TNF- and IL-1 are the primary pro-inflammatory cytokines and have similar biological activities (Camus- si et al. 1991; Dinarello 1984). They alter the temperature regulation center in the hypothalamus, thus inducing fe- ver. They act on the formatio reticularis in the brain stem (sleeping-waking center), the patient becomes somnolent or comatose. They stimulate the liberation of ACTH in the hypophysis. Via hematopoietic growth fac- tors,theyactonthebonemarrowtostimulatethesyn- thesis of neutrophils and liberate reserve neutrophils, causing peripheral leukocytosis and increased numbers of immature neutrophils (bands). They activate the neu- trophils to rapid phagocytosis and production of bacte- ricidal agents, i.e., proteases and oxygen radicals. They stimulate B and T lymphocytes and synthesis of anti- bodies and cellular immune reactions are increased; however, as sepsis persists, there is a shift to an anti-in- flammatory immunosuppressive state (transient im- mune paralysis) because of apoptosis of B cells, CD4 helper T cells, and follicular dendritic cells (Liles 1997). In the liver, they stimulate the synthesis of acute-phase proteins, e.g., C-reactive protein (CRP), complement factors, and 1 -antitrypsin. They stimulate the decay of muscle proteins (increased protein catabolism), and lib- erated amino acids are used for antibody synthesis. They activate vascular endothelial cells to produce cytokines such as PAF and NO, and promote increased vascular permeability by vascular endothelial injury and endo- thelial detachment. They up-regulate the synthesis of cell-surface molecules that enhance neutrophil–endo- thelial cell adhesion. They increase pro-coagulatory ac- tivity on endothelial cells and the synthesis of plasmino- gen activator inhibitor,and activate the complement and blood coagulation systems, which may result in micro- circulatory failure, tissue hypoxia, organ ischemia, and organ failure (Dellinger 2003; Dinarello 1984; Gogos et al. 2000; Hotchkiss and Karl 2003). On the other hand, IL-4 and IL-10 are anti-inflammatory cytokines since they inhibit the production of IL-1 and TNF (Gogos et al. 2000; Hotchkiss and Karl 2003; Russell 2006). In summary, the pathophysiological phenomena and consequences of sepsis, severe sepsis, and septic shock result in: Poorperfusionofskinandinternalorganswithre- duced arterial-venous oxygen gradient by by-pass- ing the capillaries via multiple shunts, accumula- tion of lactate (metabolic acidosis), anoxia Activation of the complement and blood coagula- tion cascades Activation of B and T lymphocytes Activation of neutrophils, thus increasing their chemotaxis and adhesiveness Increased capillary permeability (capillary leak syndrome), hemoconcentration, decreased circu- lating blood volume Accumulation of neutrophils in the lungs where they release proteases and oxygen radicals which alter alveolar-capillary permeability to increased transudation of liquid, ions, and proteins into the interstitial space, which finally results in acute re- spiratory distress syndrome (ARDS, shock lung) Myocardial depression, hypotension Accelerated apoptosis of lymphocytes and gastro- intestinal epithelial cells Disseminated intravascular coagulation (DIC) Impairment and finally failure of hepatic, renal, and pulmonary functions 5.5 Classification System Identical clinical manifestations without bacterial infection are observed in patients suffering from po- lytrauma, ischemia, hemorrhagic shock, and acute pancreatitis, resulting in intensive care physicians proposinganexpandednomenclatureandclassifica- tion. The classification system that has been amended ever since is important in evaluating the prognosis of a patient suffering from sepsis and assessing of the success of new therapeutic approaches. It is based on the following criteria (Bone et al. 1992; Reinhart et al. 2004): Criterion I: Definitive evidence of infection (positive hemoculture) or clinically suspected infection. Bacteremia may be low-grade (<10 bacteria/ml) and transient. Multiple blood cultures may be re- quired. Criterion II: Systemic inflammatory response syn- drome (SIRS) 1. Core temperature 38°C or 36°C 2. Heart rate 90 beats/min 3. Respiratory rate 20 breaths/min 4. Respiratory alkalosis PaCO 2 32 mmHg 5. White cell count ( 12×10 9 /l or 4×10 9 /l) 6. Immature neutrophils (bands) >10%. Criterion III: Multiple organ dysfunction syndrome (MODS) 1. Cardiovascular: arterial systolic blood pressure 90 mmHg or >40 mmHg less than patient’s normal blood pressure, or the mean arterial blood pressure 70 mmHg for at least 1 h de- spite adequate fluid resuscitation, adequate in- travascular volume status, or the use of vaso- pressors in an attempt to maintain a systolic blood pressure 90 mmHg 2. Renal: urine output <0.5 ml/kg of body weight/h for 1 h, despite adequate fluid resuscitation 3. Respiratory: PaO 2 75 mmHg while breathing room air, or PaO 2 /FiO 2 250 in the presence of 46 5Urosepsis Table 5.1. Classification of sepsis stages and lethality Criteria Lethality Sepsis Criterion I + 2 criteria II 2 Criteria II, 7% 3 Criteria II, 10% 4 Criteria II, 17% Severe sepsis Criterion I + 2 criteria II + 1 criterion III Per afflicted organ (liver, lung, kid- ney), lethality is increased by 15%–20% Septic shock Criterion I + 2 criteria II + refractory hypotension (crite- rion III), i.e., arterial blood pressure <90 mm systolic, or 40 mm less than patient’s nor- mal blood pressure, or mean arterial blood pressure 70 mmHg, for 2h,or need for vasopressors to maintain systolic blood pres- sure 90 mmHg or mean ar- terial pressure 70 mmHg. >50%–80% other dysfunctional organs or systems, or 200, if the lung is the only dysfunctional organ (PaO 2 , partial pressure of arterial oxygen; FiO 2 , fractional concentration of inspired O 2 [~0.21 when breathing room air]) 4. Hematologic: platelet count <80×10 9 /l or 50% decrease in platelet count from highest value re- corded over previous 3 days 5. Metabolic acidosis: a pH 7.30, or a base deficit 5 mm/l, a plasma level of lactate >1.5 times the upper limit of normal 6. Brain: somnolence, confusion, agitation, deliri- um, coma Following these criteria, sepsis can be clinically catego- rized into three different stages (Table 5.1). Prognostic criteria concerning lethality are also based on the above-mentioned classification system. Inanintensivecareunit(ICU),patient’sillnessisof- ten categorized into grades of severity following a scor- ing system, e.g., the Apache II (Acute Physiology and Chronic Health Evaluation II) system, which is based upon age, type of intensive care unit admission, a chronic health problem score, and 12 physiologic vari- ables. 5.6 Risk Factors for Urosepsis Predisposing primary diseases such as advanced age, diabetes mellitus, malignancy, cachexia, immunodefi- ciency, radiotherapy, cytostatic therapy; obstructive uropathy (e.g., urethral stricture, benign prostatic hy- perplasia [BPH]), carcinoma of the prostate, urolithia- Table 5.2. Clinical stages of urosepsis 1. Hyperdynamic early stage Precapillary sphincters shut the capillary bed, the blood rushes via precapillary arterial-venous shunts; gas ex- change and removal of metabolites, e.g., lactate, cease Hyperventilation induces respiratory alkalosis The patient is warm Cardiac output normal or increased (up to 10– 20 l/min) Peripheral vascular resistance and arterial-venous oxygen gradient reduced Central venous pressure normal or increased Patient appears as seriously ill, is pale, and sweating profusely Pulse is frequent and soft Hypotension Nausea, emesis, diarrhea Agitation, confusion, disturbance of orientation 2. Intermediate stage Accumulation of lactate results in metabolic acidosis Increasing myocardial depression Due to endothelial injury and increased vascular perme- ability,effusionofplasmaintorenal,hepatic,pulmonary interstitial space, increasing organ dysfunction followed by organ failure (shock kidney, shock liver, shock lung [ARDS]) Due to activation of the complement and coagulatory cas- cades and increased adherence of cellular elements (neu- trophils, thrombocytes, endothelial cells), disseminated intravascular coagulation (DIC) with consumption coa- gulopathy leading to hemorrhages, organ hypoxia, organ failure, and mostly lethal septic shock 3. Hypodynamic late stage Patient’s skin cold and cyanotic Reduced cardiac output Peripheral vascular resistance increased due to vasocon- striction; central venous pressure reduced sis, neurogenic disturbances of micturition, inflammato- ry diseases (e.g., pyelonephritis, acute bacterial prostati- tis, epididymitis, renal abscess, paranephritic abscess, prostatic abscess), and nosocomial infections (e.g., pa- tients with indwelling urinary catheters, after transure- thral/open surgery, endoscopy, and prostatic biopsies). 5.7 Clinical Symptoms Premonitory symptoms are tachypnea (>20 breaths/ min), tachycardia (>90 beats/min), and hyperthermia (>38°C), or hypothermia (<36°C) followed by inter- mittentboutsoffeverwithshakingchillsduringinva- sion of bacteria. The clinical course of urosepsis is dif- ferentiated in three stages (Table 5.2). 5.8 Diagnostic Procedures Typical clinical laboratory data are provided in Ta- ble 5.3: 5.8 Diagnostic Procedures 47 Table 5.3. Laboratory findings in urosepsis Erythrocyte sedimentation rate increased (normal range: females 1–25 mm/h; males 0 –17 mm/h) C-reactive protein (CRP) increased (normal range, 0.1– 8.2 mg/l, depends on the method used) Leukocytecounts(>12×10 9 /lor <4×10 9 /l)withtoxic granulation, and immature neutrophils (bands) >10% Thrombocytopenia (<80×10 9 /l) Hyperbilirubinemia (normal range, <1 mg/100 ml) Increased creatinine level (normal range, <1.5 mg/100 ml) Proteinuria Initially respiratory alkalosis, later on metabolic acidosis Hypoxemia Biomarkers of sepsis (cytokines, procalcitonin) and of blood coagulation (D-dimer, protein C, protein S, anti- thrombin) may be determined and provide further hints 5.9 Microbiology Analysis of at least two blood cultures (aerobic, anaero- bic)atthesametime,i.e.,2×10mlofvenousblood,is mandatory. Since bacteremia may be low-grade (<10 microorganisms/ml), multiple blood cultures may be required, in particular in case of negative re- sults (>50% in cases of severe sepsis!) of the initial he- mocultures. They should best be taken during the rise in body temperature, i.e., just before the fever spike. When antimicrobial therapy has already been started, blood should be drawn before repeated antibiotic ad- ministration. 5.10 Further Diagnostic Procedures The focal source of infection must be sought carefully, and specimens for microbiological analysis such as pu- rulentsecretions,urine,andabscesspusshouldbetaken. 5.11 Therapy The general goals of therapy are: 1. Stabilization of hemodynamics 2. Improvement of oxygen saturation and utilization 3. Sufficient organ perfusion 4. Improved organ function (heart, lung, liver, kidney) 5. Antimicrobial treatment of sepsis 6. Sanitization of the focal source of infection 7. Essential steps of therapy (Evans 2001; Hotchkiss and Karl 2003; Rivers et al. 2001; Reinhart et al. 2004; Russel 2006) are compiled in Table 5.4 Table 5.4. Recommended therapeutic approach to patients suf- fering from urosepsis Patients should immediately be transferred to the ICU 1. Volume replacement: infusion of 1–2 l of electrolyte solution over 1– 2 h; goal: central venous pressure (CVP) 8–12 mmHg, mean arterial blood pressure 65 mmHg, but 90 mmHg Blood transfusion in case of central venous oxygenation <70% and of hematocrit <30; optimal: fresh erythrocyte concen- trates; goal: hemoglobin value 7– 10 g/100 ml whole blood, hematocrit >30 In case of hypalbuminemia (<2 g/100 ml), the additional infu- sion of albumin solutions has been suggested but is still con- troversial 2. Controlled and assisted ventilation: tidal volume, 6 ml/kg body weight; goal: arterial oxygen saturation 93%, central venous oxygen saturation 70%. If <70%, administration of dobut- amine (initially 2.5 µg/kg/min, after 30 min each, increase by 2.5 µg/kg/min; maximum, 20 µg/kg/min) 3. Administration of vasopressors: if mean arterial pressure (MAP) <65 mmHg, give dopamine, 1–3 µg/kg/min, or nor- adrenaline (norepinephrine), 0.1 –1.0 µg/kg/min, as a continu- ous i.v. infusion 4. Control of urine excretion; goal: >30 ml/h; if necessary, give furosemide in order to inhibit tubular re-resorption (thera- peutic value not evidence-based). Tight control of blood glu- cose; goal: 80-110 mg/100 ml; exact stabilization with intensive insulin therapy (anti-apoptotic effect) (Evans 2001; Russell 2006; Van den Berghe et al. 2001) 5. Antimicrobial therapy: if possible, targeted (pathogen identi- fied, sensitivity determined), otherwise calculated, or initially untargeted (wide-spectrum): reserve beta-lactam antibiotics i.v., e.g., cefotaxime, 3×2–4 g/day, or ceftazidime, 3×1–2 g/ day,orceftriaxone,2×2gatday1,then1×2g/day,plusami- noglycoside i.v., e.g., gentamicin, 1×240–320 mg/day, by infu- sion. Monitor blood levels of aminoglycoside, trough concen- tration should be <1–2 µg/ml, and creatinine levels, three to seven times/week (Bodmann and Vogel 2001; Gilbert et al. 2006) 6. After stabilization of cardiovascular function and start of anti- microbial therapy, removal of the infectious focus is mandato- ry. Abscesses have to be drained, and pyonephrosis has to be treated either by intraureteral JJ catheters or percutaneous nephrostomy. A Foley catheter should be inserted in any case 7. Supportive measures: for patients in septic shock and/or those with proved adrenocortical insufficiency (serum cortisol level <15µg/100ml;corticotropintest:within30–60minafteri.m. or i.v. injection of 250 µg of adrenocorticotropin hormone, in- crease of serum cortisol level <9 µg/100 ml), the i.v./i.m. ad- ministration of hydrocortisone (4×50 mg/day), or equivalent, is indicated (Cooper and Stewart 2003; Hamrahian et al. 2004; Rhen and Cidlowski 2005; Russell 2006) 8. In order to inhibit imminent disseminated intravascular coag- ulation (reduced levels of plasma protein C) in cases of severe sepsis, recombinant human activated protein C (drotrecogin alpha-activated) with a dose of 24 µg/kg/h as a continuous i.v. infusion for 96 h is recommended (Bernard et al. 2001; Dellin- ger 2003; Matthay 2001; Opal et al. 2003). The drug is approved forpatientswithanApacheIIscoreof 25, but should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an Apache II score <25 (Abraham et al. 2005; Parrillo 2005; Russell 2006). The substance has antithrombotic, anti-apoptotic, antiinflam- matory, and pro-fibrinolytic properties. Potential adverse ef- fect is hemorrhagic diathesis 48 5Urosepsis References Abraham E, Laterre PF, Garg R et al (2005) Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 353:1322 Bernard GR, Vincent JL, Laterre PF et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699 Bodmann KF, Vogel F (2001) Antimikrobielle Therapie der Sepsis. Chemother J 10:43 Bone RC, Balk RA, Cerra FB et al (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 101:1644 Camussi G, Albano E, Tetta C et al (1991) The molecular action of tumor necrosis factor- .EurJBiochem202:3 Cooper MS, Stewart PM (2003) Current concepts: Corticoste- roid insufficiency in acutely ill patients. N Engl J Med 348: 727 Dellinger RP (2003) Inflammation and coagulation: implica- tions for the septic patient. Clin Infect Dis 36:1259 Dinarello CA (1984) Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med 311:1413 Evans TW (2001) Hemodynamic and metabolic therapy in critically ill patients. N Engl J Med 345:1417 Gerard C (2003) Complement C5a in the sepsis syndrome – too much of a good thing? N Engl J Med 348:167 Gilbert DN, Moellering RC, Eliopoulos GM, Sande MA (2006) The Sanford guide to antimicrobial therapy 2006, 36 th edn. Antimicrobial Therapy Inc., Sperryville, VA, USA, p 44 Gogos CA, Drosou E, Bassaris HP et al (2000) Pro-versus anti- inflammatory cytokine profile in patientswith severe sepsis: a marker for prognosis and future therapeutic options. J In- fect Dis 181:176 Hamrahian AH, Oseni TS, Arafah BM (2004) Measurement of serum free cortisol in critically ill patients. N Engl J Med 350:1629 Hotchkiss RS, Karl IE (2003) The pathophysiology and treat- ment of sepsis. N Engl J Med 348:138 Liles WC (1997) Apoptosis – role in infection and inflamma- tion. Curr Opin Infect Dis 10:165 Matthay MA (2001) Severe sepsis – a new treatment with both anticoagulant and anti-inflammatory properties. N Engl J Med 344:759 Opal SM, Garber GE, La Rosa SP et al (2003) Systemic host re- sponses in severe sepsis analyzed by causative microorgan- ism and treatment effects of drotrecogin alfa (activated). Clin Infect Dis 37:50 ParrilloJE(2005)Severesepsis and therapy with activated pro- tein C. N Engl J Med 353:1398 Reinhart K, Hüttemann E, Meier-Hellmann A (2004) Sepsis. In: Burchardi H, Larsen R, Schuster H-P, Suter PM (eds) Die Intensivmedizin. Springer Berlin Heidelberg New York, p 851 Rhen T, Cidlowski JA (2005) Anti-inflammatory action of glu- cocorticoids – new mechanisms for old drugs. N Engl J Med 353:1711 Rivers E, Nguyen B, Havstad S et al (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368 Russel JA (2006) Management of sepsis. N Engl J Med 355:1699 Van Amersfoort ES, Van Berkel TJC, Kuiper J (2003) Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock. Clin Microbiol Rev 16:379 Van den Berghe G, Wouters P, Weekers F et al (2001) Intensive insulin therapy in critically ill patients. N Engl J Med 345:1359 Wilson M, Seymour R, Henderson B (1998) Bacterial pertur- bation of cytokine networks. Infect Immun 66:2401 References 49 6 Fournier’s Gangrene C.F.Heyns,P.D.Theron 6.1 Definition and Historical Perspective 50 6.2 Etiology 50 6.3 Anatomy 52 6.4 Microbiology 53 6.5 Pathogenesis 54 6.6 Clinical Presentation 55 6.7 Special Investigations 55 6.8 Manag ement 55 6.8.1 Initial and Preoperative Management 56 6.8.2 Surgery 56 6.8.3 Postoperative Management 57 6.8.4 Hyperbaric Oxygen 58 6.8.5 Wound Care 58 6.8.6 Reconstructive Surgery 59 6.9 Complications 59 6.10 Prognosis 59 References 59 6.1 Definition and Historical Perspective Fournier’s gangrene is a synergistic polymicrobial nec- rotizing fasciitis of the perineum and genitalia. It can progress to a fulminant soft tissue infection that spreads rapidly along the fascial planes, causing necro- sis of the skin, subcutaneous soft tissue, and fascia, with associated systemic sepsis. If it is not diagnosed early and treated promptly, significant morbidity with prolonged hospital stay and even mortality will ensue. In 1764, Baurienne described a fulminant gangrene ofthemaleperineum.However,JeanAlfredFournier,a French dermatologist and venereologist, became fa- mous for this notorious condition when, in 1883, he de- scribed a series of five young men in whom gangrene of the genitalia occurred without any apparent etiologic factor. As knowledge of the condition increased over the years, it became clear that Fournier’s gangrene is most commoninoldermen(peakincidenceinthe5 th and 6 th decades) and that most cases have an identifiable cause. Fortunately, it is a rare condition, with a reported in- cidence of 1/7,500, and accounting for only 1%–2% of urologic hospital admissions (Bejanga 1979; Bahlmann et al. 1983; Hejase et al. 1996). However, the incidence is rising, most likely due to an increase in the mean age of the population, as well as increased numbers of pa- tients on immunosuppressive therapy or suffering from human immunodeficiency virus (HIV) infection, especially in Africa (McKay and Waters 1994; Elem and Ranjan 1995; Merino et al. 2001; Heyns and Fisher 2005). 6.2 Etiology Anetiologicalfactororfactorscanbeidentifiedinmore than 90% of cases and should be actively sought, be- cause it may determine the treatment and prognosis (Smith et al. 1998; Santora and Rukstalis 2001). In ap- parently idiopathic cases, the cause may have been over- looked or obscured by the necrotizing disease process. Any process where a virulent, synergistic infection gains access to the subcutaneous tissue of the perineum may serve as the point of origin. The cause of infection may be from a urogenital, anorectal, cutaneous, or ret- roperitoneal origin. The urogenital area is the most common etiologic site, where urethral stricture disease is at the top of the list (Edino et al. 2005). Knowledge of the anatomy of the perineum, urogenital area, and low- er abdomen is necessary to understand the etiology and pathogenesis of this fulminant infection. The possible causes of Fournier’s gangrene are listed in Table 6.1. Infection may originate in any of the listed areas, with extension to the fascial planes leading to a proliferating fasciitis (Jones et al. 1979; Karim 1984; Walker et al. 1984; Walther et al. 1987; Baskin etal. 1990; Sengoku et al. 1990; Gaeta et al. 1991; Attah 1992; Paty and Smith 1992; Theiss et al. 1995; Benizri et al. 1996; Hejase et al. 1996; Fialkov et al. 1998; Corman et al. 1999; Eke 2000; Kilic et al. 2001; Ali 2004; Jeong 2004; Yeniyol et al. 2004; Edino et al. 2005). Although Fournier’s gangrene is predominantly a condition of the older male, it may occur at any age, and approximately10%ofcasesoccurinfemales(Kilicet al. 2001; Quatan and Kirby 2004). Specific causes in women include pudendal nerve block or episiotomy for Chapter 6 Table 6.1. Causes of Fournier’s gangrene Urogenital Urethral stricture Indwelling transurethral catheter Prolonged or neglected use of condom catheter Urethral calculi Urethritis Transurethral surger y Infection of periurethral glands and paraurethral abscess Urogenital tuberculosis Urethral cancer Prostate biopsy Prostatic massage Prostate abscess Insertion of penile prosthesis Constriction ring device for management of ED Iatrogenic trauma Cauterization of genital warts Circumcision Manipulation of longstanding paraphimosis Noniatrogenic trauma Animal, insect, or human bite Scrotal abscess Infected hydrocele Hydrocelectomy Vasec to my Balanitis Phimosis Anorectal Ischiorectal or perianal or intersphincteric abscess Rectal mucosal biopsy Banding of hemorrhoids Anal dilatation Cancer of sigmoid or rectum Diverticulitis Rectal perforation by foreign body Ischemic colitis Anal stenosis Cutaneous Hidradenitis suppurativa Folliculitis Scrotal pressure sore Post-scrotal surgery wound infection Cellulitis of scrotum Pyoderma gangrenosum Femoral access for intravenous drug users Retroperitoneal causes Psoas abscess Perinephric abscess Appendicitis and appendix abscess Pancreatitis with retroperitoneal fat necrosis Other Inguinal hernia repair Filariasis in endemic areas Strangulated Richter hernia vaginal delivery, septic abortion, hysterectomy, and Bartholin and vulval abscess (Roberts and Hester 1972; Addison et al. 1984). A prominent feature of patients with Fournier’s gan- grene is that most of them have an underlying systemic disorder causing vascular disease or suppressed immu- nity, which increases their susceptibility to polymicro- Table 6.2. Underlying disorders in patients with Fournier’s gan- grene Diabetes mellitus Chronic alcoholism Malnutrition Obesity Liver cirrhosis Poor personal hygiene Immunosuppression: Chronic steroid use Organ transplantation Chemotherapy for malignancy HIV/AIDS Tuberculosis Syphilis bial infection (Table 6.2). Fournier’s gangrene is often a marker of an underlying disease such as diabetes melli- tus, urogenital tuberculosis, syphilis, or HIV. Diabetes mellitus is the most common associated underlying systemic disease, affecting two-thirds of pa- tients with Fournier’s gangrene. Diabetic patients have a higher incidence of urinary tract infections, due to cystopathy with urinary stasis (Baskin et al. 1990). Hy- perglycemia decreases cellular immunity by decreasing phagocytic function. It retards chemotaxis of leuko- cytes to the site of inflammation, neutrophil adhesion, and intracellular oxidative destruction of pathogens. Wound healing is also retarded due to defective epithe- lialization and collagen deposition (Hejase et al. 1996; Nisbet and Thompson 2002). Apart from hyperglyce- mia, diabetic patients also have microvascular disease, which contributes significantly to the pathogenesis. Al- though diabetes mellitus increases the risk for develop- ment of Fournier’s gangrene, it does not increase the mortality (Baskin et al. 1990; Benizri et al. 1996; Hejase et al. 1996; Yeniyol et al. 2004). Chronic alcoholism, malnutrition, liver cirrhosis, poor personal hygiene, and personal neglect are quite common in patients with Fournier’s gangrene (Benizri et al. 1996; Hejase et al. 1996; Yeniyol et al. 2004). Other conditions causing depressed immunity that may pre- dispose to the development of Fournier’s gangrene in- clude chronic steroid use, organ transplantation, che- motherapy for malignancies such as leukemia, as well as HIV infection (Paty and Smith 1992; Elem and Ran- jan 1995; Heyns and Fisher 2005). The rising incidence of HIV is paralleled by a rising incidence of Fournier’s gangrene, especially in Africa. Fournier’s gangrene may be the first presenting condi- tion in patients with HIV infection (McKay and Waters 1994; Elem and Ranjan 1995; Roca et al. 1998; Heyns and Fisher 2005). Risk factors include a CD4 count un- der 400, chemotherapy for Kaposi’s sarcoma, and fem- oral access for the administration of intravenous drugs. HIV-positive patients with Fournier’s gangrene pre- sent at a younger age and have a wider spectrum of causative bacteria (McKay and Waters 1994). 6.2 Etiology 51 anterior triangle bulbar urethra symphysis pubis perineal body urogenital membrane posterior triangle coccyx ischial tuberosity sacrotuberous ligament 6.3 Anatomy The pelvic outlet can be divided into anterior and pos- terior triangles by drawing a line between the ischial tuberosities with the symphysis pubis and coccyx being the apices (Fig. 6.1). Urogenital causes of Fournier’s gangrene lead to initial involvement of the anterior tri- angle, whereas anorectal causes primarily involve the posterior triangle. The five fascial planes that can be affected are: Col- les’fascia,dartosfascia,Buck’sfascia,Scarpa’sfascia, and Camper’s fascia. Colles’ fascia is the fascia of the anterior triangle of the perineum. Laterally it is attached to the pubic rami and fascia lata, posteriorly it fuses with the perineal membrane and perineal body, and anterosuperiorly it is continuous with Scarpa’s fascia (Smith et al. 1998). It prevents the spread of infection in a posterior or lat- eraldirection,butprovidesnoresistancetospreadin an anterosuperior direction towards the abdominal wall. The dartos fascia is the continuation of Colles’ fascia over the scrotum and penis. Buck’s fascia lies deep to the dartos fascia, covering the penile corpora. It fuses distally with the corona of Fig. 6.1.The pelvic outlet can be divid- ed into anterior and posterior trian- gles by drawing a line between the is- chial tuberosities with the symphysis pubis and coccyx being the apices (© Hohenfellner 2007) theglansandproximallywiththesuspensoryligament and crura of the penis. Camper’sfascia is the loose areolar fascial layer deep totheskinoftheabdominalwall,butsuperficialto Scarpa’sfascia.TogetherwithScarpa’sfasciaitiscon- tinuous with Colles’ fascia inferomedially. Scarpa’s fascia lies deep to Camper’s fascia, covering the muscles of the anterior abdominal wall and thorax. It terminates at the level of the clavicles. The perineal membrane lies deep to Colles’ fascia. It is triangular in shape and lies between the pubic rami from the symphysis pubis to the ischial tuberosities. It has a distinct posterior border, with the central perine- al tendon in the midline. Colles’ fascia terminates in this posterior border. The central perineal tendon (or perineal body) lies between the anus and bulbar urethra. It serves as an at- tachment for the various perineal muscles and helps to maintain the integrity of the pelvic floor. Via the internal and external fascial layers of the spermatic cord, the perineal fascia is continuous with the retroperitoneal fascia. This is a potential path for the spread of infection from the perineum to the peri- vesical and retroperitoneal areas, and vice versa (Paty and Smith 1992; Fialkov et al. 1998). Spread of infection along the fascial planes will fol- low the path of least resistance (Jones et al. 1979). Infec- tion in the anterior perineal triangle will spread prefer- entially in an anterosuperior direction along Scarpa’s 52 6Fournier’sGangrene Camper’s fascia Scarpa’s fascia suspensory ligament of penis urogenital diaphragm Buck’s fascia dartos fascia external spermatic fascia Colles’ fascia perineal body external anal sphincter Fig. 6.2.Diagram of a sagittal section showing the fascial planes of the male external genitalia, perineum, and lower abdomen (© Hohenfellner 2007) fascia, whereas lateral spread will be limited by fusion of Colles’ fascia to the ischiopubic rami, and posterior spread to the anal region will be limited by the termina- tion of Colles’ fascia in the posterior edge of the perine- al membrane (Fig. 6.2). Infection from the perianal region may sometimes penetrate Colles’ fascia, which is fenestrated at the level of the bulbocavernosus muscle, leading to spread of in- fection to the anterior triangle (Tobin and Benjamin 1949). Thus, while anterior triangle infection rarely spreads to the posterior triangle, it is possible for infec- tion to spread from the posterior to the anterior trian- gle and then to the anterior abdominal wall (Jones et al. 1979; Walker et al. 1984; Laucks 1994). In the perineum, the vascular supply to the cutane- ous and subcutaneous tissues is mainly derived from the perineal branches of the internal pudendal artery. The deep circumflex iliacartery and superficial inferior epigastric artery supply blood to the lower abdominal wall. These arteries traverse the various fascial planes, supplying nutrients and oxygen to the skin and subcu- taneous tissues. With the fascial planes infected, these vessels become thrombosed, facilitating the prolifera- tion of anaerobic bacteria. Blood supply to the testis, bladder, and rectum origi- nates directly from the aorta and not from the perineal vasculature, and for this reason they are rarely affected in Fournier’s gangrene. If the testes are affected, it may be from specific testicular pathology such as epididy- mo-orchitis, or from a retroperitoneal infection spreading along the spermatic fascia, causing throm- bosis of the testicular arteries. 6.4 Microbiology One of the characteristics of Fournier’s gangrene is that it is a polymicrobial infection, with a mean of four dif- ferent organisms usually cultured (Bahlmann et al. 1983; Baskin et al. 1990). Aerobic, anaerobic, Gram-positive and Gram-nega- tive bacteria, yeasts, and even mycobacteria can be found(Table6.3).Themostcommonlyculturedorgan- 6.4 Microbiology 53 Table 6.3. Most common causative organisms Gram-negative E. coli Klebsiell a pneumoniae Pseudomonas aeruginosa Proteus mirabilis Enterobacteria Gram-positive Staphylococcus aureus Beta-hemolytic streptococci Streptococcus faecalis Staphylococ cus epidermidis Anaerobes Bacteroides fragilis Peptococcus Fusobacterium Clostridium perfringens Mycobacteria Mycobacterium tuberculosis Ye a s t s Candida albicans isms are Escherichia coli, Bacteroides, beta-hemolytic streptococci, Staphylococcus spp., and Proteus.Besides being found in the lumen of the gastrointestinal tract, these bacteria are also normal commensal flora of the skin folds and hair follicles of the perineum (Benizri et al. 1996; Smith et al. 1998). This mixed spectrum of bac- teria acts in a synergistic fashion to produce and pro- mote a fulminant necrotizing fasciitis. Anaerobic organisms are responsible for the forma- tion of subcutaneous gas, which leads to the character- istic crepitus often found on palpation. Clostridial in- fection, classically associated with gas formation, is not commonly encountered, but should be suspected when there is a colorectal origin (Spirnak et al. 1984; Baskin et al. 1990). It is extremely important to obtain cultures in order to identify the causative organism(s), because this determines the correct choice of antibiotic treatment. Because of the difficulty of culturing anaerobic or- ganisms, a subcutaneous aspirate should be obtained, and at initial debridement a piece of infected tissue should also be sent for anaerobic culture. Microbio- logical studies should include acid fast staining for Mycobacterium tuberculosis and culture for fungal in- fection. 6.5 Pathogenesis The pathogenesis of Fournier’s gangrene is character- ized by polymicrobial aerobic and anaerobic infection with subsequent vascular thrombosis and tissue necro- sis, aggravated by poor host defense due to one or more underlying systemic disorders. Aerobic organisms cause intravascular coagulation by inducing platelet aggregation and complement fixa- tion, while anaerobes produce heparinase. Vascular thrombosis causes necrosis of tissue and decreased clearance of toxic bacterial metabolites, with subse- quent proliferation of anaerobic bacteria (Paty and Smith 1992; Hejase et al. 1996). Hypoxic tissue leads to the formation of oxygen free radicals (superoxide anions, hydrogen peroxide, hy- droxyl radicals), which play an important role in the pathogenesis.Theeffectsoffreeradicalsincludecell membrane disruption leading to cell death, decreased ATP production leading to decreased energy delivery, and DNA damage, which leads to decreased protein production (Anderson and Vaslef 1997). Anaerobic organisms secrete various enzymes and toxins. Lecithinase, collagenase, and hyaluronidase cause digestion of the fascial planes (Baskin et al.1990). They produce insoluble hydrogen and nitrogen, lead- ing to the formation of gas in the subcutaneous tissues, clinically palpable as crepitus. Aerobic bacteria pro- duce CO 2, which is soluble and rarely leads to subcuta- neous gas accumulation. Endotoxins are released from the cell walls of Gram- negative bacteria. Macrophage activation and subse- quent complement activation ensues with release of pro-inflammatory cytokines and eventual develop- ment of septic shock (Anderson and Vaslef 1997). Depending on the origin of the infection, the various paths of spread can be explained with reference to the anatomy of the fascial planes and adhesions. Infection from a urogenital cause, e.g., a patient with a urethral stricture and urinary tract infection leading to a paraurethral abscess, will spread from the corpus spongiosum by penetrating the tunica albuginea and Buck’sfascia, and will then spread under the dartos fas- cia and Colles’ fascia to Scarpa’s fascia, thereby involv- ing the anterior abdominal wall. Infection from an anorectal cause, e.g., an ischio- rectal abscess, will spread from the perirectal tissues to Colles’ fascia. Because Colles’ fascia is fenestrated, it allows spread from the perirectal area to the dartos fascia of the scrotum and penis, and from there the in- fection can spread to Scarpa’s fascia and the anterior abdominal wall. Because Colles’ fascia terminates in the perineal membrane, infection from the anterior triangle of the perineum, which contains the bulbar urethra and scrotum, cannot spread to the perirectal area, but because Colles’ fascia is fenestrated, the op- posite is possible, i.e., posterior triangle infections may sometimes spread to the anterior triangle and from there to the anterior abdominal wall. This is im- portant in trying to localize the origin of the initial in- fection. Retroperitoneal infection, e.g., from a perinephric orpsoasabscess,mayspreadalongtheinguinalcanal 54 6Fournier’sGangrene and spermatic fascia, which connects to Colles’ fascia deep to the bulbocavernosus muscle. Retroperitoneal infection should be considered as a cause of Fournier’s gangrene if no obvious point of origin can be found. 6.6 Clinical Presentation The diagnosis of Fournier’s gangrene is made on clini- cal grounds. It is usually preceded by prodromal symp- toms such as fever, prostration, nausea and vomiting, perineal discomfort, and poor glucose control in dia- betics, for a period ranging from 2 to 9 days (Bahlmann et al. 1983; Paty and Smith 1992; Benizri et al. 1996; Edi- no et al. 2005). Genital and perineal discomfort worsens, leading to pain, itching, burning sensation, erythema, swelling, and eventual skin necrosis. There may be a purulent discharge with a feculent odor.The pain may subside as neural damage develops (Corman et al. 1999). Crepitus may be difficult to elicit, due to pain on palpation, but is present in up to 50 %–60% of cases (Corman et al. 1999; Benizri et al. 1996). Clinical signs such as an elevated temperature, tachycardia, tachypnea, ileus, poor glucose control, and vascular collapse may be found, but are not very consis- tent, especially with underlying immunosuppressive disorders. The diagnosis is sometimes delayed due to morbid obesity, poor communication (stroke, dementia), or in- adequate physical examination. In Africa, patients may first seek help from a traditional healer, thereby delay- ing proper medical attention (Attah 1992). Once there is necrosis of the skin, the underlying fascia has already undergone extensive necrosis. This explains the frequent finding of systemic symptoms, which are out of proportion to the visible pathology. Other symptoms and signs depend on the origin of the infection. A history of lower urinary tract symp- toms may indicate a urethral stricture. Preceding ano- rectal symptoms such as pain, fissures, or hemorrhoids may indicate an anorectal origin of Fournier’s gan- grene. It is essential that the attending doctor have a high index of suspicion in patients presenting with perineal discomfort accompanied by systemic symptoms. A missed or delayed diagnosis may have catastrophic effects. 6.7 Special Investigations Special investigations to be done include a full blood count, clotting profile, urea, creatinine and electro- lytes, liver function tests, blood glucose, blood gases, group and screen, HIV and VDRL. Abnormal findings include anemia, thrombocyto- penia, coagulopathy, hyponatremia, and raised urea and creatinine. Hypocalcemia may occur in some cases, subsequent to the chelation of ionized calcium by triglycerides liberated by bacterial lipases. Leukocytosis with a white cell count above 15,000 mm 3 and a left shift is found in more than 90% of cases. Neutrophilia indicates overwhelming bacteri- al infection. It is noteworthy that leukocytosis may not be present in immunosuppressed patients (Baskin et al. 1990; Laucks 1994). Anemia may be present as part of the septic profile. Coagulopathy may be indicated by a raised prothrombin time (PT) and partial thrombo- plastin time (PTT), and thrombocytopenia. Raised fi- brinogen levels and positive D-dimers may herald the onset of disseminated intravascular coagulation (DIC). Blood and urine cultures, together with wound swabs and tissue specimens for bacterial culture are very important. The HIV status should be determined in all patients, as Fournier’s gangrene may be the pre- senting condition in patients with HIV. Radiologic imaging may be useful if the diagnosis is in doubt, but it should not delay the surgical manage- ment. An x-ray of the abdomen and pelvis may demon- strate gas in the subcutaneous fascial layers of the peri- neum and abdominal wall. Ultrasound provides superior imaging of the peri- neum and scrotum. The appearance of hyperacoustic shadowsinthefascialplanesisdiagnosticofgasforma- tion, and it may be more sensitive than clinical evalua- tion for crepitus (Kane et al. 1996). However, in patients with extreme tenderness on palpation, ultrasound ex- amination may be too painful. Computerized tomography (CT) is more sensitive in demonstrating subcutaneous and retroperitoneal gas and fluid collections, but the use of contrast should be avoided in patients with renal failure. Magnetic reso- nance (MR) is the most sensitive imaging modality for evaluating pathology in soft tissues, but is expensive and not readily available. 6.8 Management ThemaingoalsinthemanagementofFournier’sgan- grene are aggressive resuscitation of the patient, ad- ministration of broad-spectrum antibiotics, and de- bridement of infected and necrotic tissue. Debride- ment is paramount, and the aim should beto get the pa- tient to the operating room as soon as possible (Baskin et al. 1990; Smith et al. 1998; Quantan and Kirby 2004). 6.8 Management 55 [...]... 7.3.1 .2 7.3.1.3 7.3.1.4 7.3 .2 7.3 .2. 1 7.3 .2. 2 7.3 .2. 3 7.3.3 7.3.4 7.3.5 7.3.6 Diagnostic Procedures in the Pregnant Patient 62 Doppler Ultrasound 62 Evaluating the Dilatation of the Urinary Tract 62 The Study of Ureteral Jets 62 Vaginal Ultrasound 62 Measuring the Resistivity Index 62 Irradiation and Pregnancy 63 Risk of Fetal Malformation 63 Risk of Radiation-Induced Tumors 63 Mutagenic Risk 63 Intravenous... to a low but not inconsiderable dose of radiation, especially during the first trimester Different examination protocols have been proposed aiming to limit the radiation exposure as much as possible to three or four radiographs: plain abdomen, 30 s, 20 min (McAleer and Loughlin 20 04; Stothers and Lee 19 92) plus or minus one late x-ray (Dore 20 04); plain abdomen, 20 min, late x-ray (Klein 1984) It is... pyelonephritis in pregnancy after 24 weeks Obstet Gynecol 94:683 Wong J, Brown G (1996) Does once-daily dosing of aminoglycosides affect neuromuscular function? J Clin Pharm Ther 21 :407 Zheng W, Denstedt J (20 00) Intracorporeal lithotripsy Urol Clin North Am 27 :301 Zwergel T, Lindenmeyer T, Wullich B (1996) Management of acute hydronephrosis in pregnancy by ureteral stenting Eur Urol 29 :29 2 Chapter 8 Urologic Emergencies. .. of the infant with CAH, bearing in mind that the initial evaluation is similar for all infants with ambiguous genitalia CAH is caused by an inherited defect in cortisol metabolism occurring in 1 in 10,000 to 1 in 15,000 live births (Perry et al 20 05) (Fig 8 .2) Although numerous enzymatic defects have been identified, deficiencies in 21 -hydroxylase account for more than 90 % of cases (Forest 20 04) Deficient... Urology 32: 427 Roy C, Saussine A, Jahn C et al (1995) Fast imaging MR assessment of ureterohydronephrosis during pregnancy Magn Reson Imaging 13:767 Saidi A, Delaporte V, Lechevallier E (20 05) Probl`mes urologie ques rencontr´s au cours de la grossesse Prog Urol 15:1 e Santos JFM et al (20 02) Urinary tract infections in pregnant women Int Urogynecol J 13 :20 4 Santucci RA, Krieger JN (20 00) Gentamicin... in an increase in the rate of filtered creatinine, urea, sodium, calcium, and uric acid (Biyani and Joyce 20 02a) Hypercalciuria is induced by the decrease in the production of parathormone and by an increase in the 1 -2 5 OH-D3 produced by the placenta, which is responsible for an increase in the intestinal absorption of calcium Despite hypercalciuria and physiological hyperuricuria, the incidence of calculi... sparganosis in the scrotum Urology 63:176 Jones RB, Hirschmann JV, Brown GS, Tremann JA (1979) Fournier’s syndrome: Necrotising subcutaneous infection of the male genitalia J Urol 122 :27 9 Kane CJ, Nash P, McAninch JW (1996) Ultrasonographic appearance of necrotizing gangrene: aid in early diagnosis Urology 48:1 42 Karim MS (1984) Fournier gangrene following urethral necrosis by indwelling catheter Urology 23 :173... neoadjuvant chemotherapy (Fig 8. 12 a, b) This usually results in signifi- b Fig 8. 12 a CT demonstrating multiple bilateral renal masses found on percutaneous needle biopsy to be Wilms tumor b Followup CT in same patient after three courses of actinomycin-, vincristine-, and doxorubicin-based chemotherapy 79 80 8 Urologic Emergencies in Children: Special Considerations a b Fig 8.13 a Intraoperative photograph... therapy can be instituted following 24 – 48 h of remaining afebrile; however, a full 1 0- to 14-day course of therapy is recommended (Bloomfield et al 20 05) Fig 8.17 US demonstrating right pyonephrosis in a patient who initially presented with symptoms of a lower urinary tract infection The patient become acutely septic 5 days following antibiotic treatment and complained of abdominal and flank pain associated... diagnostic tests (plain abdomen = 1 mGy/radiograph, 1 min of image intensifier = 2 mGy) (Denstedt and Razvi 19 92) 7.3 .2. 2 Risk of Radiation-Induced Tumors Stewart estimated that an in utero irradiation of 10 – 20 mGy increases the risk of cancer in the child by 1.5 – 2 (Stewart 1973) Harvey et al (1985), who studied twin pregnancies subjected or not subjected to diagnostic radiation averaging 1 cGy, evaluated . much aspossibletothreeorfourradiographs:plainabdo- men, 30 s, 20 min (McAleer and Loughlin 20 04; Sto- thersandLee19 92) plusorminusonelatex-ray(Dore 20 04); plain abdomen, 20 min, late x-ray(Klein 1984). It is important to use high-sensitivity. (Goldstein 20 00). Add- ing clavulanic acid-inhibiting beta-lactamases has in- creased the efficacy, but 30%–40% of bacteria are cur- rently resistant to it (Goldstein 20 00). The aminopeni- cillins. 1-cm increase in the sizeofthekidneys,thesechangesresultinanincrease in the rate of filtered creatinine, urea, sodium, calci- um, and uric acid (Biyani and Joyce 20 02a). Hypercal- ciuria is induced