Critical care is an important cornerstone in the continuum of modern cancer care. The development of more oncologic therapies and advances in critical care will lead to increased survival of critically ill patients with cancer. Emergencies are characterized as chemotherapy-induced or are directly related to the neoplasm. Prompt identification and treatment of these emergencies can prolong survival and improve quality of life.

Chemotherapy-Induced Emergencies

Neutropenia

Neutrophils are the most abundant white blood cells in cats and dogs. Chemotherapy drugs are commonly associated with the development of neutropenia due to their myelosuppressive effects. In most instances of chemotherapy-induced neutropenia, the patient is asymptomatic, so it may often go unnoticed or be found incidentally when a complete blood count (CBC) is rechecked prior to the next chemotherapy treatment. Symptomatic patients often present with fever, decreased appetite, lethargy, and clinical signs of infection. These signs often present 7–10 days after a chemotherapy treatment. Many bacterial infections are mild and can be treated on an outpatient basis, but severe infections can present with systemic inflammatory response syndrome (SIRS).

Anaphylactic Reactions to Antineoplastic Agents

Several medications commonly used by oncologists can induce anaphylaxis. Anaphylaxis can induce a range of acute clinical signs, which can differ between species. In dogs, dermal and gastrointestinal clinical signs predominate. The dermal signs are primarily secondary to the vasodilatory effects of histamine, which causes erythema and pruritus. Gastrointestinal signs occur secondary to hepatic congestion and portal hypertension due to histamine leading to vomiting and diarrhea. In feline patients, gastrointestinal and respiratory signs are typical. In severe cases they can even present dyspneic.

When anaphylaxis is suspected the administration should stop, and the patient should be treated with antihistamines and glucocorticoids and for vasodilative shock. In feline patients with respiratory signs fluids should be used judiciously but never withheld in hypotensive or hypovolemic patients. In severe cases where blood pressure is not responsive to fluid therapy and antihistamines, vasopressors should be considered. In dyspneic patients’ oxygen should also be considered. After an anaphylactic event the administration of premedication with antihistamines and glucocorticoids or discontinuing further administration of the causative agent will need to be considered.

Many chemotherapy agents can induce significant tissue damage if extravasation of the drug occurs during administration. The exact mechanism behind extravasation injury is not completely understood, but it is thought to be due to tissue damage secondary to free radical formation or damage to DNA. Progression of the tissue damage and subsequent necrosis occurs following diffusion of drug/DNA complexes. Non-DNA binding complexes such as the vinca alkaloids are metabolized quickly, allowing normal healing to occur after the initial injury, while DNA binding agents will remain in the tissues and cause more prolonged injury. Tissue necrosis is noticeable 1 to 10 days after injection depending on the drug used. Severity ranges from erythema to open wounds. Immediate treatment includes applying cold packs or warm packs depending on the therapy agent used. Doxorubicin (DOX) can be treated with dimethyl sulphoxide (DMSO) and hyaluronidase (HU). Dexrazoxane has been used recently for DOX and acts as a metal ion chelator protecting against free radical toxicity. Steps to reduce the risk of EV occurring following chemotherapy administration include not performing blood draws on peripheral veins to preserve them for intravenous catheter placement.

Gastrointestinal Toxicity

Although gastrointestinal toxicity (GIT) occurs less commonly in small animal patients compared to people, it can have a major impact on quality of life. GIT can be secondary to either the underlying cancer and/or chemotherapy. Risk factors for vomiting include administration of highly emetogenic chemotherapy, smaller patient size, repetitive administration of chemotherapy, and gastrointestinal comorbidity. GIT in cancer patients is due to stimulation of the vomiting center within the medulla. This occurs secondary to gastrointestinal inflammation, over distension, and anxiety stimulating the cerebrum. Chemotherapeutic drugs stimulate the chemoreceptor trigger zone (CRTZ) which is a specialized region sensitive to substances because it lacks an intact blood brain barrier to emetic toxins and molecules can enter here easily. Once stimulated, the receptors stimulate the vomiting centers of the brain. This area controls certain autonomic functions including swallowing, gastric sensation, baroreceptor function and pharyngeal sensation. When caused by chemotherapy, the nausea occurs acutely, either during administration or within a few hours. Chemotherapy can also cause a direct toxic effect on the rapidly-diving cells of the gastrointestinal tract. Depletion of enterocytes and villi leads to poor nutrient absorption, diarrhea, nausea, and vomiting. These effects are usually reported 2–5 days after treatment. Decreased appetite, nausea, vomiting, and diarrhea commonly occur secondary to tumors that directly involve the GI tract or that cause external compression of the stomach or intestines. These signs occur secondary to GI obstruction, inflammation, or effects on GI motility and absorption. Antiemetics can also be administered, with the parenteral route preferred. Fluid therapy should be considered in patients with severe GI distress. Once vomiting has ceased, a bland diet can be reintroduced.

Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) occurs when large numbers of tumor cells release their contents into the bloodstream. These contents include things like nucleic acids, cations, and anions such as potassium and phosphorus. TLS can occur spontaneously or in response to therapy following effective chemotherapy treatments. When nucleic acids are broken down after release, they eventually form uric acid, which can have ill effects on numerous organ systems, such as the renal system. Successful treatment of TLS is dependent on symptomatic management of electrolyte imbalances and treatment of acute kidney injury. Prevention of TLS is discussed in human medicine extensively, but due to the multifactorial nature of TLS pathogenesis, it is difficult to make recommendations on prevention in veterinary medicine. This makes the prompt diagnosis and appropriate treatment important for the overall prognosis.

Hypercalcemia of Malignancy

Hypercalcemia (HC) is most often caused by neoplasia in canine patients. In feline patients, neoplasia is the third most common cause following idiopathic and renal disease. Paraneoplastic causes of HC include ectopic production of parathyroid hormone or PTH-related proteins. PTH is produced by the chief cells of the parathyroid gland and is involved in control of calcium homeostasis in the body. PTH-related protein stimulates osteoclastic bone resorption, increased renal tubular calcium reabsorption, and decreased renal tubular phosphate reabsorption. Some cancers can lead to HC due to interleukin transforming growth factor, which works synergistically with PTH-related proteins. Osteolytic metastasis and excessive calcium release from bones seen in carcinomas of the prostate, mammary gland, liver, and lung can also lead to HC. Primary bone tumors are rarely associated with HC in dogs and cats. However, Hematological malignancies in the bone marrow can result in cytokine-induced HC. Hypercalcemia has effects on multiple organ systems and displays a variety of clinical signs such as polyuria, polydipsia, anorexia, constipation, and renal changes. HC leads to renal arterial vasoconstriction reducing GFR.

Azotemia results due to acute tubular necrosis from toxic effects of calcium on renal epithelium, nephrocalcinosis, and inflammation. Cardiac effects of HC include arrhythmias and cardiac tissue mineralization.

Treatment for HC involves treatment of the underlying cancer by surgical removal or reducing the size of the tumor with medical therapy. Medical treatment often starts with correction of dehydration via fluid therapy followed by loop diuretics. Steroids can also be utilized to reduce calcium by decreasing bone and intestinal calcium reabsorption. Calcitonin can have rapid effects, making it an attractive treatment in emergent treatment of HC. Patients must be monitored for hypocalcemia post-treatment. Bisphosphonates are used for chronic management of HC. This treatment can take up to 5 days to show results, but effects can last up to 6 weeks. There are a variety of effects from bisphosphonates including gastrointestinal toxicity, electrolyte disturbances, tissue irritation, and nephrotoxic potential. It is important to treat HC, but it will be difficult to control without treatment of the underlying cause.

Hypoglycemia

Insulinoma is the most common malignancy associated with hypoglycemia (HG) but can be reported with hepatocellular carcinoma, hepatoma, LSA, leiomyosarcoma, adenocarcinoma, and hemangiosarcoma. Animals experiencing HG often exhibit neurological clinical signs including weakness, disorientation, and seizures. Treatments include dextrose infusions, glucocorticoids, glucagon, and beta blockers to promote normoglycemia until the underlying neoplasia can be identified and addressed.

Neoplasia-Related Emergencies

Hemorrhagic Effusions

Neoplasia is the most common cause of pericardial effusion in dogs. Neoplasia is most commonly found in the right atrium and base of the heart with the most common neoplasm being hemangiosarcoma. Clinical signs noted in canine patients include muffled heart sounds, tachypnea, and weakness including exercise intolerance. These patients often exhibit ventricular arrhythmias and can develop pericardial tamponade with can be fatal if untreated. Pericardial tamponade occurs when the inter-pericardial pressures increase causing venous return, ventricular filling, stroke volume, and cardiac output to decrease. Physical exam will show weak peripheral pulses, jugular venous distention, and labored breathing. Primary treatment involves removal of the fluid via pericardiocentesis to release pressure around the heart. A Pericardectomy can be performed but survival rates are often short in these cases.

Peritoneal Effusions

For most small animal patients, peritoneal effusion is caused by neoplasia, usually secondary to splenic ruptures. Hemangiosarcoma is the most common tumor associated with splenic neoplasia and peritoneal effusions. Presenting concerns are often weakness and collapse. Signs such as abdominal distention, pale mucus membranes and ataxia are also reported. Peritoneal effusion is often noted on ultrasound, and a sample should be collected via abdominocentesis to evaluate if the fluid is hemorrhagic. Fine needle aspiration of the mass can be performed but can be non-diagnostic and, due to the vascular nature of these tumors, could cause further bleeding. Surgical resection is the best option, and diagnostic evaluation of the tumor usually happens postoperatively. Initial treatment should be focused on stabilizing the patient to prepare for surgery. Hypovolemia secondary to hemorrhage should be treated with fluid therapy possibly including colloids and hypertonic solutions. If the patient is unresponsive to fluid resuscitation and evidence of severe hemorrhage is noted, blood products should be considered. In severe hemorrhage when blood products are not available, autotransfusions have been attempted. There is concern about the dissemination of malignant cells. Arrhythmias can also develop in these patients and are often ventricular in nature. These arrhythmias can be diagnosed on initial presentation or not be noted until postoperative period. These arrhythmias can be associated with poor myocardial perfusion secondary to hypoxia, hypovolemia, and anemia and may need to be treated to avoid hemodynamic instability.

Providing excellent patient care for the critical patient may be the difference between the patient surviving and thriving. The best technicians for critical care are the ones who are proactive and have forward-thinking skills. Oncological emergencies can occur at any time during the course of a malignancy and need to be recognized promptly to maximize successful outcomes.