administered when thrombi are recently formed, and are most effective when administered directly onto the surface of the thrombus. In human medicine, they are used for treatment of cardiac infarcts caused by acute coronary artery disease. A catheter is placed directly into the coronary artery for delivery of the drug, and time is of the essence relative to the beginning of clinical signs. In veterinary patients with pulmonary thromboembolism, we usually do not have the luxury of rapid timing or of a catheter placed in the pulmonary artery for administration of the clotbuster drugs. Instead, we tend to administer these drugs systemically, often when the clot has been established for some time. Complications therefore include failure of thrombolysis, and increased risk of hemorrhage at remote sites.

Thus, clotbuster (fibrinolytic) drugs are typically not used to treat acute pulmonary thromboembolism in dogs, unless the embolic event is so severe that it is affecting hemodynamics by decreasing venous return to the left side of the heart. If the thromboembolism is so extensive that it is causing shock, then fibrinolytic drugs should be considered, and may be the only hope to save the patient.

Specific therapy: anticoagulants

If the animal is at high risk for thromboembolic disease, or if a clot is suspected, then prophylactic/therapeutic management with heparin may be considered. It is important to recognize that heparin is not expected to have any significant effect on clots that are already present. Rather, heparin is used to prevent enlargement of current thrombi, or formation of new thrombi. Heparin therapy should be continued until clinical and clinicopathologic signs of thrombosis have resolved, or until in-hospital risk factors such as central intravenous catheters have been removed. If risk factors for thrombosis continue after discharge from the hospital (for example in a dog with immune-mediated hemolytic anemia discharged from the hospital on high-dose corticosteroids), then ongoing anticoagulant therapy should be continued, either orally using warfarin, or parenterally using heparin which the owner continues to inject at home.

We commonly use unfractionated heparin doses of 100-300 iu/kg SQ q 6 hours, or administered as a continuous infusion at 10-60 iu/kg/hr. A loading dose of 50-200 iu/kg can be given initially intravenously. Administration of heparin intravenously as a CRI is convenient because the drug can be added to the patients intravenous fluids, and therefore helps to maintain catheter patency in these hypercoagulable patients. Unfractionated heparin therapy must be monitored by daily measurement of PTT. We aim to cause prolongation of the PTT by 50% from the baseline. If the PTT has not been prolonged, then the dose is increased, and the PTT re-measured the next day.

Alternatively, low molecular weight heparin can be administered. It is given subcutaneously two or three times daily. The advantage of low molecular weight heparin is that its effects are more predictable because it is more consistently absorbed from the subcutaneous tissue than unfractionated heparin. Furthermore, monitoring is easier because it is monitored using anti-factor-Xa, which needs only to be measured one time during therapy. However, low molecular weight heparin is expensive and is therefore not used for most of our medium to large-size pulmonary thromboembolism patients.

The main risk associated with all forms of heparin therapy is the possibility of excessive anticoagulation which can result in hemorrhage. While on heparin therapy, the patient should be carefully monitored for evidence of hemorrhage, which may need to be treated with transfusions or even protamine to reverse the effects of the heparin. All types of heparin therapy must be gradually weaned, as rebound hypercoagulability may occur if it is suddenly withdrawn.

References available on request