Fever = T > 101oF (38.3oC) taken by any route or T > 100oF (38oC) [< 101 oF] repeatedly in a 24 hours period.
Rationale for Broad Spectrum "Emergency" Antibiotics: 1) Signs of infection altered (especially if ANC < 100/mcl): decreased exudate, fluctuance, necrosis, drainage, swelling, dysuria, consolidation (pneumonia). Erythema and pain, although diminished, are often present.
2) High morbidity/mortality: approximately 50% of neutropenic patients with untreated gram-negative bacteremia die within 48 to 72 hours.
Pertinent History: 1) Dates of last chemotherapy and type of chemotherapy (most ANC nadirs occur between days 7 - 14 post chemo and last three to five days before signs of myeloid recovery appear). The degree and duration of neutropenia directly correlate with the risk of infection. 2) Previous documented infections
3) Presence of central line (single or double lumen).
4) Previous splenectomy
5) Infectious disease exposure
6) Symptoms: cough, dyspnea, chest pain, retrosternal pain, sore throat, dysphagia, heart burn, abdominal pain, pain with defecation, vomiting, diarrhea, skin sores.
Physical Exam: Special attention to: vital signs; TMs; oral mucosa; oral pharynx; lungs (tachypnea, grunting, flaring, retractions, hypoxia); perirectal area, (visual inspection and pain assessment with external pressure but no routine rectal exam while neutropenic); skin (erythema, vesicles, pustules, ecthyma gangrenosum); catheter exit site or subcutaneous port site and catheter tract; sites of previous bone marrow aspirates or spinal taps, venipunctures, finger sticks.
Diagnostic Evaluation: Cultures:
Blood cultures: One blood culture from each lumen of a central venous catheter is initially required. Peripheral cultures (“arm poke”) are not required unless the patient has no central line, in which case one peripheral blood culture should be obtained.
Urinalysis and urine culture (do not wait for sample before starting antibiotics).
Areas of localized signs of infection require appropriate procedure for culture. Oral mucosal lesions or perirectal lesions may be cultured for herpes simplex, aerobes, anaerobes, fungus.
Radiographs: Routine chest x-rays are not indicated unless a pulmonary sign or symptom is present or fever persists beyond 48 hours.
Organisms: Intestinal tract, skin, and respiratory tract (lungs and sinuses) are the likely sources of microorganisms
Treatment: 1) Start Broad spectrum antibacterial antibiotics immediately (even before exam):
a) Cefepime 50 mg/kg/dose given every 8 hours (unless allergic)
Other antibiotics to consider:
Vancomycin 40 mg/kg/day q 6-8 hours (adult max usually 2 gm/day q 12h) Trough levels need to be followed if the patient has impaired renal function, will be on it >3 days, or has persistent fevers. Vancomycin should be started on the following patients ASAP:
all patients whose preceding chemotherapy course included high dose cytarabine (1-3 g/m2) (high incidence of -strep bacteremia)
previous history of coag negative staph with the same central line, alpha strep or enterococcal bacteremia.
c) Anaerobic bacterial coverage in patients with F and N:
Treatment with IV Clindamycin or IV Metronidazole (Flagyl) may initially be indicated if the physical exam or x-rays reveal:
a) perirectal pain or erythema
b) abdominal pain and possible typhlitis,
c) severe or recurrent sinusitis,
d) severe oral/esophageal mucositis
Hydration with either D51/2 NS (at least maintenance rate) or NS (see shock below) should begin as soon as possible after the patient is evaluated in the ED or inpatient unit, regardless of fluid or circulatory status. Patients with bacteremia (especially with gram neg rods) but clinically stable may suddenly develop signs of endotoxic shock during or after the antibiotic is infused. Unless a patient with fever and neutropenia looks quite well, an initial bolus of 10 ml/kg x ½ -1 hour should be given at the time of initiation of antibiotics. This rate and subsequent fluid should be adjusted to the clinical course (see shock below).
3) Anti-pyretics (for T>101oF [38.3oC] ) : Acetominophen (15 mg/kg) q 4 hour p.o. (no routine rectal meds). Ibuprofen may be given after discussion with the fellow and attending.
F and N with clinical signs of septic shock: often warm shock with borderlne BP
Aggressive fluid resuscitation (NS boluses up to 60 cc/kg x 1 h) is more important than antibiotics. Initial treatment should include Cefepime, Vancomycin, and an aminoglycoside, like gentamicin. Continue fluid resuscitation with crystalloid or colloid (blood products or albumin) until impending pulmonary edema. Dopamine for vascular support and ICU admission may be necessary.
Duration of Antibiotic Treatment: 1) Documented bacteremia: treat for 10 to 14 days with appropriate antibiotics, or until ANC > 500, if longer. Document negative blood culture before stopping treatment.
2) Culture proven source: treat for duration recommended for source in normal host, or until ANC > 500 if longer.
3) No documented source: treat at least 48 hours with IV broad-spectrum antibiotics. In all likelihood, a patient with F & N without documented source of infection (and no URI symptoms) had a “nidus” of bacteria stimulating fever that was “nipped in the bud” with antibiotics. Criteria for discontinuing antibiotics and discharging to home regardless of ANC include:
1) Admission cultures remain negative after 48 hours and no source on exam
Minimum of 24 hours afebrile and looking well prior to d/c
Parents of patients discharged with ANC < 500 should be advised to notify oncology service, as usual, for T>101oF [38.3oC].
For patients on G-CSF, evidence of rising ANC (or APC = WBC x % [segs + bands + monos] is usually required.
The majority of patients with F and N become afebrile within the first 36 hours of admission on antibiotics. If fever persists beyond 48 hours, one should consider additional antibiotic coverage (i.e. Vancomycin, anaerobic coverage, Acyclovir). The patient should be re-evaluated for a source of infection (thorough physical exam, chest x-ray, sinus films, etc.)
Fever lasting > 72 - 96 hours: begin evaluation for fungal disease (e.g. CXR and/or chest CT, urine culture for fungus, ophthalmologic exam, CT scan of sinuses and sometimes of liver, spleen, kidneys to detect fungal “abscesses"). Empiric antifungal therapy (micafungin or voriconazole) should be added after 72 – 96 hours febrile, depending on the patient's degree and expected duration of neutropenia. (< 25% of patients with autopsy-proven fungal disease had positive fungal cultures antemortem).
Note: Different guidelines for treatment and evaluation of fever or F & N may apply to bone marrow transplant patients.
II. SPECIAL INFECTIOUS PROBLEMS:
A) Pulmonary symptomatology present on exam: Immunocompromised patients are predisposed to pulmonary infections with CMV and other viruses, mycoplasma, Pneumocystis carinii, legionella, and fungus, whether or not they are neutropenic. The majority of patients on chemo receive prophylactic septra (TMP/SMZ) throughout treatment (2.5 mg/kg/dose TMP equiv BID each Sat/Sun). Chest x-ray and pulse-oximetry should be obtained in any patient with tachypnea or auscultatory findings on exam. Nasal wash for all viruses should be obtained. CMV PCR of blood should be considered. An O2 requirement is an indication for chest CT scan, pulmonary consultation and broncho-alveolar lavage (BAL). Empiric treatment with Azithromycin, and TMP/SMZ (depending on compliance history) should be considered (along with Cefepime +/- Vancomycin if neutropenic) while awaiting work-up results. Chest CT is much more likely to identify pulmonary nodules than CXR. Subsequent interventional radiology aspiration of a pulmonary nodule or open lung biopsy may be required for precise diagnosis.
B) Rule out typhlitis: Typhlitis is similar to NEC in newborns. It is an inflammatory cellulitis of the intestines, particularly the cecum. It occurs primarily in patients with ALL and AML during the first several weeks following diagnosis. These patients are usually neutropenic, anemic, and thrombocytopenic at the time of presentation with typhlitis. Abdominal signs may be subtle in these patients because of neutropenia and because Prednisone or Dexamethasone (treatment for ALL) further masks signs of inflammation. Mild abdominal pain in these patients should be aggressively evaluated and managed, with serial abdominal exams and serial abdominal films to evaluate bowel wall thickening, mucosal edema, pneumatosis intestinalis, or free air. CT scan of the abdomen is usually helpful in defining typhlitis. Serial blood cultures and serum HCO3 should be obtained. Surgical consult should be obtained at the time typhlitis enters the differential. Patients should be NPO. Antibiotics should include gram-positive, gram-negative and anaerobic coverage. Emergency surgery may be indicated to remove infarcted or perforated bowel.
Differential diagnosis of abdominal pain during ALL Induction:
constipation/obstipation (ileus from Vincristine)
gastritis/ulcer (from steroids + stress)
pancreatitis (from PEG Asparaginase)
(median time from Peg Asp injection until clinical pancreatitis is 10 days)
Oncology patients are at risk for central line infections even when not neutropenic. The decision whether or not to empirically treat pending culture results (despite ANC > 500) requires thoughtful clinical judgment. Obvious signs of infection related to the catheter require early treatment after blood cultures are drawn. A significantly higher than normal WBC and/or band count for the particular patient should raise suspicions of line infection. (Bandemia is common [up to about 20%] as bone marrow recovery follows chemotherapy, but is usually associated with monocytosis and ANC < 1000.) Ceftriaxone IV q day as outpatient is generally inadequate empiric treatment of presumed line infection, as coag - staph and pseudomonas are resistant to that drug.
Coag negative staph catheter infection may require treatment x 14-21 days, as coag negative staph makes “slime” that sticks to catheters. After full treatment, a vancomycin lock q 24 hours x 7-14 days, which allows the catheter lumen to “bathe in vanco”, may be beneficial for recurrent staph epi infections and prevent or forestall the need for line removal
D) Criteria for central venous catheter removal: (with or without neutropenia)
1) septic shock not responsive to fluid and pressors
2) persistent bacteremia after about 48 hours of appropriate antibiotic treatment
3) prolonged fever with a documented line infection
4) bacterial endocarditis
5) tunnel infection (along catheter tract) or cellulitis around infusaport
E) Clostridium difficile enterocolitis: This is not uncommon in the oncology population. Any oncology patient who develops diarrhea (with or without blood) should have stool tested for c. difficile toxin and, depending on clinical suspicion, for enteric bacterial pathogens and viruses as well (parasites are uncommon in this population, except for Giardia). If there is a high index of suspicion for c. difficile, or the patient has significant GI symptoms, like crampy abdominal pain, empiric treatment with oral Metronidazole (Flagyl 30 mg/kg/day divided TID, maximum 1 gram/day) may be started while waiting for test results. Full treatment is for 7-10 days. Oral Vancomycin (40 mg/kg/day divided QID, max 2 grams) may be required for multiply recurrent c. diff., although its use may predispose to VRE. In patients who have severe colitis, oral Cholestyramine (Questran) may help eradicate toxin after antibiotic course is completed. Lactobacillus or cultured yogurt can help repopulate the gut with innocuous flora. The false negative rate is up to 40% for c. difficile testing; therefore, repeat testing of persistent diarrhea is indicated.
F) Herpes simplex mucositis/stomatitis: Chemotherapy-induced mucositis may be aggravated by herpes simplex. These lesions may be in the mouth and/or esophagus. Lesions of mucositis should be cultured for herpes simplex, although empiric treatment may be indicated. Any neutropenic patient who develops swollen lips, with or without crusting lesions, should be cultured for herpes simplex and empirically treated with Acyclovir 10 mg/kg/dose q 8 h IV. A patient with mucositis known to have previous problems with herpes simplex should be started on the above dose of acyclovir prior to culture results. These patients are often already on prophylactic doses of acyclovir.
G) Varicella/Zoster: Visceral dissemination occurred in about one-third of untreated immunocompromised patients (pneumonia, hepatitis, pancreatitis, encephalitis) with a mortality of about 25% before Acyclovir was available. These infections are especially severe if the absolute lymphocyte count (ALC = WBC x % lymph) is < 500/mcl or if chemotherapy (particularly steroids) is continued through the infection. Intense abdominal pain can precede varicella by several days. Intense lumbosacral pain (with or without fever or rash) is often a prodrome of herpes zoster.
IVIG: Oncology patients without a history of varicella infection or without documented + varicella titer S/P vaccine, should be considered seronegative (varicella titers may have been measured at diagnosis before blood product transfusion). If a varicella sero-negative child is exposed to varicella, IVIG 400 mg/kg over 2-4 hours should be given as soon as possible after exposure. IVIG may not have efficacy if given later than 96 hours after exposure. Exposure is defined as a face-face household contact, playmate contact, classroom or lunchroom contact, or hospital contact. A person is considered infectious with varicella starting 24 hours before the onset of rash and until all vesicles are crusted over (see Red Book). Exposure also includes contact with a person with disseminated herpes zoster. Exposed patients should be kept away from other immunocompromised hosts from 10 days following exposure to day 28.
Acyclovir should be given as soon as possible once pox are suspected or recognized. Acyclovir (1500 mg/M2/day or 50 mg/kg/day q 8 hours) is generally given IV until no new lesions appear. Depending on the patient's course, Acyclovir (or other oral anti-herpes drugs) may be continued for a full 10 days p.o. at 3000 mg/M2/day 4 x/day.
III. TUMOR LYSIS SYNDROME (TLS)
Metabolic Triad of:
hypoxanthine xanthine uric acid
Hyperkalemia TLS is caused by the rapid release of intracellular metabolites when chemotherapy-induced cell lysis occurs. Each of the metabolic derangements can occur as an isolated problem or in combination. Uric acid and hypoxanthine crystals can precipitate in the kidneys and cause renal damage with hypertension or oliguria. Hyperphosphatemia is usually accompanied by hypocalcemia, with or without oliguria. Hyperkalemia is rare as an isolated problem but can occur when oliguria results from hyperuricemia or hyperphosphatemia. TLS is most commonly seen in patients with large burdens of tumor whose cells have very rapid doubling times and are very sensitive to chemotherapy, particularly Burkitt's lymphoma and acute leukemias. It is occasionally observed prior to treatment secondary to spontaneous cell lysis. When seen with leukemias, a very high white count and extramedullary disease is usually present (as in the T-cell ALL/lymphoma syndrome). TLS is virtually never seen in association with treatment of non-hematopoietic tumors such as rhabdomyosarcoma, osteogenic sarcoma, Wilms' tumor, and neuroblastoma, although isolated hyperuricemia can occur.
Management: 1) Institute precautionary measures necessary to deal with anticipated metabolic changes before chemo begins:
Allopurinol (300 – 500 mg/M2/day divided TID; max 800 mg/day) to decrease uric acid production (xanthine oxidase inhibitor that reduces hypoxanthine and uric acid production). Because of its expense and potential immunogenicity, Rasburicase (recombinant urate oxidase - converts uric acid to more soluble allantoin, and thereby decreases levels of relatively insoluble hypoxanthine) should be reserved for patients with elevated uric acid and/or creatinine: 0.15-0.2 mg/kg/dose IV x 1 (1.5 mg vials); may repeat q 24 hours x 3 – 7 days for increased uric acid. If Rasburicase is given, allopurinol and alkalinization should be discontinued; tumor lysis labs should be sent on ice so the Rasburicase in plasma sample does not reduce uric acid level spuriously.
[Rasburicase is contraindicated in patients with possible G6PD deficiency, as it will induce hemolysis.]
Hydration at 1½ - 2 x maintenance IV with D5 1/4 NS plus 30 - 40mEq sodium bicarb/liter (as long as oliguria not present). Withhold KCI until serum K level < 3.0 mEq/L. Hydration may need to be increased to keep urine output adequate at 2-3 cc/kg/hr. Mannitol 0.5g/kg (max 25 g) q 6-12 h should be started 1-2 days before chemotherapy begins if significant TLS is anticipated, and increased to q 6 h once chemotherapy starts, with increased IV hydration as indicated. Mannitol helps excrete PO4, K, (and Mg) through the proximal tubules. Furosemide IV ( 1 mg/kg q 4-8 h) may be used in addition for oliguria, working at the distal tubules.
c) Alkalinization with sodium bicarb as indicated in b) above to keep urine pH 6.5 and 7.5. Uric acid is most soluble within that pH range; urine pH > 7.5 can allow precipitation of hypoxanthine and calcium phosphate crystals. Stop alkalinization once serum phosphorus is elevated.
d) Use phosphate-binders like Sevelamer (Renogel) 20-40mg/kg/dose TID to decrease phosphate absorption if serum phosphorus elevated or elevation anticipated. Place on low phosphate diet (no milk products). Calcium carbonate (Tums) 10-25 mg/kg/dose TID may be useful if hypocalcemia is present in addition or instead of Sevelamer to bind PO4 and provide small amounts of calcium.
e) Consider renal ultrasound to assess degree of tumor infiltration or uric acid/ phosphate precipitation or possible ureteral obstruction from lymphadenopathy.
f) Consult nephrology early if the chance of severe tumor lysis syndrome appears high.
2) Monitor renal function and metabolic status closely once chemo has begun:
Electrolytes, creatinine, uric acid, calcium, phosphorus at least BID; strict I & Os, cc urine output/kg/4-6 hrs, daily or BID weights.
3) General indications for hemodialysis
a) K+ > 6.5 mEq/L: treat emergently with calcium gluconate, sodium bicarb, insulin, glucose, follow cardiac monitor, IV Furosemide may be helpful. (Administer oral Kayexalate for K+ > 6 mEq/L.) Occasionally in patients with very high white counts, a falsely elevated K is reported by the central lab, as the WBC in the blood tube autolyse and raise the serum K+ level. Running the serum K+ STAT on the ICU machine may be helpful. However, when in doubt, assume the elevated K is real.
b) Tetany or severe neurological symptoms secondary to hypocalcemia: give small calcium boluses for these symptoms, risking increasing the calcium: phosphorus product. Consider use of oral calcium carbonate (Tums) (20-65 mg/kg ÷ QID) to provide Ca++ and bind PO4.
c) phosphorus > 10 mg/dl or calcium: phosphorus product > 60 mg/dl. Discontinue alkalinization since calcium phosphate crystals are less soluble at urine pH > 6. Alkalosis decreases ionized calcium and can increase tetany. If phosphorus and uric acid both elevated, consider use of Acetazolamide (Diamox) 5mg/kg/dose BID-TID p.o. or IV, as this drug will acidify serum and alkalinize urine.
d) uric acid > 15 mg/dl
e) creatinine > 3 mg/dl
oliguria with volume overload despite repeated large doses of Furosemide or Mannitol: may consider low dose Dopamine prior to instituting hemodialysis.
IV. SUPERIOR VENA CAVA (SVC) AND SUPERIOR MEDIASTINAL SYNDROMES: SVC Syndrome is caused by compression or obstruction of the SVC. It is often part of the superior mediastinal syndrome (SMS) that involves tracheal compression and respiratory compromise as well. It occurs at presentation in about 15% of pediatric malignant anterior mediastinal tumors (Non-Hodgkin's Lymphoma involving the lymph nodes and thymus surrounding the SVC is the most common malignancy). Pleural and/or pericardial effusions may co-exist. Progressive vascular compromise may result in thromboembolic phenomena, extreme increases in intracranial pressure, or decreased cardiac output. Progressive tracheal and bronchial compromise can result in respiratory failure. Pericardial effusions or direct cardiac compression by tumor can impede cardiac output or cause cardiac tamponade and require emergency pericardiocentesis.
Symptoms of SVCS and SMS (usually progresses rapidly in children):
Cough, hoarseness, dyspnea, orthopnea, chest pain, headache, visual impairment, and lethargy.
Swelling, plethora, and cyanosis of face, neck and upper extremities; suffusion and edema of conjunctiva; distended neck and chest wall veins; diaphoresis; wheezing; stridor; pulsus paradox.
Diagnosis: is made by history, physical, chest x-ray/chest CT scan, and echocardiogram
Management (malignancy is presumed cause):
Assess airway compression and cardiac status: PE, O2 sat, emergency
1) Tissue diagnosis: make diagnosis by least invasive procedure possible. And do not attempt to make any diagnosis if there is any risk of intubation as a result!
a) CBC may show leukemia associated with mediastinal mass (as in T-cell ALL/Lymphoma syndrome).
b) Thoracentesis often provides diagnostic material in the case of Non-Hodgkin's Lymphoma.
c) Bone marrow aspirate and biopsy may reveal leukemia or marrow involvement with lymphoma.
d) Peripheral node biopsy (supraclavicular, cervical, etc.) if local anesthetic tolerable.
2) Avoid anesthesia or heavy sedatives. The supine position may further impede venous return or air flow. General anesthesia decreases respiratory muscle tone, relaxes bronchial smooth muscle, and decreases lung volume. Anesthesia and heavy sedatives can impede venous return and decrease cardiac output by causing peripheral vasodilatation. Extubation may be impossible following anesthesia until tumor bulk is reduced.
3) Delay definitive diagnosis if necessary.
In addition to the above studies listed in 1), obtain serum for alpha fetoprotein and beta HCG (germ cell tumors rarely may cause SVCS/SMS), along with uric acid and LDH. Chest CT scan to define mass should be done when patient clinically stable if diagnosis of lymphoma in doubt.
4) Emergency Steroids Emergency steroids (Methylprednisolone 5 - 16 mg/M2/dose q 8 hours; Dexamethasone 0.5 - 2 mg/kg/dose q 8hrs) may be necessary to rapidly reduce symptoms. (Tumor lysis syndrome may inevitably develop following steroid treatment.)
5) Respiratory and circulatory support: ICU management is often initially warranted: O2, bronchodilators, steroids, thoracentesis, pericardiocentesis, CVP line; begin chemotherapy as soon as possible (managing TLS as well – often with dialysis). Mechanical ventilation only if no other management choice remains.
6) Evaluate for intraluminal thrombosis if SVCS/SMS does not resolve with radiation therapy, steroids, or chemotherapy within several days.
V. HYPERLEUKOCYTOSIS (WBC >100,000/mcl):Seen at presentation in 10 to 15% of patients with ALL or AML. Complications result from leukostasis, microthrombi, and hyperviscosity. CNS and pulmonary problems are most common. Signs of hyperviscosity include blurred vision, confusion progressing to stupor, labored breathing, and hypoxia. CNS or pulmonary hemorrhage or thrombosis and priapism can also occur. Blood viscosity depends on the packed red cell volume and the packed leukocyte volume. Myeloblasts are large cells: 350 to 450 microns in diameter; lymphoblasts are smaller (250 to 350 microns). Thus, hyperviscosity syndrome is more commonly seen with hyperleukocytosis of AML than of ALL.
Management 1) Institute precautionary measures of tumor lysis syndrome management: hydration, alkalinization, allopurinol, etc.
2) If platelets <20,000/mcl, transfuse with platelets (to prevent hemorrhage).
3) Delay transfusion with packed red cells until WBC <100,000/mcl, unless signs of cardiovascular decompensation secondary to anemia are present. Partial exchange transfusion to correct anemia or leukopheresis with pRBC and plasma if congestive heart failure present.
4) Institute emergency leukopheresis if signs/symptoms of leucostasis or hyperviscosity are present. This procedure is not always effective at significantly decreasing WBC, particularly if blasts have very rapid doubling times. (Leukopheresis is generally not indicated purely as a means to prevent/diminish tumor lysis syndrome.)
5) Institute chemotherapy as soon as the patient is metabolically ready, or dialysis support is in preparation.