- Email: [email protected]
Nursing care of the child with neutropenic enterocolitis
Nursing Care of the Child with Neutropenic Enterocolitis Nancy King, MSN, CRNP, CPON Neutropenic enterocolitis (NE) is a serious complication in neutropenic patients. Once exclusively thought to be found in patients with leukemia and lymphoma, it is now being seen with increased frequency during bone marrow transplant, chemotherapy for solid tumors, and in patients suffering from acquired immune deficiency syndrome and cyclic neutropenia. The pathophysiology of NE is not completely understood, but unquestionably involves neutropenia, mucosal barrier damage, and infection resulting in a necrotizing process of the bowel wall. The cecum, ileus, and ascending colon are most commonly involved. Initial symptoms are usually nonspecific abdominal pain and fever. Localized, severe right lower quadrant pain, sepsis, and bowel perforation may rapidly develop. Once considered a fatal complication, the outcome for the child with NE has improved with better diagnostic imaging techniques and antibiotics. Most children can be successfully managed conservatively with early introduction of broadspectrum antibiotics and supportive care. However, a significant number will need surgical intervention. Nursing care of these children requires knowledge of the disease process, excellent clinical assessment skills, and a compassionate, family-centered approach. 䊚 2002 by Association of Pediatric Oncology Nurses
K
arl is a 12-year-old Caucasian male who was diagnosed with acute myelocytic leukemia 2 and one-half weeks ago. His induction regimen included cytarabine, etoposide, and daunorubicin. His absolute neutrophil count had been zero since day 7 of treatment and his platelet count has remained between 20,000 and 40,000/mm3. During his therapy he experienced intense nausea and vomiting despite administration of antiemetics around the clock. Eighteen days after diagnosis he developed a fever of 38.3°C (oral) that rose to 38.7°C within 1 hour. His other vital signs were stable. He was given acetaminophen orally (15 mg/kg), had two blood cultures drawn, and was started empirically on ceftazidime intravenously (IV) ev-
From the Children’s Hospital, Denver, Colorado. Address reprint requests to Nancy King MSN, CRNP, CPON, Advanced Practice Nurse, The Children’s Hospital, 1056 E. 19th Ave, Denver, CO 80218. © 2002 by Association of Pediatric Oncology Nurses 1043-4542/02/1906-0002$35.00/0 doi:10.1053/jpon.2002.127223 198
ery 8 hours (50 mg/kg/dose, maximum dose 2000 mg/day). Karl’s only complaint was mild, nonlocalized abdominal discomfort, which he attributed to his frequent emesis. His abdomen was soft, nondistended, and nontender to deep palpation. Bowel sounds were present and active in all quadrants. Over the next several hours, his fever rose to 40.1°C and his color became quite pale. His abdominal discomfort increased and became localized to the right lower quadrant with significant rebound pain and guarding. His bowel sounds became hypoactive, he had continual bilious emesis, and copious watery diarrhea developed. A nasogastric tube was placed for gastric decompression to relieve his nausea. A flat-plate x-ray was negative for air-fluid levels, intussusception, and perforation. An abdominal computed tomography (CT) scan showed transmural thickening of the bowel wall at the ileocecal junction and the presence of fluid in the bowel. The diagnosis of neutropenic enterocolitis was made and additional antibiotic coverage was immediately in-
Journal of Pediatric Oncology Nursing, Vol 19, No 6 (November-December), 2002: pp 198-204
Neutropenic Enterocolitis
stituted with metronidazole IV every 6 hours (30 mg/kg/day) and gentamicin IV every 8 hours (2 mg/kg/dose).
Pathophysiology Neutropenic enterocolitis (NE) is a necrotizing inflammation of the cecum and proximal colon seen in patients with neutropenia. Dr. J.V. Cooke published the first description of an enteropathic process associated with leukemia in 1933 based upon his postmortem examinations of children with leukemia (Cooke, 1933). In the 1970s the term typhlitis (from the Greek word typhon meaning cecum) was coined to identify a necrotizing, inflammatory process most commonly involving the cecum and thought to be unique to leukemia (Klein & Adler, 2000). Other terms used to describe the same condition in the literature, such as ileocecal disease, necrotizing enteropathy, and neutropenic colitis, suggest that NE is most likely the result of several combined pathologic changes rather than a discrete process (Williams & Scott, 1997). Although most commonly seen in patients with leukemia and lymphoma, there is now increasing incidence in patients with solid tumors and those undergoing bone marrow transplant (Song et al., 1998; Avigan et al., 1998). Yaniv et al. (2000) identified neutropenic enterocolitis as a significant consequence for patients with B-cell lymphoma undergoing chemotherapy with the intensified French LMB protocol. This most likely reflects the use of aggressive chemotherapy treatments for these conditions that produce longer periods of neutropenia and increase the risk of mucosal damage. NE has also been reported in nonmalignant conditions associated with neutropenia, such as aplastic anemia and cyclic neutropenia (Gomez, Martino, & Rolston, 1998). Occurrences in patients with acquired immunodeficiency syndrome and after administration of the antiinflammatory agents dipyrone and sulfasalazine have also been cited in the adult literature (Abbasoglu & Cakmakci, 1993; Daphan, Abbasoglu, Agalar, & Yagmurdur, 1999; Williams & Scott, 1997). Until the 1970s NE was considered a fatal complication; the prognosis today is far more hopeful. The outcome for a patient diagnosed
199
with NE is most favorable when antibiotic therapy and supportive measures are initiated before bowel perforation or overwhelming bacterial sepsis occurs (Song et al., 1998). Advancements in diagnostic imaging techniques, antibiotic therapy, and supportive care techniques have made this possible in the majority of cases although mortality rates from less than 20% to as high as 45% are still reported in the literature (Gomez et al., 1998; Jain, Arya, & Kataria, 2000). The mechanism by which NE occurs is not fully understood and is most likely multifactorial (de Brito et al., 1998). Prolonged neutropenia appears to be the requisite factor in conjunction with injury to the bowel mucosa (Williams & Scott, 1997). Granulocyte recovery often precedes resolution of symptoms, further substantiating the importance of neutropenia in this process (Song et al., 1998). NE most commonly involves the cecum, terminal ileum, and ascending colon (Kinrade, 1988). The cecum is the least vascularized area of the lower intestine and the most distensible, which may result in increased ischemia in the face of infection (de Brito et al., 1998). This may explain the predilection of NE for this section of the bowel. After the bowel mucosa becomes infected and inflamed, progression to full-thickness infarction and perforation can occur (Shamberger, Weinstein, DeLorey, & Levy, 1986). Mucosal barrier damage clearly plays a significant role in the development of NE. The gastrointestinal tract renews its mucosa every 3 to 5 days (Aggarwal, Williams, & Beath, 1998), thus it is particularly sensitive to the cytotoxic effects of chemotherapy. The gut is largely composed of lymphoid tissue; consequently, the mucosa is a common infiltration site for leukemia and lymphoma cells (Williams & Scott, 1997). As pockets of malignant cells are killed by chemotherapy, areas of weakness and necrosis may occur. Mucosal insults from chemotherapy agents such as cytarabine, anthracyclines, methotrexate, and increasingly with taxanes, can leave the bowel wall denuded and ulcerated; this permits passage of enteric bacteria into the blood stream (de Brito et al., 1998; Kouroussis et al., 2000). Radiation therapy to the abdomen is another source of damage to the bowel mucosa. Bacterial and fungal infections or hypotension-
200
Nancy King
induced ischemia from sepsis may also contribute to mucosal injury (Williams & Scott, 1997). Other factors may also affect bowel integrity and increase the risk of developing NE. Steroids given as part of chemotherapeutic regimens may impair tissue healing, permit overgrowth of normal gastrointestinal flora, and alter response to infection (Aggarwal et al., 1998). Decreases in gastric acid production from malnutrition or from use of H2 blockers inhibit bactericidal action in the stomach. Consequently, more microorganisms survive passage into the gut, thereby increasing the risk of infection (Aggarwal et al., 1998). Secondary infection may occur from pathogens such as Escherichia coli (E. coli), Klebsiella, Pseudomonas, Staphylococcus, Enterobacter, Clostridium species, yeast, and less commonly from fungi (de Brito et al., 1998).
Diagnosis The clinical presentation of NE may be subtle and insidious developing over days, or sudden and acute progressing rapidly over hours as described in the case study (de Brito et al., 1998). Overwhelming septicemia may occur before the presence of significant clinical symptoms and an aggressive onset is frequently fatal (Williams & Scott, 1997). Common symptoms include fever and abdominal discomfort that is initially diffuse and progresses to localized right lower quadrant pain. Other symptoms may include nausea, vomiting, water loss or bloody diarrhea, ileus, and symptoms of systemic inflammatory response or sepsis (Gomez et al., 1998). Peritonitis and perforation may occur with little advance warning. Because of the accompanying neutropenia, leukocytosis is unlikely (Williams & Scott, 1987). NE is a diagnostic challenge as symptoms often mimic those of other abdominal conditions and complications of cancer therapy. The differential diagnosis of the neutropenic patient with abdominal pain must also include more common etiologies such as mucositis, appendicitis, pseudomembranous colitis, intussusception, bowel obstruction, and opportunistic infections (deBrito et al., 1997). Diagnostic imaging studies are essential in order to make a diagnosis of NE. The hallmark findings are cecal wall thickening and pericolic fluid collections in the presence of neutropenia
and clinical symptoms of abdominal infection (Williams & Scott, 1997). Plain film x-rays are least sensitive for diagnosing NE and studies have indicated that up to 50% of patients may have normal radiographs (deBrito et al., 1998). X-rays can be helpful for exclusion of intussusception and other more common bowel disorders. Perforation, obstruction, and pneumatosis can be easily seen on plain films (John, 1999). Because of the risk of bowel perforation and low yield of useful information, barium studies are no longer recommended (Williams & Scott, 1997). Examination of the abdomen by ultrasound is an easy and noninvasive technique to identify pseudopolypoid changes of cecal mucosa and pericolic fluid collections. Ultrasonography is an extremely useful tool for frequent progress monitoring in the child with NE because it does not involve radiation (Williams & Scott, 1997; Cartoni et al., 2001). CT scans provide the most sensitive way to look specifically for cecal wall thickening. The ability to differentiate between NE and other etiologies such as appendicitis, pseudomembranous colitis, or abscess is a major benefit of CT (deBrito et al., 1998; McNamara et al., 1986). Laboratory data are rarely helpful in diagnosis except to confirm the presence of bacteremia (de Brito et al., 1998). Blood cultures will be positive for enteric organisms in more than 50% of cases (Williams & Scott, 1997). Following data such as complete blood counts, serum chemistries, and coagulation studies is helpful in the overall evaluation of the patient. Laboratory findings may alert the health care provider to concurrent complications such as electrolyte imbalances, dehydration, disseminated intravascular coagulation associated with sepsis, and bleeding or hemorrhage in the bowel (de Brito et al., 1998).
Treatment A nonsurgical approach for treatment of NE is preferred to minimize operative risks associated with neutropenia (Song et al., 1993). Conservative management involves broad-spectrum antibiotics and supportive care including bowel rest and decompression, fluid replacement, electrolyte correction, nutritional support, and possibly inotropic blood pressure support (Williams
Neutropenic Enterocolitis
& Scott, 1997; Wade, Nava, & Douglass, 1992). Empiric antibiotic regimens must include agents for which anaerobic enteric organisms are generally sensitive. Metronidazole is commonly used in conjunction with an aminoglycoside, such as gentamicin, or amikacin, and an antipseudomonal antibiotic such as ceftazidime to provide broad-spectrum coverage (Song et al., 1998). Imipenem plus an aminoglycoside is another acceptable combination (Yaniv et al., 2000). Antifungals may be added when fevers persist in spite of broad-spectrum coverage or when the blood culture is positive for fungus. Blood cultures should be drawn before institution of antibiotics and with recurrent fever episodes to identify specific organisms and sensitivities to antimicrobials. In the case of bacteremia, subsequent blood culture specimens must be obtained until the cultures are negative. Most patients with NE will respond well without need for surgical intervention if appropriate antibiotics are instituted before overwhelming sepsis or perforation occurs (Gomez et al., 1998). Surgery becomes necessary when there is perforation of the bowel and in cases in which conservative management does not lead to clinical improvement. Surgical management most often involves resection of necrotic bowel and creation of a mucus fistula and ileostomy; peritoneal washing and drainage may be required as well (Williams & Scott, 1997; Chirletti et al., 1993). End-to-end anastomosis is sometimes done at the initial surgery, but is usually delayed when extensive peritoneal spilling of bowel contents has occurred or the patient is septic (Williams & Scott, 1997). Generally, anastomosis is possible once complete healing has taken place and the patient is no longer neutropenic (Shamberger et al., 1986). Postoperative morbidity and mortality is high because of impaired healing ability and risks for additional infection and sepsis (Starnes et al., 1986). However, surgery should not be delayed when clear indications exist (Weinberger, Hollingsworth, Feuerstein, Young, & Pizzo, 1993). Pain may be the primary presenting symptom of an acute abdominal process in the patient with neutropenia (Starnes et al., 1986); therefore, all abdominal complaints in the neutropenic child should be taken seriously. As illustrated in the case study, NE initially presents
201
with mild, diffuse, nonspecific abdominal discomfort that progresses to intense pain localized in the right lower quadrant. Pain management with adequate doses of narcotic analgesics may be necessary because peritoneal irritation can cause excruciating pain (de Brito et al., 1998). After the diagnosis of NE is made, effective pain management should be a priority and intravenous pain medications such as morphine should be titrated as necessary to maintain comfort. Signs of improvement in the clinical status of a patient with NE can usually be seen within 24 hours after adequate treatment, whether conservative or surgical, has been initiated. Children who do not show prompt signs of improvement with treatment often have a less favorable outcome. Supportive treatments continue until the patient has resolution of all abdominal symptoms and related clinical findings, has return of normal bowel motility, remains afebrile, and has documentation of negative blood cultures. Antibiotics and, when necessary, antifungal agents, should be continued for their full courses, usually 10 to 14 days.
Nursing Assessment and Management Nursing care of the child with NE requires a sound knowledge base, skill, and compassion. These children are frequently critically ill and experience rapid changes in physiologic status as the infection progresses. Nursing assessment and care is a key factor in successful management of patients with this life-threatening complication. Nurses have an advantage in patient assessment because their frequent contact with the child and family allows them to be alert to subtle alterations in the child’s baseline behavior and demeanor. NE can affect many physiologic systems; therefore, assessments need to be comprehensive and follow a head-to-toe progression to ensure that significant changes are not missed. Bearing in mind the rapidity with which clinical changes can occur, assessments should be done at frequent intervals during the shift and whenever there is an apparent change in the child’s status. Table 1 summarizes common assessment findings and potential causes. Abdominal assessment should include inspection, auscultation, palpation, and measurement of girth. Percussion is a useful technique to
Nancy King
202
TABLE 1. Common Assessment Findings in the Child with Neutropenic Enterocolitis System
Assessment Finding
Neurologic
Change in behavior, 2 level of consciousness, hypotonia
Skin and mucous membranes Cardiovascular
2 Skin turgor, dryness of oral mucous membranes, lack of tears 1 Heart rate, bounding or thready pulse, 2 blood pressure, slow capillary refill, diminished peripheral pulses, pale or ashen color, 2 peripheral perfusion, widening of pulse pressure or 2 BP, bleeding, development of petechiae 1 Respiratory rate, 2 depth of respiration, grunting, crackles, 2 respiratory effectiveness, 1 work of breathing, respiratory acidosis, 1 oxygen requirement
Respiratory
Potential Cause Exhaustion, dehydration, electrolyte imbalance, pain, hypovolemia, shock Dehydration Fever, dehydration, hypovolemia, fluid overload, impending shock, hemorrhage, systemic inflammatory response syndrome, DIC Fever, dehydration, pain, abdominal distention, fluid overload
Gastrointestinal
2 Bowel tones, 1 distention, 1 tenderness, guarding, rebound, rigidity, diarrhea/ emesis
Increasing peritoneal irritation, accumulation of ascites, ileus, perforation
Renal
2 Urine output
Musculoskeletal
Refusal to walk, reluctance to turn in bed, rigid positioning
Dehydration, hypovolemia, shock Increasing peritoneal irritation and pain
Psychosocial
Refusal to participate in previously enjoyed diversions, withdrawal, tearfulness, behavior changes
Pain, fear and anxiety, ineffective coping skills
Nursing Actions Frequent assessment of level of consciousness Assess skin turgor, condition of mucus membranes with each vital sign check Continuous cardio-respiratory monitor Frequent blood pressure monitoring Assessment of perfusion status with vital sign checks Assess for bleeding Assess breath sounds and respiratory effort/adequacy frequently Continuous pulse oximetry Respiratory support as needed with oxygen/mechanical ventilation Frequent auscultation of bowel sounds Measure abdominal girth every 2–4 hours Assess changes in complaints of abdominal discomfort Strict measurement of intake and output Observe, record, and report changes in patient’s willingness to mobilize Comfort measures Provide frequent updates to family and child regarding plan and progress Emotional support Comfort measures
DIC, Disseminated intravascular coagulation.
identify areas of density but may not be welltolerated because of pain. Increases in peritoneal inflammation are frequently reflected in the abdominal exam (Hartman, 2000). A change in the quality and intensity of abdominal discomfort is often the first and most reliable symptom of disease progression in the neutropenic patient. Consistent use of an appropriate pain assessment tool and documentation of findings is essential in following the progression of NE. Distention and rigidity of the abdomen are wor-
risome for perforation (Shamberger et al., 1986) and require immediate assessment by a physician. Assessment of the cardiovascular and hemodynamic status of the patient with presumed or confirmed NE cannot be overemphasized. Volume losses from vomiting, diarrhea, and fluid shifts can be impressive; therefore, hypovolemia and electrolyte imbalance are significant risks. Continuous cardiorespiratory monitoring in conjunction with frequent physical assessment is
Neutropenic Enterocolitis
important. Accurate monitoring of intake and output and timely replacement of fluid losses is essential. The child’s color, quality and rate of the pulse, perfusion, and capillary refill should be checked and documented frequently. Measures of hydration status should also be assessed such as urine output, condition of the mucous membranes, and skin turgor. Blood pressure is an important measurement of the body’s ability to maintain homeostasis. A widening of the pulse pressures may indicate a decline in hemodynamic stability; a dropping blood pressure is a late symptom of shock and an ominous sign. Fluid resuscitation or inotropic support of the blood pressure may become necessary, particularly when gram-negative sepsis is present (Powell, 2000). Following the fever curve is very helpful in monitoring the progress of NE and assessing the effectiveness of antibiotics, thus it is important to avoid around-the-clock administration of antipyretics. A temperature graph may be useful for identifying fever patterns. Oral rather than rectal administration of antipyretics is preferred in children who are neutropenic because of the risk of injuring the rectal mucosa, thereby creating an additional risk for bacterial invasion. Emotional support is an essential component of nursing care for the family and child. Anxiety, confusion, and fear may result when facing a serious complication of an already life-threatening process (Kinrade, 1988). Establishing and maintaining a therapeutic professional relationship will be most helpful to both the child and family (McKlindon & Barnsteiner, 1999). The nurse can solicit the concerns and observations of the child and parents, clarify misinformation or misunderstanding, respond to their questions, and support their hope. A plan for promoting the child’s comfort should be created with input from the child and family and updated frequently. Consideration of the child’s developmental level should guide all nursing plans and interventions. Of equal importance to patient assessment is documentation and communication of findings (Kinrade, 1988). For example, a small change in the abdominal girth may seem insignificant with the first measurement, but successive increases may be a signal that an ileus or ascites is developing. Charting must be detailed and complete
203
so comparisons of findings can be made. Timely communication of findings and concerns to health team members is essential to ensure early response.
Case Study Outcome Twelve hours after Karl’s symptoms started, the nurse noted a trend of widening pulse pressures and prolonged capillary refill in his nail beds. He was arousable but lethargic. His fluid losses from diarrhea had been difficult to replace because of frequent, large-volume stools. Additionally, his blood cultures were already positive for E. coli. Fluid resuscitation with two rapid infusions of normal saline at 20 mL/kg improved his blood pressure. A plain-film x-ray showed no evidence of perforation. Nursing measures included hourly intake and output measurements. Vital signs with assessment were done every 2 hours for the first 24 hours until his condition stabilized. He received packed red blood cell transfusions to maintain his hematocrit above 25 gm% and platelets to maintain his count above 20,000/mm3. His pain was managed with morphine administered by a patientcontrolled analgesia pump and dosages were adjusted based upon his pain scale scores and clinical status. Karl was afebrile 2 days after the onset of symptoms. His abdominal exam was normal by the fifth day, at which time his absolute neutrophil count had risen to 750. He continued treatment with intravenous antibiotics for 10 days. Repeat blood cultures were negative after 24 hours of antibiotics. The nurses met with Karl and his parents daily to ascertain their concerns, answer their questions, and plan his care for the day. Karl’s parents later stated that the support they received during his illness allowed them to maintain a sense of control and they felt they were a valued part of his care team. Karl recovered completely and was able to be discharged for a few days before being readmitted to resume his chemotherapy.
Summary Neutropenic enterocolitis is a life-threatening complication for children with cancer and other conditions associated with profound neutropenia. Advances in antibiotic therapy, supportive
204
Nancy King
care, and imaging techniques have improved the prognosis for many children who develop this condition; however, the risks of sepsis and bowel perforation remain significantly high. Comprehensive, frequent nursing assessment
and communication of findings in these patients is critical. Early detection and intervention may enable successful conservative treatment with antibiotics and supportive cares, thereby avoiding the significant risks associated with surgery.
References Abbasoglu, O., & Cakmakci, M. (1993). Neutropenic enterocolitis in patients without leukemia. Surgery, 113(1), 113-116. Aggarwal, V., Williams, M.D., & Beath, S.V. (1998). Gastrointestinal problems in the immunosuppressed patient. Archives of Disease in Childhood, 78(1), 5-8. Avigan, D., Richardson, P., Elias, A., Demetri, G., Shapiro, M., Schnipper, L., & Wheeler, C. (1998). Neutropenic enterocolitis as a complication of high dose chemotherapy with stem cell rescue in patients with solid tumors: A case series with a review of the literature. Cancer, 83(3), 409-414. Cartoni, C., Dragoni, F., Micozzi, A., Pescarmona, E., Mecarocci, S., Chirletti, P., Petti, M. C., Meoni, G., & Mandelli, F. (2001). Neutropenic enterocolitis in patients with acute leukemia: Prognostic significance of bowel wall thickening detected by ultrasonography. Journal of Clinical Oncology, 19(3), 756-761. Chirletti, P., Barillari, P., Sammartino, P., Cardi, M., Carona, R., Arcese, W., Petti, C., & Stipa, V. (1993). The surgical choice in neutropenic patients with hematological disorders and acute abdominal complications. Leukemia and Lymphoma, 9(3), 237-241. Cooke, J. V. (1933). Acute leukaemia in children. Journal of the American Medical Association, 101, 432-435. Daphan, C. E., Abbasoglu, O., Agalar, F., & Yagmurdur, M.C. (1999). Neutropenic enterocolitis due to dipyrone use. Australian and New Zealand Journal of Surgery, 69(9), 680-681. de Brito, D., Barton, E., Spears, K. L., Cranmer, H. H., Karp, S. J., Anglin, D., & Hutson, H. R. (1998). Acute right lower quadrant pain in a patient with leukemia. Annals of Emergency Medicine, 32(1), 98-101. Gomez, L, Martino, R., & Rolston, K. V. (1998). Neutropenic enterocolitis: Spectrum of the disease and comparison of definite and possible cases. Clinical Infectious Diseases, 27, 695-699. Hartman, G. E. (2000). Acute appendicitis. In R. E. Berhman, R. M. Kliegman, & H. B. Jenson (Eds.). Nelson textbook of pediatrics (16th ed.). Philadelphia: Saunders. Jain, Y., Arya, L. S., & Kataria, R. (2000). Neutropenic enterocolitis in children with acute lymphoblastic leukemia. Pediatric Hematology and Oncology, 17(1), 99-103. John, S. D. (1999). Advances in emergency radiology II: Trends in pediatric emergency imaging. Radiologic Clinics of North America, 37(5), 995-1034. Kinrade, L. C. (1988). Typhlitis: A complication of neutropenia. Pediatric Nursing, 14(4), 291-295.
Klein, S. G. & Adler, I. N., (2000). Radiological case of the month. Archives of Pediatrics and Adolescent Medicine, 154(6) 629-630. Kouroussis, C., Samonis, G., Androulakis, N, Souglakos, J., Voloudaki, A., Dimonpoulos, M. A., Kitsakis, T., Kakolyris, S., Kalbakis, K., & Georgoulias, V (2000). Successful conservative treatment of neutropenic enterocolitis complicating taxane-based chemotherapy: A report of five cases. American Journal of Clinical Oncology, 23(3), 309-313. McKlindon, D. & Barnsteiner, J. H. (1999). Therapeutic relationships: Evolution of the Children’s Hospital of Philadelphia model. Maternal Child Nursing, 24(5) 237-243. McNamara, M. J., Chalmers, A. G., Morgan, M., & Smith, E. W. (1986). Typhlitis in acute childhood leukaemia: Radiological features. Clinical Radiology, 37, 83-86. Powell, K. R. (2000). Sepsis and shock. In R. E. Berhman, R. M. Kliegman, & H. B. Jenson (Eds.). Nelson textbook of pediatrics (16th ed.). Philadelphia: Saunders. Shamberger, R. C., Weinstein, H. J., DeLorey, M. J., & Levey, R. H. (1986). The medical and surgical management of typhlitis in children with acute nonlymphocytic (myelogenous) leukemia. Cancer, 57(3), 603-608. Song, H. K., Kreisel, D., Canter, R., Krupnik, A. S., Stadtmauer, E. A., & Buzby G. (1998). Changing presentation and management of neutropenic enterocolitis. Archives of Surgery, 133(9), 979-982. Starnes, H. F., Moore, F. D., Mentzer, S., Osteen, R. T., Steele, G. D., & Wilson, R. E. (1986). Abdominal pain in neutropenic cancer patients. Cancer, 57(3), 616-621. Wade, D. S., Nava, H. R., & Douglass, H. O. (1992). Neutropenic enterocolitis. Clinical diagnosis and treatment. Cancer, 69(1), 17-23. Weinberger, M., Hollingsworth, H., Feuerstein, I. M., Young, N. S., & Pizzo, P. A. (1993). Successful surgical management of neutropenic enterocolitis in two patients with severe aplastic anemia. Case reports and review of the literature. Archives of Internal Medicine, 153(1), 107-113. Williams, N., & Scott, A. D. N. (1997). Neutropenic colitis: A continuing surgical challenge. The British Journal of Surgery, 84(9), 1200-1205. Yaniv, I., Fischer, S., Mor, C., Stark, B., Goshen, Y., Stein, J., Cohen, I. J., & Zaizov, R. (2000). Improved outcome in childhood B-cell lymphoma with the intensified French LMB protocol. Medical and Pediatric Oncology, 35(8), 8-12.
K
arl is a 12-year-old Caucasian male who was diagnosed with acute myelocytic leukemia 2 and one-half weeks ago. His induction regimen included cytarabine, etoposide, and daunorubicin. His absolute neutrophil count had been zero since day 7 of treatment and his platelet count has remained between 20,000 and 40,000/mm3. During his therapy he experienced intense nausea and vomiting despite administration of antiemetics around the clock. Eighteen days after diagnosis he developed a fever of 38.3°C (oral) that rose to 38.7°C within 1 hour. His other vital signs were stable. He was given acetaminophen orally (15 mg/kg), had two blood cultures drawn, and was started empirically on ceftazidime intravenously (IV) ev-
From the Children’s Hospital, Denver, Colorado. Address reprint requests to Nancy King MSN, CRNP, CPON, Advanced Practice Nurse, The Children’s Hospital, 1056 E. 19th Ave, Denver, CO 80218. © 2002 by Association of Pediatric Oncology Nurses 1043-4542/02/1906-0002$35.00/0 doi:10.1053/jpon.2002.127223 198
ery 8 hours (50 mg/kg/dose, maximum dose 2000 mg/day). Karl’s only complaint was mild, nonlocalized abdominal discomfort, which he attributed to his frequent emesis. His abdomen was soft, nondistended, and nontender to deep palpation. Bowel sounds were present and active in all quadrants. Over the next several hours, his fever rose to 40.1°C and his color became quite pale. His abdominal discomfort increased and became localized to the right lower quadrant with significant rebound pain and guarding. His bowel sounds became hypoactive, he had continual bilious emesis, and copious watery diarrhea developed. A nasogastric tube was placed for gastric decompression to relieve his nausea. A flat-plate x-ray was negative for air-fluid levels, intussusception, and perforation. An abdominal computed tomography (CT) scan showed transmural thickening of the bowel wall at the ileocecal junction and the presence of fluid in the bowel. The diagnosis of neutropenic enterocolitis was made and additional antibiotic coverage was immediately in-
Journal of Pediatric Oncology Nursing, Vol 19, No 6 (November-December), 2002: pp 198-204
Neutropenic Enterocolitis
stituted with metronidazole IV every 6 hours (30 mg/kg/day) and gentamicin IV every 8 hours (2 mg/kg/dose).
Pathophysiology Neutropenic enterocolitis (NE) is a necrotizing inflammation of the cecum and proximal colon seen in patients with neutropenia. Dr. J.V. Cooke published the first description of an enteropathic process associated with leukemia in 1933 based upon his postmortem examinations of children with leukemia (Cooke, 1933). In the 1970s the term typhlitis (from the Greek word typhon meaning cecum) was coined to identify a necrotizing, inflammatory process most commonly involving the cecum and thought to be unique to leukemia (Klein & Adler, 2000). Other terms used to describe the same condition in the literature, such as ileocecal disease, necrotizing enteropathy, and neutropenic colitis, suggest that NE is most likely the result of several combined pathologic changes rather than a discrete process (Williams & Scott, 1997). Although most commonly seen in patients with leukemia and lymphoma, there is now increasing incidence in patients with solid tumors and those undergoing bone marrow transplant (Song et al., 1998; Avigan et al., 1998). Yaniv et al. (2000) identified neutropenic enterocolitis as a significant consequence for patients with B-cell lymphoma undergoing chemotherapy with the intensified French LMB protocol. This most likely reflects the use of aggressive chemotherapy treatments for these conditions that produce longer periods of neutropenia and increase the risk of mucosal damage. NE has also been reported in nonmalignant conditions associated with neutropenia, such as aplastic anemia and cyclic neutropenia (Gomez, Martino, & Rolston, 1998). Occurrences in patients with acquired immunodeficiency syndrome and after administration of the antiinflammatory agents dipyrone and sulfasalazine have also been cited in the adult literature (Abbasoglu & Cakmakci, 1993; Daphan, Abbasoglu, Agalar, & Yagmurdur, 1999; Williams & Scott, 1997). Until the 1970s NE was considered a fatal complication; the prognosis today is far more hopeful. The outcome for a patient diagnosed
199
with NE is most favorable when antibiotic therapy and supportive measures are initiated before bowel perforation or overwhelming bacterial sepsis occurs (Song et al., 1998). Advancements in diagnostic imaging techniques, antibiotic therapy, and supportive care techniques have made this possible in the majority of cases although mortality rates from less than 20% to as high as 45% are still reported in the literature (Gomez et al., 1998; Jain, Arya, & Kataria, 2000). The mechanism by which NE occurs is not fully understood and is most likely multifactorial (de Brito et al., 1998). Prolonged neutropenia appears to be the requisite factor in conjunction with injury to the bowel mucosa (Williams & Scott, 1997). Granulocyte recovery often precedes resolution of symptoms, further substantiating the importance of neutropenia in this process (Song et al., 1998). NE most commonly involves the cecum, terminal ileum, and ascending colon (Kinrade, 1988). The cecum is the least vascularized area of the lower intestine and the most distensible, which may result in increased ischemia in the face of infection (de Brito et al., 1998). This may explain the predilection of NE for this section of the bowel. After the bowel mucosa becomes infected and inflamed, progression to full-thickness infarction and perforation can occur (Shamberger, Weinstein, DeLorey, & Levy, 1986). Mucosal barrier damage clearly plays a significant role in the development of NE. The gastrointestinal tract renews its mucosa every 3 to 5 days (Aggarwal, Williams, & Beath, 1998), thus it is particularly sensitive to the cytotoxic effects of chemotherapy. The gut is largely composed of lymphoid tissue; consequently, the mucosa is a common infiltration site for leukemia and lymphoma cells (Williams & Scott, 1997). As pockets of malignant cells are killed by chemotherapy, areas of weakness and necrosis may occur. Mucosal insults from chemotherapy agents such as cytarabine, anthracyclines, methotrexate, and increasingly with taxanes, can leave the bowel wall denuded and ulcerated; this permits passage of enteric bacteria into the blood stream (de Brito et al., 1998; Kouroussis et al., 2000). Radiation therapy to the abdomen is another source of damage to the bowel mucosa. Bacterial and fungal infections or hypotension-
200
Nancy King
induced ischemia from sepsis may also contribute to mucosal injury (Williams & Scott, 1997). Other factors may also affect bowel integrity and increase the risk of developing NE. Steroids given as part of chemotherapeutic regimens may impair tissue healing, permit overgrowth of normal gastrointestinal flora, and alter response to infection (Aggarwal et al., 1998). Decreases in gastric acid production from malnutrition or from use of H2 blockers inhibit bactericidal action in the stomach. Consequently, more microorganisms survive passage into the gut, thereby increasing the risk of infection (Aggarwal et al., 1998). Secondary infection may occur from pathogens such as Escherichia coli (E. coli), Klebsiella, Pseudomonas, Staphylococcus, Enterobacter, Clostridium species, yeast, and less commonly from fungi (de Brito et al., 1998).
Diagnosis The clinical presentation of NE may be subtle and insidious developing over days, or sudden and acute progressing rapidly over hours as described in the case study (de Brito et al., 1998). Overwhelming septicemia may occur before the presence of significant clinical symptoms and an aggressive onset is frequently fatal (Williams & Scott, 1997). Common symptoms include fever and abdominal discomfort that is initially diffuse and progresses to localized right lower quadrant pain. Other symptoms may include nausea, vomiting, water loss or bloody diarrhea, ileus, and symptoms of systemic inflammatory response or sepsis (Gomez et al., 1998). Peritonitis and perforation may occur with little advance warning. Because of the accompanying neutropenia, leukocytosis is unlikely (Williams & Scott, 1987). NE is a diagnostic challenge as symptoms often mimic those of other abdominal conditions and complications of cancer therapy. The differential diagnosis of the neutropenic patient with abdominal pain must also include more common etiologies such as mucositis, appendicitis, pseudomembranous colitis, intussusception, bowel obstruction, and opportunistic infections (deBrito et al., 1997). Diagnostic imaging studies are essential in order to make a diagnosis of NE. The hallmark findings are cecal wall thickening and pericolic fluid collections in the presence of neutropenia
and clinical symptoms of abdominal infection (Williams & Scott, 1997). Plain film x-rays are least sensitive for diagnosing NE and studies have indicated that up to 50% of patients may have normal radiographs (deBrito et al., 1998). X-rays can be helpful for exclusion of intussusception and other more common bowel disorders. Perforation, obstruction, and pneumatosis can be easily seen on plain films (John, 1999). Because of the risk of bowel perforation and low yield of useful information, barium studies are no longer recommended (Williams & Scott, 1997). Examination of the abdomen by ultrasound is an easy and noninvasive technique to identify pseudopolypoid changes of cecal mucosa and pericolic fluid collections. Ultrasonography is an extremely useful tool for frequent progress monitoring in the child with NE because it does not involve radiation (Williams & Scott, 1997; Cartoni et al., 2001). CT scans provide the most sensitive way to look specifically for cecal wall thickening. The ability to differentiate between NE and other etiologies such as appendicitis, pseudomembranous colitis, or abscess is a major benefit of CT (deBrito et al., 1998; McNamara et al., 1986). Laboratory data are rarely helpful in diagnosis except to confirm the presence of bacteremia (de Brito et al., 1998). Blood cultures will be positive for enteric organisms in more than 50% of cases (Williams & Scott, 1997). Following data such as complete blood counts, serum chemistries, and coagulation studies is helpful in the overall evaluation of the patient. Laboratory findings may alert the health care provider to concurrent complications such as electrolyte imbalances, dehydration, disseminated intravascular coagulation associated with sepsis, and bleeding or hemorrhage in the bowel (de Brito et al., 1998).
Treatment A nonsurgical approach for treatment of NE is preferred to minimize operative risks associated with neutropenia (Song et al., 1993). Conservative management involves broad-spectrum antibiotics and supportive care including bowel rest and decompression, fluid replacement, electrolyte correction, nutritional support, and possibly inotropic blood pressure support (Williams
Neutropenic Enterocolitis
& Scott, 1997; Wade, Nava, & Douglass, 1992). Empiric antibiotic regimens must include agents for which anaerobic enteric organisms are generally sensitive. Metronidazole is commonly used in conjunction with an aminoglycoside, such as gentamicin, or amikacin, and an antipseudomonal antibiotic such as ceftazidime to provide broad-spectrum coverage (Song et al., 1998). Imipenem plus an aminoglycoside is another acceptable combination (Yaniv et al., 2000). Antifungals may be added when fevers persist in spite of broad-spectrum coverage or when the blood culture is positive for fungus. Blood cultures should be drawn before institution of antibiotics and with recurrent fever episodes to identify specific organisms and sensitivities to antimicrobials. In the case of bacteremia, subsequent blood culture specimens must be obtained until the cultures are negative. Most patients with NE will respond well without need for surgical intervention if appropriate antibiotics are instituted before overwhelming sepsis or perforation occurs (Gomez et al., 1998). Surgery becomes necessary when there is perforation of the bowel and in cases in which conservative management does not lead to clinical improvement. Surgical management most often involves resection of necrotic bowel and creation of a mucus fistula and ileostomy; peritoneal washing and drainage may be required as well (Williams & Scott, 1997; Chirletti et al., 1993). End-to-end anastomosis is sometimes done at the initial surgery, but is usually delayed when extensive peritoneal spilling of bowel contents has occurred or the patient is septic (Williams & Scott, 1997). Generally, anastomosis is possible once complete healing has taken place and the patient is no longer neutropenic (Shamberger et al., 1986). Postoperative morbidity and mortality is high because of impaired healing ability and risks for additional infection and sepsis (Starnes et al., 1986). However, surgery should not be delayed when clear indications exist (Weinberger, Hollingsworth, Feuerstein, Young, & Pizzo, 1993). Pain may be the primary presenting symptom of an acute abdominal process in the patient with neutropenia (Starnes et al., 1986); therefore, all abdominal complaints in the neutropenic child should be taken seriously. As illustrated in the case study, NE initially presents
201
with mild, diffuse, nonspecific abdominal discomfort that progresses to intense pain localized in the right lower quadrant. Pain management with adequate doses of narcotic analgesics may be necessary because peritoneal irritation can cause excruciating pain (de Brito et al., 1998). After the diagnosis of NE is made, effective pain management should be a priority and intravenous pain medications such as morphine should be titrated as necessary to maintain comfort. Signs of improvement in the clinical status of a patient with NE can usually be seen within 24 hours after adequate treatment, whether conservative or surgical, has been initiated. Children who do not show prompt signs of improvement with treatment often have a less favorable outcome. Supportive treatments continue until the patient has resolution of all abdominal symptoms and related clinical findings, has return of normal bowel motility, remains afebrile, and has documentation of negative blood cultures. Antibiotics and, when necessary, antifungal agents, should be continued for their full courses, usually 10 to 14 days.
Nursing Assessment and Management Nursing care of the child with NE requires a sound knowledge base, skill, and compassion. These children are frequently critically ill and experience rapid changes in physiologic status as the infection progresses. Nursing assessment and care is a key factor in successful management of patients with this life-threatening complication. Nurses have an advantage in patient assessment because their frequent contact with the child and family allows them to be alert to subtle alterations in the child’s baseline behavior and demeanor. NE can affect many physiologic systems; therefore, assessments need to be comprehensive and follow a head-to-toe progression to ensure that significant changes are not missed. Bearing in mind the rapidity with which clinical changes can occur, assessments should be done at frequent intervals during the shift and whenever there is an apparent change in the child’s status. Table 1 summarizes common assessment findings and potential causes. Abdominal assessment should include inspection, auscultation, palpation, and measurement of girth. Percussion is a useful technique to
Nancy King
202
TABLE 1. Common Assessment Findings in the Child with Neutropenic Enterocolitis System
Assessment Finding
Neurologic
Change in behavior, 2 level of consciousness, hypotonia
Skin and mucous membranes Cardiovascular
2 Skin turgor, dryness of oral mucous membranes, lack of tears 1 Heart rate, bounding or thready pulse, 2 blood pressure, slow capillary refill, diminished peripheral pulses, pale or ashen color, 2 peripheral perfusion, widening of pulse pressure or 2 BP, bleeding, development of petechiae 1 Respiratory rate, 2 depth of respiration, grunting, crackles, 2 respiratory effectiveness, 1 work of breathing, respiratory acidosis, 1 oxygen requirement
Respiratory
Potential Cause Exhaustion, dehydration, electrolyte imbalance, pain, hypovolemia, shock Dehydration Fever, dehydration, hypovolemia, fluid overload, impending shock, hemorrhage, systemic inflammatory response syndrome, DIC Fever, dehydration, pain, abdominal distention, fluid overload
Gastrointestinal
2 Bowel tones, 1 distention, 1 tenderness, guarding, rebound, rigidity, diarrhea/ emesis
Increasing peritoneal irritation, accumulation of ascites, ileus, perforation
Renal
2 Urine output
Musculoskeletal
Refusal to walk, reluctance to turn in bed, rigid positioning
Dehydration, hypovolemia, shock Increasing peritoneal irritation and pain
Psychosocial
Refusal to participate in previously enjoyed diversions, withdrawal, tearfulness, behavior changes
Pain, fear and anxiety, ineffective coping skills
Nursing Actions Frequent assessment of level of consciousness Assess skin turgor, condition of mucus membranes with each vital sign check Continuous cardio-respiratory monitor Frequent blood pressure monitoring Assessment of perfusion status with vital sign checks Assess for bleeding Assess breath sounds and respiratory effort/adequacy frequently Continuous pulse oximetry Respiratory support as needed with oxygen/mechanical ventilation Frequent auscultation of bowel sounds Measure abdominal girth every 2–4 hours Assess changes in complaints of abdominal discomfort Strict measurement of intake and output Observe, record, and report changes in patient’s willingness to mobilize Comfort measures Provide frequent updates to family and child regarding plan and progress Emotional support Comfort measures
DIC, Disseminated intravascular coagulation.
identify areas of density but may not be welltolerated because of pain. Increases in peritoneal inflammation are frequently reflected in the abdominal exam (Hartman, 2000). A change in the quality and intensity of abdominal discomfort is often the first and most reliable symptom of disease progression in the neutropenic patient. Consistent use of an appropriate pain assessment tool and documentation of findings is essential in following the progression of NE. Distention and rigidity of the abdomen are wor-
risome for perforation (Shamberger et al., 1986) and require immediate assessment by a physician. Assessment of the cardiovascular and hemodynamic status of the patient with presumed or confirmed NE cannot be overemphasized. Volume losses from vomiting, diarrhea, and fluid shifts can be impressive; therefore, hypovolemia and electrolyte imbalance are significant risks. Continuous cardiorespiratory monitoring in conjunction with frequent physical assessment is
Neutropenic Enterocolitis
important. Accurate monitoring of intake and output and timely replacement of fluid losses is essential. The child’s color, quality and rate of the pulse, perfusion, and capillary refill should be checked and documented frequently. Measures of hydration status should also be assessed such as urine output, condition of the mucous membranes, and skin turgor. Blood pressure is an important measurement of the body’s ability to maintain homeostasis. A widening of the pulse pressures may indicate a decline in hemodynamic stability; a dropping blood pressure is a late symptom of shock and an ominous sign. Fluid resuscitation or inotropic support of the blood pressure may become necessary, particularly when gram-negative sepsis is present (Powell, 2000). Following the fever curve is very helpful in monitoring the progress of NE and assessing the effectiveness of antibiotics, thus it is important to avoid around-the-clock administration of antipyretics. A temperature graph may be useful for identifying fever patterns. Oral rather than rectal administration of antipyretics is preferred in children who are neutropenic because of the risk of injuring the rectal mucosa, thereby creating an additional risk for bacterial invasion. Emotional support is an essential component of nursing care for the family and child. Anxiety, confusion, and fear may result when facing a serious complication of an already life-threatening process (Kinrade, 1988). Establishing and maintaining a therapeutic professional relationship will be most helpful to both the child and family (McKlindon & Barnsteiner, 1999). The nurse can solicit the concerns and observations of the child and parents, clarify misinformation or misunderstanding, respond to their questions, and support their hope. A plan for promoting the child’s comfort should be created with input from the child and family and updated frequently. Consideration of the child’s developmental level should guide all nursing plans and interventions. Of equal importance to patient assessment is documentation and communication of findings (Kinrade, 1988). For example, a small change in the abdominal girth may seem insignificant with the first measurement, but successive increases may be a signal that an ileus or ascites is developing. Charting must be detailed and complete
203
so comparisons of findings can be made. Timely communication of findings and concerns to health team members is essential to ensure early response.
Case Study Outcome Twelve hours after Karl’s symptoms started, the nurse noted a trend of widening pulse pressures and prolonged capillary refill in his nail beds. He was arousable but lethargic. His fluid losses from diarrhea had been difficult to replace because of frequent, large-volume stools. Additionally, his blood cultures were already positive for E. coli. Fluid resuscitation with two rapid infusions of normal saline at 20 mL/kg improved his blood pressure. A plain-film x-ray showed no evidence of perforation. Nursing measures included hourly intake and output measurements. Vital signs with assessment were done every 2 hours for the first 24 hours until his condition stabilized. He received packed red blood cell transfusions to maintain his hematocrit above 25 gm% and platelets to maintain his count above 20,000/mm3. His pain was managed with morphine administered by a patientcontrolled analgesia pump and dosages were adjusted based upon his pain scale scores and clinical status. Karl was afebrile 2 days after the onset of symptoms. His abdominal exam was normal by the fifth day, at which time his absolute neutrophil count had risen to 750. He continued treatment with intravenous antibiotics for 10 days. Repeat blood cultures were negative after 24 hours of antibiotics. The nurses met with Karl and his parents daily to ascertain their concerns, answer their questions, and plan his care for the day. Karl’s parents later stated that the support they received during his illness allowed them to maintain a sense of control and they felt they were a valued part of his care team. Karl recovered completely and was able to be discharged for a few days before being readmitted to resume his chemotherapy.
Summary Neutropenic enterocolitis is a life-threatening complication for children with cancer and other conditions associated with profound neutropenia. Advances in antibiotic therapy, supportive
204
Nancy King
care, and imaging techniques have improved the prognosis for many children who develop this condition; however, the risks of sepsis and bowel perforation remain significantly high. Comprehensive, frequent nursing assessment
and communication of findings in these patients is critical. Early detection and intervention may enable successful conservative treatment with antibiotics and supportive cares, thereby avoiding the significant risks associated with surgery.
References Abbasoglu, O., & Cakmakci, M. (1993). Neutropenic enterocolitis in patients without leukemia. Surgery, 113(1), 113-116. Aggarwal, V., Williams, M.D., & Beath, S.V. (1998). Gastrointestinal problems in the immunosuppressed patient. Archives of Disease in Childhood, 78(1), 5-8. Avigan, D., Richardson, P., Elias, A., Demetri, G., Shapiro, M., Schnipper, L., & Wheeler, C. (1998). Neutropenic enterocolitis as a complication of high dose chemotherapy with stem cell rescue in patients with solid tumors: A case series with a review of the literature. Cancer, 83(3), 409-414. Cartoni, C., Dragoni, F., Micozzi, A., Pescarmona, E., Mecarocci, S., Chirletti, P., Petti, M. C., Meoni, G., & Mandelli, F. (2001). Neutropenic enterocolitis in patients with acute leukemia: Prognostic significance of bowel wall thickening detected by ultrasonography. Journal of Clinical Oncology, 19(3), 756-761. Chirletti, P., Barillari, P., Sammartino, P., Cardi, M., Carona, R., Arcese, W., Petti, C., & Stipa, V. (1993). The surgical choice in neutropenic patients with hematological disorders and acute abdominal complications. Leukemia and Lymphoma, 9(3), 237-241. Cooke, J. V. (1933). Acute leukaemia in children. Journal of the American Medical Association, 101, 432-435. Daphan, C. E., Abbasoglu, O., Agalar, F., & Yagmurdur, M.C. (1999). Neutropenic enterocolitis due to dipyrone use. Australian and New Zealand Journal of Surgery, 69(9), 680-681. de Brito, D., Barton, E., Spears, K. L., Cranmer, H. H., Karp, S. J., Anglin, D., & Hutson, H. R. (1998). Acute right lower quadrant pain in a patient with leukemia. Annals of Emergency Medicine, 32(1), 98-101. Gomez, L, Martino, R., & Rolston, K. V. (1998). Neutropenic enterocolitis: Spectrum of the disease and comparison of definite and possible cases. Clinical Infectious Diseases, 27, 695-699. Hartman, G. E. (2000). Acute appendicitis. In R. E. Berhman, R. M. Kliegman, & H. B. Jenson (Eds.). Nelson textbook of pediatrics (16th ed.). Philadelphia: Saunders. Jain, Y., Arya, L. S., & Kataria, R. (2000). Neutropenic enterocolitis in children with acute lymphoblastic leukemia. Pediatric Hematology and Oncology, 17(1), 99-103. John, S. D. (1999). Advances in emergency radiology II: Trends in pediatric emergency imaging. Radiologic Clinics of North America, 37(5), 995-1034. Kinrade, L. C. (1988). Typhlitis: A complication of neutropenia. Pediatric Nursing, 14(4), 291-295.
Klein, S. G. & Adler, I. N., (2000). Radiological case of the month. Archives of Pediatrics and Adolescent Medicine, 154(6) 629-630. Kouroussis, C., Samonis, G., Androulakis, N, Souglakos, J., Voloudaki, A., Dimonpoulos, M. A., Kitsakis, T., Kakolyris, S., Kalbakis, K., & Georgoulias, V (2000). Successful conservative treatment of neutropenic enterocolitis complicating taxane-based chemotherapy: A report of five cases. American Journal of Clinical Oncology, 23(3), 309-313. McKlindon, D. & Barnsteiner, J. H. (1999). Therapeutic relationships: Evolution of the Children’s Hospital of Philadelphia model. Maternal Child Nursing, 24(5) 237-243. McNamara, M. J., Chalmers, A. G., Morgan, M., & Smith, E. W. (1986). Typhlitis in acute childhood leukaemia: Radiological features. Clinical Radiology, 37, 83-86. Powell, K. R. (2000). Sepsis and shock. In R. E. Berhman, R. M. Kliegman, & H. B. Jenson (Eds.). Nelson textbook of pediatrics (16th ed.). Philadelphia: Saunders. Shamberger, R. C., Weinstein, H. J., DeLorey, M. J., & Levey, R. H. (1986). The medical and surgical management of typhlitis in children with acute nonlymphocytic (myelogenous) leukemia. Cancer, 57(3), 603-608. Song, H. K., Kreisel, D., Canter, R., Krupnik, A. S., Stadtmauer, E. A., & Buzby G. (1998). Changing presentation and management of neutropenic enterocolitis. Archives of Surgery, 133(9), 979-982. Starnes, H. F., Moore, F. D., Mentzer, S., Osteen, R. T., Steele, G. D., & Wilson, R. E. (1986). Abdominal pain in neutropenic cancer patients. Cancer, 57(3), 616-621. Wade, D. S., Nava, H. R., & Douglass, H. O. (1992). Neutropenic enterocolitis. Clinical diagnosis and treatment. Cancer, 69(1), 17-23. Weinberger, M., Hollingsworth, H., Feuerstein, I. M., Young, N. S., & Pizzo, P. A. (1993). Successful surgical management of neutropenic enterocolitis in two patients with severe aplastic anemia. Case reports and review of the literature. Archives of Internal Medicine, 153(1), 107-113. Williams, N., & Scott, A. D. N. (1997). Neutropenic colitis: A continuing surgical challenge. The British Journal of Surgery, 84(9), 1200-1205. Yaniv, I., Fischer, S., Mor, C., Stark, B., Goshen, Y., Stein, J., Cohen, I. J., & Zaizov, R. (2000). Improved outcome in childhood B-cell lymphoma with the intensified French LMB protocol. Medical and Pediatric Oncology, 35(8), 8-12.