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  • Print publication year: 2008
  • Online publication date: August 2009

8 - Cognitive dysfunction related to chemotherapy and biological response modifiers


Chemotherapy-related cognitive dysfunction

The successful management of many cancers has been achieved largely through aggressive use of therapy, which now generally combines surgery, radiation, chemotherapy, and immunotherapy. Many of these treatment strategies, including chemotherapy, are not highly specific and therefore place normal tissues and organs at risk. While the brain is afforded some protection from systemic treatments via the blood–brain barrier, it is increasingly recognized that many agents gain access to this environment via direct and/or indirect mechanisms, potentially contributing to central nervous system (CNS) toxicity. Furthermore, treatment strategies designed to disrupt or penetrate the blood–brain barrier are being explored as treatment options for a number of cancers including primary CNS lymphoma and brain metastases (Doolittle et al., 2006). Evidence will be presented supporting the existence of both chemotherapy-related cognitive dysfunction and unique neurobehavioral/psychiatric manifestations associated with biological response modifiers generally, and interferon alpha in particular.

Incidence and nature of chemotherapy-related cognitive dysfunction

Adult patients presenting with complaints of “chemobrain” or “chemofog” typically report cognitive symptoms arising soon after initiating treatment. For many patients, these symptoms persist even after therapy is complete. It is not uncommon for many patients and providers to treat these symptoms as an expected, albeit unfortunate, side-effect of treatment. Persistent symptoms are also a cause of considerable distress for individuals who are unable to return to their previous scholastic, occupational, or social activities (or are able to do so only with significant additional mental effort).

Ahles, TA, Saykin, AJ, Noll, WWet al. (2003). The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy. Psychooncology 12: 612–619.
Alcaraz, A, Rey, C, Concha, Aet al. (2002). Intrathecal vincristine: fatal myeloencephalopathy despite cerebrospinal fluid perfusion. J Toxicol Clin Toxicol 40: 557–561.
Anderson-Hanley, C, Sherman, ML, Riggs, Ret al. (2003). Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature. J Int Neuropsychol Soc 9: 967–982.
Barton, D, Loprinzi, C (2002). Novel approaches to preventing chemotherapy-induced cognitive dysfunction in breast cancer: the art of the possible. Clin Breast Cancer 3 [Suppl. 3]: S121–S127.
Bender, CM, Yasko, JM, Kirkwood, JMet al. (2000). Cognitive function and quality of life in interferon therapy for melanoma. Clin Nurs Res 9: 352–363.
Bender, CM, Sereika, SM, Berga, SLet al. (2006). Cognitive impairment associated with adjuvant therapy in breast cancer. Psychooncology 15: 422–430.
Birgegård, G, Aapro, MS, Bokemeyer, Cet al. (2005). Cancer-related anemia: pathogenesis, prevalence, and treatment. Oncology 68 [Suppl. 1], 3–11.
Blalock, JE, Smith, EM (1980). Human leukocyte interferon: structural and biological relatedness to adrenocorticotropic hormones and endorphins. Proc Natl Acad Sci USA 77: 5972–5974.
Blalock, JE, Stanton, JD (1980). Common pathways of interferon and hormonal action. Nature 283: 406–408.
Brown, MS, Stemmer, SM, Simon, JHet al. (1998). White matter disease induced by high-dose chemotherapy: longitudinal study with MR imaging and proton spectroscopy. Am J Neuroradiol 19: 217–221.
Brown, WS, Marsh, JT, Wolcott, Det al. (1991). Cognitive function, mood and p3 latency: effects of the amelioration of anemia in dialysis patients. Neuropsychologia 29: 35–45.
Büntzel, J, Küttner, K (1998). Chemoprevention with interferon alfa and 13-cis retinoic acid in the adjunctive treatment of head and neck cancer. Auris Nasus Larynx 25: 413–418.
Capuron, L, Ravaud, A, Miller, AHet al. (2004). Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy. Brain Behav Immun 18: 205–213.
Caraceni, A, Gangeri, L, Martini, Cet al. (1998). Neurotoxicity of interferon-α in melanoma therapy: results from a randomized clinical trial. Cancer 83: 482–489.
Castellon, SA, Ganz, PA, Bower, JEet al. (2004). Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. J Clin Exp Neuropsychol 26: 955–969.
Chen, Y, Lomnitski, L, Michaelson, DMet al. (1997). Motor and cognitive deficits in apolipoprotein E-deficient mice after closed head injury. Neuroscience 80: 1255–1262.
Cirelly, R, Tyring, SK (1995). Major therapeutic uses of interferons. Clin Immunother 3: 27–87.
Clark, JW (1996). Biological response modifiers. Cancer Chemother Biol Response Modif16: 239–273.
Crandall, J, Sakai, Y, Zhang, Jet al. (2004). 13-cis-Retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice. Proc Natl Acad Sci USA 101: 5111–5116.
Cunningham, RS (2003). Anemia in the oncology patient: cognitive function and cancer. Cancer Nurs 26: 38S–42S.
Delattre, JY, Posner, JB (1995). Neurological complications of chemotherapy and radiation therapy. In Aminoff MJ (ed.). Neurology and General Medicine (2nd edn.) (pp. 421–445). New York: Churchill Livingstone.
Dieperink, E, Willenbring, M, Ho, SB (2000). Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: a review. Am J Psychiatry 157: 867–876.
Doolittle, ND, Peereboom, DM, Christoforidis, GAet al. (2006). Delivery of chemotherapy and antibodies across the blood-brain barrier and the role of chemoprotection, in primary and metastatic brain tumors: report of the Eleventh Annual Blood-Brain Barrier Consortium meeting. J Neurooncol 81: 81–91.
Eberling, JL, Wu, C, Tong-Turnbeaugh, Ret al. (2004). Estrogen- and tamoxifen-associated effects on brain structure and function. Neuroimage 21: 364–371.
Egan, MF, Goldberg, TE, Kolachana, BSet al. (2001). Effect of COMT Val108/158 met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 98: 6917–6922.
Egan, MF, Kojima, M, Callicott, JHet al. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112: 257–269.
Farkkila, M, Iivanainen, M, Roine, Ret al. (1984). Neurotoxic and other side effects of high dose interferon in amyotrophic lateral sclerosis. Acta Neurol Scand 70: 42–46.
Fliessbach, K, Urbach, H, Helmstaedter, Cet al. (2003). Cognitive performance and magnetic resonance imaging findings after high-dose systemic and intraventricular chemotherapy for primary central nervous system lymphoma. Arch Neurol 60: 563–568.
Garcia-Tena, J, Lopez-Andreu, JA, Ferris, Jet al. (1995). Intrathecal chemotherapy related myeloencephalopathy in a young child with acute lymphoblastic leukemia. Pediatr Hematol Oncol 12: 377–385.
Gilbert, MR, Armstrong, TS (1996). Neurotoxicities. In Kirkwood, J, Lotze, M, J, Yasko (eds.) Current Cancer Therapeutics (2nd edn.) (pp. 364–371). Philadelphia, PA: Current Medicine.
Goldman, LS (1994). Successful treatment of interferon alfa-induced mood disorder with nortriptyline. Psychosomatics 35: 412–413.
Green, HJ, Pakenham, KI, Headley, BCet al. (2002). Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: a randomized controlled trial. BJU Int 90: 427–432.
Groopman, JE, Itri, LM (1999). Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 91: 1616–1634.
Haykin, ME, Gorman, M, Hoff, Jet al. (2006). Diffusion-weighted MRI correlates of subacute methotrexate-related neurotoxicity. J Neurooncol 76: 153–157.
Heflin, LH, Meyerowitz, BE, Hall, Pet al. (2005). Cancer as a risk factor for long-term cognitive deficits and dementia. J Natl Cancer Inst 97: 854–856.
Honigsberger, L, Fielding, JW, Priestman, TJ (1983). Neurological effects of recombinant human interferon. Br J Med 286: 719.
Jansen, C, Miakowski, C, Dodd, Met al. (2005). Potential mechanisms for chemotherapy-induced impairments in cognitive function. Oncol Nurs Forum 32: 1151–1163.
Jenkins, VA, Shilling, V, Fallowfield, Let al. (2004). Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psychooncology 13: 61–66.
Jenkins, VA, Bloomfield, DJ, Shilling, VMet al. (2005). Does neoadjuvant hormone therapy for early prostate cancer affect cognition? Results from a pilot study. BJU Int 96: 48–53.
Jenkins, V, Shilling, V, Deutsch, Get al. (2006). A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer. Br J Cancer 94: 828–834.
Jensen, BV (2006). Cardiotoxic consequences of anthracycline-containing therapy in patients with breast cancer. Semin Oncol 33 [Suppl. 8]: S15–S21.
Johnson, SA (2006). Anthracycline-induced cardiotoxicity in adult hematologic malignancies. Semin Oncol 33 [Suppl. 8]: S22–S27.
Joshi, G, Sultana, R, Tangpong, Jet al. (2005). Free radical mediated oxidative stress and toxic side effects in brain induced by the anti cancer drug adriamycin: insight into chemobrain. Free Radic Res 39: 1147–1154.
Juengling, FD, Ebert, D, Gut, Oet al. (2000). Prefrontal cortical hypometabolism during low-dose interferon alpha treatment. Psychopharmacology 152: 383–389.
Kayl, AE, Wefel, JS, Meyers, CA (2006). Chemotherapy and cognition: effects, potential mechanisms and management. Am J Ther 13: 362–369.
Keime-Guibert, F, Napolitano, M, Delattre, JY (1998). Neurological complications of radiotherapy and chemotherapy. J Neurol 245: 695–708.
Kim, YA, Chung, HC, Choi, HJet al. (2006). Intermediate dose 5-fluorouracil-induced encephalopathy. Jpn J Clin Oncol 36: 55–59.
Knobf, MT (2006). Reproductive and hormonal sequelae of chemotherapy in women. Am J Nurs 106 [Suppl. 3]: 60–65.
Krajinovic, M, Robaey, P, Chiasson, Set al. (2005). Polymorphisms of genes controlling homocysteine levels and IQ score following treatment for childhood ALL. Pharmacogenomics 6: 293–302.
Krause, I, Valesini, G, Scrivo, Ret al. (2003). Autoimmune aspects of cytokine and anticytokine therapies. Am J Med 115: 390–397.
Kreukels, BPC, Schagen, SB, Ridderinkhof, KRet al. (2006). Effects of high-dose and conventional-dose adjuvant chemotherapy in patients with breast cancer: an electrophysiologic study. Clin Breast Cancer 7: 67–78.
Lacosta, S, Merali, Z, Anisman, H (2000). Central monoamine activity following acute and repeated systemic interleukin-2 administration. Neuroimmunomodulation 8: 83–90.
Largillier, R, Etienne-Grimaldi, MC, Formento, JLet al. (2006). Pharmacogenetics of capecitabine in advanced breast cancer patients. Clin Cancer Res 12: 5496–5502.
Lee, BN, Dantzer, R, Langley, KEet al. (2004). A cytokine-based neuroimmunologic mechanism of cancer-related symptoms. Neuroimmunomodulation 11: 279–292.
Linnebank, M, Pels, H, Klecza, Net al. (2005). MTX-induced white matter changes are associated with polymorphisms of methionine metabolism. Neurology 64: 912–913.
Lipp, HP (1999). Neurotoxicity (including sensory toxicity) induced by cytostatics. In Lipp, HP (ed.). Anticancer Drug Toxicity: Prevention, Management, and Clinical Pharmacokinetics (pp. 431–453). New York: Marcel Dekker, Inc.
Lipshultz, SE (2006). Exposure to anthracyclines during childhood causes cardiac injury. Semin Oncol 33 [Suppl. 8]: 8–14.
Madhyastha, S, Somayaji, SN, Rao, MSet al. (2002). Hippocampal brain amines in methotrexate-induced learning and memory deficit. Can J Physiol Pharmacol 80: 1076–1084.
Malek-Ahmadi, P, Ghandour, E (2004). Bupropion for treatment of interferon-induced depression. Ann Pharmacother 38: 1202–1205.
Malik, UR, Makower, DF, Wadler, S (2001). Interferon-mediated fatigue. Cancer 92 [Suppl]: 1664–1668.
Massa, E, Madeddu, C, Lusso, MRet al. (2006). Evaluation of the effectiveness of treatment with erythropoietin on anemia, cognitive functioning and functions studied by comprehensive geriatric assessment in elderly cancer patients with anemia related to cancer chemotherapy. Crit Rev Oncol Hematol 57: 175–182.
Mayr, N, Zeitlhofer, J, Deecke, Let al. (1999). Neurological function during long-term therapy with recombinant interferon alpha. J Clin Neurosci 11: 343–348.
McAllister, TW, Ahles, TA, Saykin, AJet al. (2004). Cognitive effects of cytotoxic cancer chemotherapy: predisposing risk factors and potential treatments. Curr Psychiatr Rep 6: 364–371.
McEwen, BS, Alves, SE (1999). Estrogen actions in the central nervous system. Endocr Rev 20: 279–307.
Menzies, R, Phelps, C, Wiranowska, Met al. (1996). The effect of interferon-alpha on the pituitary-adrenal axis. J Interferon Cytokine Res 16: 619–629.
Meyers, CA, Valentine, AD (1995). Neurological and psychiatric effects of immunological therapy. CNS Drugs 3: 56–68.
Meyers, CA, Scheibel, RS, Forman, AD (1991). Persistent neurotoxicity of systemically administered interferon-alpha. Neurology 41: 672–676.
Meyers, CA, Kudelka, AP, Conrad, CAet al. (1997). Neurotoxicity of CI-980, a novel mitotic inhibitor. Clin Cancer Res 3: 419–422.
Meyers, CA, Weitzner, MA, Valentine, ADet al. (1998). Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. J Clin Oncol 16: 2522–2527.
Meyers, JN, Whiteside, TL (1996). Immunotherapy of squamous cell carcinoma of the head and neck. In Meyers, EN, Suen, JY (eds.). Cancer of the Head and Neck (pp. 805–817). Philadelphia, PA: WB Saunders Company.
Mihich, E (2000). Historical overview of biologic response modifiers. Cancer Invest 18: 456–466.
Moleski, M (2000). Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. Arch Clin Neuropsychol 15: 603–630.
Molina, JR, Barton, DL, Loprinzi, CL (2005). Chemotherapy-induced ovarian failure. Drug Safety 28: 401–416.
Moor, BD (2005). Neurocognitive outcomes in survivors of childhood cancer. J Pediatr Psychol 30: 51–63.
Mottet, N, Prayer-Galetti, T, Hammerer, Pet al. (2006). Optimizing outcomes and quality of life in the hormonal treatment of prostate cancer. BJU Int 98: 20–27.
Musselman, DL, Lawson, DH, Gumnick, JFet al. (2001). Paroxetine for the prevention of depression induced by high-dose interferon alpha. N Engl J Med 344: 961–966.
National Institutes of Health (2003). Biological Therapy. Treatments that use your Immune System to Fight Cancer. [Brochure]. NIH Publication No. 03–5406.
Nemeroff, CB, Krishnan, KR, Reed, Det al. (1992). Adrenal gland enlargement in major depression: a computed tomographic study. Arch Gen Psychiatry 49: 384–387.
Okcu, MF, Selvan, M, Wang, Let al. (2004). Glutathione S-transferase polymorphisms and survival in primary malignant glioma. Clin Cancer Res 10: 2618–2625.
O'Shaughnessy, JA, Svetislava, JV, Holmes, FAet al. (2005). Feasibility of quantifying the effects of epoetin alpha therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. Clin Breast Cancer 5: 439–446.
Pavol, MA, Meyers, CA, Rexer, JLet al. (1995). Pattern of neurobehavioral deficits associated with interferon alpha therapy for leukemia. Neurology 45: 947–950.
Penson, RT, Kronish, K, Duan, Zet al. (2000). Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNF-alpha in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel. Int J Gynecol Cancer 1: 33–41.
Pusztai, L, Mendoza, TR, Reuben, JMet al. (2004). Changes in plasma level of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine 25: 94–102.
Quinn, CT, Kamen, BA (1996). A biochemical perspective of methotrexate neurotoxicity with insight on nonfolate rescue modalities. J Invest Med 44: 522–530.
Roe, CM, Behrens, MI, Xiong, Cet al. (2005). Alzheimer disease and cancer. Neurology 64: 895–898.
Rottenberg, DA (ed.) (1991). Neurological Complications of Cancer Treatment. Boston, MA: Butterworth-Heinemann.
Saykin, AJ, Ahles, TA, McDonald, BC (2003). Mechanisms of chemotherapy-induced cognitive disorders: neuropsychological, pathophysiological, and neuroimaging perspectives. Semin Clin Neuropsychiatry 8: 201–216.
Schaefer, M, Engelbrecht, MA, Gut, Oet al. (2002). Interferon alpha (IFN-α) and psychiatric syndromes: a review. Prog Neuropsychopharmacol Biol Psychiatry 26: 731–746.
Schaefer, M, Schwiger, M, Pich, Met al. (2003). Neurotransmitter changes by interferon-alpha and therapeutic implications. Pharmacopsychiatry 36 [Suppl. 3]: S203–S206.
Schagen, SB, Muller, MJ, Boogerd, Wet al. (2002). Cognitive dysfunction and chemotherapy: neuropsychological findings in perspective. Clin Breast Cancer 3 [Suppl]: S100–S108.
Scheibel, RS, Valentine, AD, O'Brien, Set al. (2004). Cognitive dysfunction and depression during treatment with interferon alpha and chemotherapy. J Neuropsychiatry Clin Neurosci 16: 1–7.
Schneiderman, B (2004). Hippocampal volumes smaller in chemotherapy patients. Lancet Oncol 5: 202.
Shah, RR (2005). Mechanistic basis of adverse drug reactions: the perils of inappropriate dose schedules. Expert Opinion Drug Safety 4: 103–128.
Shapiro, CL, Recht, A (2001). Drug therapy – side effects of adjuvant treatment of breast cancer. New Engl J Med 344: 1997–2008.
Sheline, GE, Wara, WM, Smith, V (1980). Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phys 6: 1215–1228.
Shilling, V, Jenkins, V, Morris, Ret al. (2005). The effects of adjuvant chemotherapy on cognition in women with breast cancer – preliminary results of an observational longitudinal study. Breast 14: 142–150.
Shin, DM, Khuri, FR, Murphy, Bet al. (2001). Combined interferon-alpha, 13-cis-retinoic acid, and alpha tocopherol in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase II trial. J Clin Oncol 19: 3010–3017.
Shin, DM, Glisson, BS, Khuri, FRet al. (2002). Phase II and biological study of interferon alpha, retinoic acid, and cisplatin in advanced squamous cell skin cancer. J Clin Oncol 20: 364–370.
Shuper, A, Stark, B, Kornreich, Let al. (2000). Methotrexate treatment protocols and the central nervous system: significant cure with significant neurotoxicity. J Child Neurol 15: 573–580.
Silverman, DH, Dy, CJ, Castellon, SAet al. (2007). Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. Breast Cancer Res Treat 103(3): 303–311.
Smedley, H, Katrak, M, Sikora, Ket al. (1983). Neurological effects of recombinant interferon alpha. Br Med J 286: 262–264.
Smith, A, Tyrrell, D, Coyle, Ket al. (1988). Effects of interferon alpha on performance in man: a preliminary report. Psychopharmacology 96: 414–416.
Spiegel, RJ (1989). The alpha interferons: clinical overview. Urology 34: 75–79.
Staat, K, Segatore, M (2005). The phenomenon of chemo brain. Clin J Oncol Nurs 9: 713–721.
Steinherz, LJ, Yahalom, J (1993). Cardiac complications of cancer therapy. In DeVita, VT, Hellman, S, Rosenberg, SA (eds.) Cancer Principles and Practice of Oncology (4th edn.) (pp. 2370–2385). Philadephia, PA: J.B. Lippincott Company.
Strite, D, Valentine, AD, Meyers, CA (1997). Manic episodes in two patients treated with interferon alpha. J Neuropsychiatry 9: 273–276.
Sul, JK, DeAngelis, LM (2006). Neurologic complications of cancer chemotherapy. Semin Oncol 33: 324–332.
Taphoorn, MJB, Klein, M (2004). Cognitive deficits in adult patients with brain tumors. Lancet Neurol 3: 159–168.
Taylor, JL, Grossberg, SE (1998). The effects of interferon-α on the production and action of other cytokines. Semin Oncol 25 [Suppl. 1]: S3–S29.
Tompkins, WA (1999). Immunomodulation and therapeutic effects of the oral use of interferon-α: mechanism of action. J Interferon Cytokine Res 19: 817–828.
Tsavaris, N, Kosmas, C, Vadiaka, Met al. (2002). Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes. Br J Cancer 87: 21–27.
Valentine, AD, Meyers, CA (2005). Neurobehavioral effects of interferon therapy. Curr Psychiatry Rep 7: 391–395.
Valentine, AD, Meyers, CA, Talpaz, M (1995). Treatment of neurotoxic side effects of interferon-alpha with naltrexone. Cancer Invest 13: 561–566.
Valentine, AD, Meyers, CA, Kling, MAet al. (1998). Mood and cognitive side effects of interferon-α therapy. Semin Oncol 25: 39–47.
Wagner, LI, Sweet, JJ, Desa, Jet al. (2005). Prechemotherapy hemoglobin (Hgb) and cognitive impairment among breast cancer patients. J Clin Oncol 23: 760S.
Wefel, JS, Meyers, CA (2005). Cancer as a risk factor for dementia: a house built on shifting sand. J Natl Cancer Inst 97: 788–789.
Wefel, JS, Lenzi, R, Theriault, Ret al. (2004a). “Chemobrain” in breast cancer? A prologue. Cancer 101: 466–475.
Wefel, JS, Lenzi, R, Theriault, Ret al. (2004b). The cognitive sequelae of standard dose adjuvant chemotherapy in women with breast cancer: results of a prospective, randomized, longitudinal trial. Cancer 100: 2292–2299.
Weiss, RB, Vogelzang, NJ (1993). Miscellaneous toxicities. In DeVita, VT, Hellman, S, Rosenberg, SA (eds.) Cancer Principles and Practice of Oncology (4th edn.) (pp. 2349–2358). Philadelphia, PA: JB Lippincott Company.
Wood, LJ, Nail, LM, Gilster, Aet al. (2006). Cancer chemotherapy-related symptoms: evidence to suggest a role for proinflammatory cytokines. Oncol Nurs Forum 33: 535–542.
Yaffe, K, Sawaya, G, Lieberburg, Iet al. (1998). Estrogen therapy in postmenopausal women effects of cognitive function and dementia. J Am Med Assoc 279: 688–695.
Yoshikawa, E, Matsuoka, Y, Inagaki, Met al. (2005). No adverse effects of adjuvant chemotherapy on hippocampal volume in Japanese breast cancer survivors. Breast Cancer Res Treat 92: 81–84.
Zaloga, GP, Bhatt, B, Marik, P (2001). Critical illness and systemic inflammation. In Becker, KL (ed.) Endocrinology and Metabolism (3rd edn.) (pp. 2068–2076). Philadelphia, PA: Lippincott Williams & Wilkins.