Successful treatments with polymyxin B hemoperfusion and recombinant human thrombomodulin for fulminant Clostridium difficile-associated colitis with septic shock and disseminated intravascular coagulation: a case report
© The Author(s). 2016
Received: 13 May 2016
Accepted: 1 July 2016
Published: 28 July 2016
Clostridium difficile (CD)‐associated colitis (CDAC) is endemic and a common nosocomial enteric disease encountered by surgeons in modern hospitals due to prophylactic or therapeutic antibiotic therapies. Currently, the incidence of fulminant CDAC, which readily causes septic shock followed by multiple organ dysfunction syndromes, is increasing. Fulminant CDAC requires surgeons to perform a prompt surgery, such as subtotal colectomy, to remove the septic source. It is known that fulminant CDAC is caused by the shift from an inflammatory response at a local mucosal level to a general systemic inflammatory reaction in which CD toxin-induced mediators’ cascades disseminate. Recently, it has been proven that polymyxin B hemoperfusion (PMX-HP) improves septic shock and recombinant human thrombomodulin (rhTM) controls disseminated intravascular coagulation (DIC). In addition, clinically and basically, it has been shown that these treatments can control serous chemical mediators. Therefore, it is considered that these treatments are promising ones for patients with fulminant CDAC. In the current report, we present that these treatments without surgery contributed to the improvement of sepsis due to fulminant CDAC.
We encountered a case who developed fulminant CDAC with septic shock and DIC after laparoscopic gastrectomy for gastric cancer. At admission to the intensive care unit, his APACHE II score was 22, which indicated an estimated risk of hospital death of 42.4 %. Our therapies were not the subtotal colectomy to remove septic sources but the combination treatments with both PMX-HP and rhTM. These combination therapies resulted in excellent outcomes, namely the dramatic improvement of septic shock and DIC and the patient’s survival. We speculate that these combination therapies completely inhibit the CD toxin-induced mediators’ cascades and correspond to the removal of septic sources.
We recommend both PMX-HP and rhTM for patients who develop fulminant CDAC with septic shock and DIC to increase the survival benefit and replace the need for surgical treatment.
Clostridium difficile (CD)-associated colitis (CDAC), which is one of the common nosocomial enteric diseases encountered by surgeons, is typically due to the exposure of antibiotics and consequently endemic disease in modern hospitals [1–3]. Recently, the incidence of fulminant CDAC, which readily causes septic shock followed by multiple organ dysfunction syndromes (MODS), is increasing [4–7]. Fulminant CDAC often requires surgeons to perform a prompt invasive surgical treatment, such as a subtotal colectomy, in order to remove the septic source and improve the patient’s fatal situation [7–19].
Recently, it has been proven that polymyxin B hemoperfusion (PMX-HP) improves septic shock [20–23] and recombinant human thrombomodulin (rhTM) controls disseminated intravascular coagulation (DIC) [24–29]. In addition, clinically and basically it has been shown that these treatments can control serous chemical mediators. On the other hand, it is known that fulminant CDAC with MODS is caused by the shift from an inflammatory response at a local mucosal level to a general systemic inflammatory reaction in which CD toxin-induced mediators’ cascades disseminate [30–36]. Therefore, it is considered that these treatments are promising ones for patients with fulminant CDAC.
In the current report, we present that these treatments without surgery contributed to the improvement of sepsis due to fulminant CDAC.
Vital signs, APACHE II score, and laboratory data at the time of ICU transfer
Body temperature (°C)
Symbolic blood pressure (mmHg)
Median blood pressure (mmHg)
Administration of dopamin (γ)
T. bil (mg/dl)
Heart rate (/min)
Respiratory rate (/min)
Urine output (ml/h)
Glasgow coma scale
APACHE II score
Estimated risk of hospital death (%)
Currently, CDAC is endemic and a common nosocomial enteric disease encountered by surgeons in modern hospitals due to prophylactic or therapeutic antibiotic therapies [1–3]. Recently, both the incidence and the severity of CDAC have been increasing, and one possible explanation for these increases is the emergence of highly toxigenic and lethal strains of CD [4–7]. The above shows the need for surgeons to consider more serious treatment against CDAC. In fulminant CDAC, which has a higher lethal rate, it is especially necessary for surgeons to promptly decide whether or not to perform an invasive surgical treatment, such as subtotal colectomy, which means the removal of the septic sources and probable improvement of the patients’ ill condition [7–19].
In our case that suddenly developed fulminant CDAC with septic shock requiring vasopressor agents and MODS composed of DIC and ARF, prompt surgical treatment in order to remove the septic sources was recommended. However, we alternatively treated the patient with both PMX-HP and rhTM therapies. The reason for having chosen these treatments is as follows: (1) there was neither colonic perforation nor toxic megacolon, which absolutely requires surgery; (2) PMX-HP is an effective extracorporeal blood purification treatment for improving septic shock ; and (3) rhTM can effectively inhibit systemic dissemination of intravascular coagulation [24–29]. The combination therapies produced excellent outcomes in this case, namely the dramatic improvement of septic shock and DIC, the inhibition of MODS progression, and the patient’s survival. We speculate that the two below-mentioned factors corresponded to the removal of the septic source, namely as result of the surgical treatment. First, oral VCM medication could suppress CD’s proliferation and the further production of CD toxins. Second, both PMX-HP and rhTM could completely inhibit the CD toxin-induced mediators’ cascades. This notion is based on the following evidence. First, fulminant CDAC with MODS is caused by the shift from an inflammatory response at a local mucosal level to a general systemic inflammatory reaction in which CD toxin-induced mediators’ cascades disseminate [30–36]. Second, although PMX-HP removes circulating endotoxin by adsorption and theoretically prevents the progression of the biological cascade of sepsis, several studies and published reports have demonstrated that PMX-HP can reduce the plasma levels of cytokines and sepsis-related factors, namely TNF-α, IL-6, IL-10, N-arachidonoylethanolamine (AEA), 2-arachidonoyl glycerol (2-AG), and high-mobility group box-1 (HMGB-1) [21, 23, 38, 39]. Indeed, there were case reports published which showed that PMX-HP decreases the serum levels of endogenous cannabinoids (anandamide and 2-AG) and inflammatory cytokine (IL-6) in parallel with the clinical improvement of fulminant CDAC [40, 41]. Third, many studies and fundamental researches have shown that rhTM also has an anti-inflammatory ability through both the activated protein C and the lectin-like domain-dependent pathway [42–46]. In particular, the thrombin-rhTM complex demonstrates an anti-inflammatory ability through neutralizing HMGB-1 [47, 48], which is known to be a mediator of lethality and is released from necrotic cells or macrophages/activated dendritic cells with potent pro-inflammatory function, which in turn causes shock or MODS when being disseminated in the systemic circulation [49–51]. Finally, septic shock and MODS in our case were not induced by endotoxemia or bacteremia, and a dramatic improvement was observed immediately after the initiation of the combination therapies.
Both PMX-HP and rhTM therapies for patients who develop fulminant CDAC with septic shock and DIC can provide survival benefits and replace the need for invasive surgical treatments to remove the septic sources.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
APACHE II, Acute Physiology and Chronic Health Evaluation II; BT, body temperature; CD, Clostridium difficile; CDAC, Clostridium difficile-associated colitis; CHDF, continuous hemodiafiltration; CRP, C-reactive protein; DIC, disseminated intravascular coagulation; FDP, fibrin degradation product; MODS, multiple organ dysfunction syndromes; PMX-HP, polymyxin B hemoperfusion; rhTM, recombinant human thrombomodulin; SBP, systolic blood pressure; VCM, vancomycin; WBC, white blood cell
The authors thank Dr. Brian Quinn for the assistance in editing the manuscript.
SY contributed in writing the paper and supervised the study. YD, YM, and IM supervised the study. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- McFarland LV, Mulligan ME, Kwok RY, et al. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med. 1989;320:204–10.View ArticlePubMedGoogle Scholar
- Gerding DN, Johnson S, Peterson LR, et al. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol. 1995;16:459–77.View ArticlePubMedGoogle Scholar
- Wiesen P, Van Gossum A, Preiser JC. Diarrhoea in the critically ill. Curr Opin Crit Care. 2006;12:149–54.View ArticlePubMedGoogle Scholar
- Pepin J, Valiquette L, Alary ME, et al. Clostridium difficile-associated diarrhea in region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ. 2004;171:466–72.View ArticlePubMedPubMed CentralGoogle Scholar
- Warny M, Pepin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet. 2005;366:1079–84.View ArticlePubMedGoogle Scholar
- Chernak E, Johnson CC, Weltman A, Wiggs L, Killgore G, Thompson A, LeMaile-Williams M, Tan E, Lewis FM. Severe Clostridium difficile-associated disease in populations previously at low risk―four states, 2005. MMWR Morb Mortal Wkly Rep. 2005;54(47):1201–1205.Google Scholar
- Lamontagne F, Labbe AC, Haeck O, et al. Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann Surg. 2007;171:47–8.Google Scholar
- Synnott K, Mealy K, Merry C, et al. Timing of surgery for fulminant pseudomembranous colitis. Br J Surg. 1998;85:229–31.View ArticlePubMedGoogle Scholar
- Dallal RM, Harbrecht BG, Boujoukas AJ, et al. Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications. Ann Surg. 2002;235:363–72.View ArticlePubMedPubMed CentralGoogle Scholar
- Longo WE, Mazuski JE, Virgo KS, et al. Outcome after colectomy for Clostridium difficile colitis. Dis Colon Rectum. 2004;47:1620–6.View ArticlePubMedGoogle Scholar
- Koss K, Clark MA, Sanders DS, et al. The outcome of surgery in fulminant Clostridium difficile colitis. Colorectal Dis. 2006;8:149–54.View ArticlePubMedGoogle Scholar
- Byrn JC, Maun DC, Gingold DS, et al. Predictors of mortality after colectomy for fulminant Clostridium difficile colitis. Arch Surg. 2008;143:150–4.View ArticlePubMedGoogle Scholar
- Ali SO, Weich JP, Dring RJ. Early surgical intervention for fulminant pseudomembranous colitis. Am Surg. 2008;74:20–6.PubMedGoogle Scholar
- Sailhamer EA, Carson K, Chang Y, et al. Fulminant Clostridium difficile colitis: patterns of care and predictors of mortality. Arch Surg. 2009;144:433–9.View ArticlePubMedGoogle Scholar
- Christopher WS, Mario RV, James R, et al. Early colectomy may be associated with improved survival in fulminant Clostridium difficile colitis: an 8-year experience. Am J Surg. 2009;197:302–7.View ArticleGoogle Scholar
- Parag B, Celia MD. Surgical aspects of fulminant Clostridium difficile Colitis. Am J Surg. 2010;200:131–5.View ArticleGoogle Scholar
- Osman KA, Ahmed MH, Hamad MA, et al. Emergency colectomy for fulminant Clostridium difficile colitis: striking the right balance. Scand J Gastroenterol. 2011;46:1222–7.View ArticlePubMedGoogle Scholar
- Bhangu A, Nepogodiev D, Gupta A, et al. Systematic review and meta-analysis of outcomes following emergency surgery for Clostridium difficile colitis. Br J Surg. 2012;99:1501–13.View ArticlePubMedGoogle Scholar
- Andrew JK, Alexey M. Current status of surgical treatment for fulminant Clostridium difficile colitis. World J Gastrointest Surg. 2013;5(6):167–72.View ArticleGoogle Scholar
- Cruz DN, Perazella MA, Bellomo R, et al. Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systemic review. Crit Care. 2007;1:R47.View ArticleGoogle Scholar
- Shimizu T, Hanasawa K, Sato K, et al. The clinical significance of serum procalcitonin levels following direct hemoperfusion with polymyxin B-immobilized fiber column in septic patients with colorectal perforation. Eur Surg. 2009;42:109–17.View ArticleGoogle Scholar
- Cruz DN, Antonelli M, Fumagalli R, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. 2009;301(23):2445–52.View ArticlePubMedGoogle Scholar
- Zagli G, Bonizzoli M, Spina R, et al. Effects of hemoperfusion with an immobilized polymyxin-B fiber column on cytokine plasma levels in patients with abdominal sepsis. Minerva Anestesiol. 2010;76:1–8.Google Scholar
- Maruyama I. Recombinant thrombomodulin and activated protein C in the treatment of disseminated intravascular coagulation. Thromb Haemost. 1999;82:718–21.PubMedGoogle Scholar
- Mohri M, Sugimoto E, Sato M, et al. The inhibitory effect of recombinant human soluble thrombomodulin on initiation and extension of coagulation—a comparison with other anticoagulants. Thromb Haemost. 1999;82:1687–93.PubMedGoogle Scholar
- Esmon CT. The interactions between inflammation and coagulation. Br J Haematol. 2005;131:417–30.View ArticlePubMedGoogle Scholar
- Saito H, Maruyama I, Shimazaki S, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of phase III, randomized, double-blind clinical trial. J Thromb Haemost. 2007;5(1):31–41.View ArticlePubMedGoogle Scholar
- Yamakawa K, Fujimi S, Mohri T, et al. Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study. Crit Care. 2011;15:R123.View ArticlePubMedPubMed CentralGoogle Scholar
- Aikawa N, Shimazaki S, Yamamoto Y, et al. Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: subanalysis from the phase 3 trial. SHOCK. 2011;35(4):349–54.View ArticlePubMedGoogle Scholar
- Lamontagne F, Labbe AC, Haceck O, et al. Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann Surg. 2007;245:267–72.View ArticlePubMedPubMed CentralGoogle Scholar
- Flegel WA, Muller F, Daubener W, et al. Cytokine response by human monocytes to Clostridium difficile toxin A and toxin B. Infect Immun. 1991;59:3659–66.PubMedPubMed CentralGoogle Scholar
- Castagliuolo I, Keates AC, Wang CC, et al. Clostridium difficile toxin A stimulates macrophage-inflammatory protein-2 production in rat intestinal epithelial cells. J Immunol. 1998;160:6039–45.PubMedGoogle Scholar
- Bianco M, Fedele G, Quattrini A, et al. Immunomodulatory activities of surface-layer proteins obtained from epidemic and hypervirulent Clostridium difficile strain. J Med Microbiol. 2011;60:1162–7.View ArticlePubMedGoogle Scholar
- Melo-Filho A, Souza M, Lyerly D, et al. Role of tumor necrosis factor and nitric oxide in the cytotoxic effects of Clostridium difficile toxin A and toxin B on macrophages. Toxicon. 1997;35:743–52.View ArticlePubMedGoogle Scholar
- Cunney R, Magee C, McNamara E, et al. Clostridium difficile colitis associated with chronic renal failure. Nephrol Dial Transplant. 1998;13:2842–6.View ArticlePubMedGoogle Scholar
- Dobson G, Hickey C, Trinder J. Clostridium difficile colitis causing toxic megacolon, severe sepsis and multiple organ dysfunction syndrome. Intensive Care Med. 2003;29:1030.View ArticlePubMedGoogle Scholar
- Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13(10):818–29.View ArticlePubMedGoogle Scholar
- Sakamoto Y, Mashiko K, Matumoto H, et al. Relationship between effect of polymyxin B-immobilized fiber and high-mobility group box-1 protein in septic shock patients. ASAIO J. 2007;53:324–8.View ArticlePubMedGoogle Scholar
- Sakamoto Y, Mashiko K, Obata T, et al. Effects of polymyxin B-immobilized fiber treatment on postoperative septic shock evaluated from various sepsis relation factors and various cytokines using multiple suppression array system. Jpn J Crit Endotoxiemia. 2010;14:97–103.Google Scholar
- Kimura Y, Sato K, Tokuda H, et al. Effects of combination therapy with direct hemoperfusion using polymyxin B-immobilized fiber and oral vancomycin on fulminant pseudomembranous colitis with septic shock. Dig Dis Sci. 2007;52:675–8.View ArticlePubMedGoogle Scholar
- Kimura Y, Sato K, Tokuda H, et al. Combination therapy with direct hemoperfusion using polymyxin B-immobilized fiber and oral vancomycin improves fulminant pseudomembranous colitis by reducing the elevated endogenous cannabinoids and inflammatory cytokines: report of a case. Hepato- Gastroenterology. 2008;55:956–8.PubMedGoogle Scholar
- Esmon CT. Coagulation and inflammation. J Endotoxin Res. 2003;9(3):192–8.View ArticlePubMedGoogle Scholar
- Esmon CT. Crosstalk between inflammation and thrombosis. Maturitas. 2004;47(4):305–14.View ArticlePubMedGoogle Scholar
- Shimizu S, Gabazza EC, Taguchi O, et al. Activated protein C inhibits the expression of platelet-derived growth factor in the lung. Am J Respir Crit Care Med. 2003;167:1416–26.View ArticlePubMedGoogle Scholar
- Suzuki K, Gabazza EC, Hayashi T, et al. Protective role of activated protein C in lung and airway remodeling. Crit Care Med. 2004;32 Suppl 5:S262–5.View ArticlePubMedGoogle Scholar
- Van de Wouwer M, Collen D, Conway EM. Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol. 2004;24(8):1374–83.View ArticlePubMedGoogle Scholar
- Abeyama K, Stern DM, Ito Y, et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel anti-inflammatory mechanism. J Clin Invest. 2005;115(5):1267–74.View ArticlePubMedPubMed CentralGoogle Scholar
- Ito T, Kawahara K, Okamoto K, et al. Proteolytic cleavage of high mobility group box 1 protein by thrombin-thrombomodulin complexes. Arterioscler Thromb Vasc Biol. 2008;28:1825–30.View ArticlePubMedGoogle Scholar
- Bianchi ME, Manfredi AA. High-mobility group box 1(HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev. 2007;220:34–46.View ArticleGoogle Scholar
- Wang H, Bloom O, Zhang M, et al. HMG1 as a late mediator of endotoxin lethality in mice. Science. 1999;285(5425):248–51.View ArticlePubMedGoogle Scholar
- Ito T, Kawahara K, Nakamura T, et al. High-mobility group box 1 protein promotes development of microvascular thrombosis in rats. J Thromb Haemost. 2007;5(1):109–16.View ArticlePubMedGoogle Scholar