Secondary peritonitis in cirrhosis: “Oil in fire”
Authors: Reiner Wiest, Juergen Schoelmerich
Journal: Journal of Hepatology (2009)

Spontaneous bacterial peritonitis (SBP) is the most common type of infection in cirrhosis and its diagnostic criteria, risk factors, and therapeutic algorithms have been defined by consensus [[1]Rimola A. Garcia-Tsao G. Navasa M. Piddock L.J. Planas R. Bernard B. et al.Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.J Hepatol. 2000; 32: 142-153Abstract Full Text Full Text PDF PubMed Scopus (877) Google Scholar]. In contrast, there is large paucity of clinical investigations on secondary peritonitis in liver cirrhosis in the last two decades and diagnostic markers for early suspicion as well as parameters determining outcome are less clear. Peritonitis can be secondary to perforation or acute inflammation of intra-abdominal organs, abdominal wall infections or previous abdominal surgical procedures or trauma. Except for the latter two, in which the precise nature of peritoneal infection usually is obvious, the differential diagnosis between SBP and secondary peritonitis can be very difficult. In this issue of the Journal of Hepatology, Soriano and co-workers present a retrospective investigation performed in two tertiary hospitals in Spain, extending over an observation period of seven years [[2]Soriano G. Castellote J. Álvarez C.E. Girbau A. Gordillo J. Baliellas C. et al.Secondary bacterial peritonitis in cirrhosis: A retrospective study of clinical and analytical characteristics, diagnosis and management.J Hepatol. 2010; 52: 39-44Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar] that helps to re-appraise this important but often neglected clinical issue. In fact, the observed mortality of two out of three cirrhotic patients developing secondary peritonitis dying during hospitalization is reported to be significantly higher than in patients with SBP. Mortality found in the latter group (26.4%) is comparable to previous investigations, but could have been improved by more a consequent use of albumin [[3]Sort P. Navasa M. Arroyo V. Aldeguer X. Planas R. Ruiz-Del-Arbol L. et al.Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.N Engl J Med. 1999; 341: 403-409Crossref PubMed Scopus (1293) Google Scholar]; thus, further emphasizing the differences in severity of disease between the two entities. With respect to the frequency of secondary peritonitis, in this largest reported cohort so far 1.25 episodes/year are diagnosed and thus represent only 4.5% of all peritonitis in cirrhotic ascitic patients seen at one of the participating institutions. These data confirm the rarity of secondary peritonitis reported earlier [[4]Akriviadis E.A. Runyon B.A. Utility of an algorithm in differentiating spontaneous from secondary bacterial peritonitis.Gastroenterology. 1990; 98: 127-133Abstract PubMed Google Scholar] although others have reported that up to 15% of cirrhotic patients with peritonitis may have secondary causes [[5]Hoefs J.C. Runyon B.A. Spontaneous bacterial peritonitis.Dis Mon. 1985; 31: 1-48Abstract Full Text PDF PubMed Scopus (192) Google Scholar]. SBP is shown to occur in more advanced stages of disease as compared to secondary peritonitis. This reflects the well-known observation that SBP develops selectively in patients with low ascitic protein levels with increasing incidence dependent on further additional risk factors such as bilirubin >3.2 mg/dL and platelet count <98.000/mm3[6Guarner C. Sola R. Soriano G. Andreu M. Novella M.T. Vila M.C. et al.Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels.Gastroenterology. 1999; 117: 414-419Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 7Fernandez J. Navasa M. Planas R. Montoliu S. Monfort D. Soriano G. et al.Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis.Gastroenterology. 2007; 133: 818-824Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar]. In contrast, secondary peritonitis develops independently from the presence and/or severity of cirrhosis. The observed mortality in cirrhotic patients developing secondary peritonitis is clearly higher than reports in non-cirrhotic patient groups, usually remaining below 30% [[8]Evans H.L. Raymond D.P. Pelletier S.J. Crabtree T.D. Pruett T.L. Sawyer R.G. Diagnosis of intra-abdominal infection in the critically ill patient.Curr Opin Crit Care. 2001; 7: 117-121Crossref PubMed Scopus (56) Google Scholar]. Thus, it needs to be emphasized that underlying cirrhosis sets the stage for fatality. This is due to marked deficiencies in local and systemic host defence mechanisms against bacteria including dysfunction of cellular and humoral immunity in advanced cirrhosis limiting peritoneal bacterial clearance. Moreover, ascites per se may contribute to worsen prognosis of any type of peritonitis since in healthy conditions peritoneal host defence mechanisms are very efficient, and i.p. injection of various numbers of single organisms does not cause peritonitis unless adjuvant substances or ascites are present [[9]Dunn D.L. Barke R.A. Ahrenholz D.H. Humphrey E.W. Simmons R.L. The adjuvant effect of peritoneal fluid in experimental peritonitis. Mechanism and clinical implications.Ann Surg. 1984; 199: 37-43Crossref PubMed Scopus (74) Google Scholar]. Finally, increased porto-systemic shunting as well as the hyperdynamic circulation with enhanced susceptibility for hemodynamic instability in case of further vasodilatory stimuli act in concert to determine the course of disease [[10]Groszmann R.J. Hyperdynamic circulation of liver disease 40 years later: pathophysiology and clinical consequences [editorial; comment]. [Review] [64 refs].Hepatology. 1994; 20: 1359-1363Crossref PubMed Scopus (334) Google Scholar]. The finding of exaggerated mortality in secondary peritonitis as compared to SBP is most likely due to the presumably higher bacterial load and the frequently polymicrobial nature induced by secondary causes. For instance, experimental cecal ligation and puncture with prior cecal lavage has been reported to present with a 100% survival rate as compared to animals with normal gut flora, emphasizing the importance of intestinal bacteria in the development of abdominal sepsis [[11]Enoh V.T. Fairchild C.D. Lin C.Y. Varma T.K. Sherwood E.R. Differential effect of imipenem treatment on wild-type and NK cell-deficient CD8 knockout mice during acute intra-abdominal injury.Am J Physiol Regul Integr Comp Physiol. 2006; 290: R685-R693Crossref PubMed Scopus (20) Google Scholar]. It is tempting to speculate that bacterial overgrowth as a well-known feature in decompensated cirrhosis may additionally contribute to aggravate this scenario in peritonitis due to intestinal perforation. Moreover, bacterial synergism in polymicrobial infection due to interaction of two or more bacterial species produces results which cannot be achieved by an individual bacterial species alone [[12]Meleney F.L. Bacterial synergism in disease processes: with a confirmation of the synergistic bacterial etiology of a certain type of progressive gangrene of the abdominal wall.Ann Surg. 1931; 94: 961-981Crossref PubMed Google Scholar]. In accordance with this concept of "dose of bacterial burden", secondary peritonitis was characterized by more leucocyte recruitment to the peritoneal cavity showing up to threefold higher levels of ascitic PMN count as compared to SBP. In this context, the level of pro-inflammatory mediators aimed at activation of leucocytes that enable bacterial clearance are known to correlate with severity of peritonitis as well as severity of critical illness and to be predictive for outcome [13Fugger R. Zadrobilek E. Gotzinger P. Klimann S. Rogy M. Winkler S. et al.Perioperative TNF alpha and IL-6 concentrations correlate with septic state, organ function, and APACHE II scores in intra-abdominal infection.Eur J Surg. 1993; 159: 525-529PubMed Google Scholar, 14Holzheimer R.G. Schein M. Wittmann D.H. Inflammatory response in peritoneal exudate and plasma of patients undergoing planned relaparotomy for severe secondary peritonitis.Arch Surg. 1995; 130: 1314-1319Crossref PubMed Scopus (120) Google Scholar]. In fact, when inflammatory response becomes overwhelming antibiotics can no longer alter outcome in experimental secondary peritonitis [[15]Turnbull I.R. Javadi P. Buchman T.G. Hotchkiss R.S. Karl I.E. Coopersmith C.M. Antibiotics improve survival in sepsis independent of injury severity but do not change mortality in mice with markedly elevated interleukin 6 levels.Shock. 2004; 21: 121-125Crossref PubMed Scopus (83) Google Scholar]. The priming of PMN present in advanced cirrhosis in conjunction with a vast bacterial load in secondary peritonitis may therefore lead to an excessively pronounced, antibiotic-resistant, and ultimately fatal systemic inflammatory response. In other words, secondary peritonitis occurring in a decompensated cirrhotic patient is like pouring oil into the fire. However, the outcome of secondary peritonitis in contrast to SBP is apparently independent from the severity of underlying liver disease. Despite having major concerns in mind regarding selection bias, the only variables found to predict survival in patients with secondary peritonitis were high blood pressure and high protein concentration in ascites. This clearly points towards the severity of sepsis determining poor outcome as has been indicated many times before. However, the authors unfortunately do not report any scoring system usually applied in intensive care medicine, e.g. Sequential Organ Failure Assessment (SOFA)-based scores. The prognosis in peritonitis has repeatedly been shown to be decisively influenced by the health status of the patient at the beginning of treatment which can be predicted fairly accurately on the basis of SOFA-derivatives [[16]Koperna T. Schulz F. Laparotomy for abdominal sepsis in the critically ill.Br J Surg. 1996; 83: 1300-1301Crossref PubMed Scopus (4) Google Scholar]. In fact, in critically ill cirrhotic patients the SOFA-score has been demonstrated to exhibit the best predictive ability and to perform better than liver-specific scores such as the Child classification [[17]Cholongitas E. Senzolo M. Patch D. Shaw S. Hui C. Burroughs A.K. Review article: scoring systems for assessing prognosis in critically ill adult cirrhotics.Aliment Pharmacol Ther. 2006; 24: 453-464Crossref PubMed Scopus (129) Google Scholar]. Therefore, the use of established prognostic ICU-indices is strongly recommended and should be implemented more rigorously in hepatology. Finally, patients being operated on and particularly those with early intervention tended to have better outcomes. Although not statistically significant and prone to selection bias, it is self-evident and known since 1889 [[18]Mikulicz J. Experiences in surgery for peritonitis due to intestinal perforation.Arch Klin Chir (Berl). 1889; 39: 756-784Google Scholar] that early and complete surgical resolution of the abdominal septic focus is of upmost prognostic relevance. Soriano et al. indeed observe that all patients with perforated secondary peritonitis not undergoing surgery die during hospitalization. The median time to surgery in the current series of cases was 3.2 ± 2.4 days in survivors (as compared to 7.2 ± 6.1 days in non-survivors). Therefore, unless the patient is in pre-terminal or non-operable conditions, delayed diagnostic work-up is futile, whereas early imaging and surgical intervention increase chances for cure. Conversely, surgical therapy may be accompanied by significant deterioration in the clinical status of cirrhotic patients with SBP and thus, should be avoided. Therefore, timing and accuracy of diagnosis correctly separating SBP and secondary peritonitis is crucial. Clinical signs and symptoms are clearly not helpful in this regard. The study by Soriano et al. reinforces suggestions made beforehand that secondary peritonitis should be suspected when one of the following criteria is present: (a) no response to antibiotic therapy; (b) more than one organism isolated from ascites and (c) Runyon's criteria, namely neutrocytic ascites with at least two of three criteria: ascitic fluid total protein >1 g/dl (in contrast to SBP which selectively occurs in low-protein ascites), glucose <50 mg/dl (due to bacterial glucose utilization), or LDH >225 mU/ml (most likely due to more rapid metabolic rate and disintegration of ascitic PMN) [[19]Garrison R.N. Cryer H.M. Howard D.A. Polk Jr, H.C. Clarification of risk factors for abdominal operations in patients with hepatic cirrhosis.Ann Surg. 1984; 199: 648-655Crossref PubMed Scopus (432) Google Scholar]. Polymicrobial culture (OR 587.5; 33–10247) followed by Runyon's criteria (OR 61.2; 6–540) were the only independent predictive factors associated with secondary peritonitis. Moreover, although strata are not stated, the extreme separating power reported for these parameters (AUC of ROC curve 0.952) appears to be present at each level of risk. Uniformly, SBP is reported to be monomicrobial in the vast majority of cases (88–100%) and hence, polymicrobial ascites and/or presence of anaerobic bacteria or fungi, usually not acquired during SBP, clearly indicates the presence of secondary peritonitis. However, it needs to be stressed that microbiology results may be obtained too late in the course of disease. Likewise, re-paracentesis for control of therapeutic efficacy is mostly not diagnostic within 12 or 24 h after initiation of antibiotics and thus is recommended on day two with a PMN cell count reduction of less than 25% of the initial value defining lack of response [[4]Akriviadis E.A. Runyon B.A. Utility of an algorithm in differentiating spontaneous from secondary bacterial peritonitis.Gastroenterology. 1990; 98: 127-133Abstract PubMed Google Scholar]. Therefore, rapid "chemical" parameters available at the day of paracentesis with sufficient sensitivity and positive predictive value are needed for effective screening. Sensitivity of Runyon's criteria has been reported to reach 97% in some cohorts [[20]Runyon B.A. Hoefs J.C. Ascitic fluid analysis in the differentiation of spontaneous bacterial peritonitis from gastrointestinal tract perforation into ascitic fluid.Hepatology. 1984; 4: 447-450Crossref PubMed Scopus (117) Google Scholar] but elsewhere ranges below 68% [2Soriano G. Castellote J. Álvarez C.E. Girbau A. Gordillo J. Baliellas C. et al.Secondary bacterial peritonitis in cirrhosis: A retrospective study of clinical and analytical characteristics, diagnosis and management.J Hepatol. 2010; 52: 39-44Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 19Garrison R.N. Cryer H.M. Howard D.A. Polk Jr, H.C. Clarification of risk factors for abdominal operations in patients with hepatic cirrhosis.Ann Surg. 1984; 199: 648-655Crossref PubMed Scopus (432) Google Scholar] and thus can be optimized. In this regard, Wu et al. have used carcinoembryonic antigen (CEA) present in colonic enterocytes and alkaline phosphatase (AP) occurring throughout the gastrointestinal tract. Ascitic elevations in both are not likely to be result of inflammatory changes but rather specific for intestinal perforation. In fact, ascitic fluid presenting with either AP >240 U/l or CEA >5 ng/ml in 80% of cases reflects peritonitis of secondary origin [[21]Wu S.S. Lin O.S. Chen Y.Y. Hwang K.L. Soon M.S. Keeffe E.B. Ascitic fluid carcinoembryonic antigen and alkaline phosphatase levels for the differentiation of primary from secondary bacterial peritonitis with intestinal perforation.J Hepatol. 2001; 34: 215-221Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. Although no data are available on the diagnostic accuracy of combined criteria, fulfilling either Wu's or Runyon's criteria will most likely improve sensitivity. In such cases: (i) antibiotic regimen must include agents against anaerobes and enterococci and (ii) secondary peritonitis has to be ruled out thoroughly. Therefore, we strongly recommend initiation of abdominal computer tomography (CT) as soon as any of these features are present. This appears to be the only approach to ensure timely diagnosis of secondary causes; therefore, enabling appropriate surgical treatment. In this regard, data by Soriano et al. underscore the usefulness of performing CT since it was diagnostic in more than 91% of patients. In cases in which CT will be performed without contrast agent, e.g. in the presence of advanced renal insufficiency, abdominal sonography can clearly add diagnostic power and should be performed. In summary, secondary peritonitis in decompensated cirrhosis is a rare entity that requires the meticulous vigilance of clinicians. Its occurrence in cirrhosis delivers a devastating prognosis due to the limited pre-morbid reserves combined with a presumably overwhelmingly severe systemic inflammatory response. Since the first parameter cannot be changed the condition sine qua non for success is timely diagnosis and surgical intervention to stop delivery of bacteria and adjuvants into the peritoneal cavity. Both authors do have nothing to disclose.