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Intra-abdominal sepsis; epidemiology, aetiology and management G.P. Hadley FRCS, FC PaedSurg SA

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Cite this article as: G.P. Hadley FRCS, FC PaedSurg SA, Intra-abdominal sepsis; epidemiology, aetiology and management, Seminars in Pediatric Surgery, http: //dx.doi.org/10.1053/j.sempedsurg.2014.06.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

#7  Intra‐abdominal sepsis; epidemiology, aetiology and management    Hadley GP FRCS, FC PaedSurg SA  Department of Paediatric Surgery  Nelson R Mandela School of Medicine  University of KwaZulu‐Natal  Durban    e‐mail; [email protected]  Mail; Private Bag 17039  Congella 4013  South Africa      Key Words; peritonitis, epidemiology, damage control, abscess.    Abstract  Peritonitis is a progressive disease leading inexorably from local peritoneal irritation to overwhelming  sepsis and death unless this trajectory is interrupted by timely and effective therapy.  In children peritonitis is usually secondary to intraperitoneal disease the nature of which varies around  the world. In rich countries appendicitis is the principal cause whilst in poor countries diseases such as  typhoid must be considered in the differential diagnosis.  Where resources are limited the clinical diagnosis of peritonitis mandates laparotomy for diagnosis and  source control. In regions with unlimited resources radiological investigation, ultrasound, CT scan or  MRI, may be used to select patients for non‐operative management.  For patients with appendicitis laparoscopic surgery has achieved results comparable to open operation  however in many centres open operation remains the standard.  1   

In complicated peritonitis “damage control surgery” may be appropriate wherein source control is  undertaken as an emergency with definitive repair or reconstruction awaiting improvement in the  patient’s general condition. Awareness of abdominal compartment syndrome is essential.  Primary peritonitis in rich countries is seen in high‐risk groups such as steroid‐dependent nephrotic  syndrome patients whilst in poor countries the at‐risk population is less well defined and the diagnosis is  often made at surgery. (196 words)    Introduction Peritoneal inflammation is the final common pathway of a myriad of primary intra-abdominal insults. Both the primary disease and the peritoneal inflammation have sequelae outside the peritoneal cavity and result in systemic illness. Whilst peritonitis may be generalized or localized, acute or chronic, primary or secondary and bacterial or non-bacterial, overwhelmingly the most common is acute bacterial peritonitis secondary to some primary intra-abdominal disease. In small children the lack of omental fat inhibits the omentum’s function as a barrier to the spread of an infected effusion and generalized peritonitis is more commonly seen than in adults. Omental fat deposits increase with age having important metabolic sequelae which may presage adult obesity1. Whilst local inflammation may result in a leucocyte rich effusion into the peritoneal cavity2 with few constitutional symptoms other than pain, fever, and anorexia, the absorption of bacteria and toxins via sub-epithelial lymphatics3 promotes the systemic manifestations of the disease ranging from SIRS through MODS, to septic shock and ultimately death. Mortality rates are clearly influenced by the nature of the primary insult and the severity of systemic disease at presentation. Measuring the severity of the local and systemic disease is not easy but is essential if comparison of outcomes is to be rational and one approach is to use the disordered physiology that the disease process has caused as a surrogate for disease severity. As no custom designed scoring system exists modification of the Apache II score to suit children is a reasonable compromise4

Peritonitis The peritoneum has traditionally been thought of as little more than a lubricated semi-permeable serosal membrane that prevents abdominal organs from snagging during movement and provides a large surface area for peritoneal dialysis. It is now realized that the peritoneum has important mechanical, immunological and synthetic functions that are essential to homeostasis5 and that the omentum is an important immunological and endocrine organ6.

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The cellular response to any intraperitoneal insult requires the co-ordinated efforts of both peritoneal macrophages and the mesothelial cell2 and the clinical picture to a large extent depends upon the success of localization, primarily an omental function6, the nature and magnitude of the insult as well as general patient factors such as nutritional status, age and co-morbidities. With the exception of chronic peritonitis which is seen in patients undergoing continuous ambulatory peritoneal dialysis and in some patients with tuberculosis, the clinical picture is of an “acute abdomen” with attendant abdominal pain, guarding and rebound tenderness over the affected region, varying degrees of toxaemia and signs of intestinal paralysis. However in acute peritonitis the peritoneal effusion, rich in macrophages, complement, immunoglobulins and cytokines7 may significantly deplete intravascular volume. Additionally fluid will accumulate within static loops of bowel exacerbating the fluid deficit. Either the primary insult or translocation of organisms, that have thrived in static bowel loops, across an impaired intestinal mucosa result in endotoxaemia and septicaemia with attendant multi-organ dysfunction.

Epidemiology The primary diseases that lead to peritonitis differ from region to region around the world, and also differ according to the age of the patient. Amongst older children in rich countries appendicitis is by far the most common cause, reaching 82% of patients with acute abdominal symptoms in America8 and 92% in Israel9 whilst necrotizing enterocolitis (NEC) predominates in neonates10 11

neonatal problem

In Africa NEC is still a common

but in half of older children with peritonitis the primary cause is perforation of the

ileum due to typhoid12. Appendicitis is frequent, and perhaps increasing in frequency in Africa13 but remains outweighed by typhoid, ascariasis, trauma, intussusception and primary peritonitis. In India, whilst appendicitis is the most common single pathology diseases such as typhoid, tuberculosis and ascariasis are prominent14 In some parts of the world unusual pathologies predominate, for example pigbel in the Highlands of Papua New Guinea15, and this informs local investigational, preventative and therapeutic algorithms. Whilst the aetiology of acute bacterial peritonitis varies around the world so do morbidity and mortality. In rich countries the overall mortality from appendicitis in children hovers around 0.04% and in the age group 9yrs-19years is around 0.006%16. In Nigeria the reported mortality is 0.9%17 and in a South African series which contained both adults and children the mortality was 2%18. These high mortalities relate to delayed presentation and systemic sepsis syndromes related to difficulties in accessing healthcare structures as well as a lack of resources including, inter alia, access to intensive care19. Even within rich

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countries there are socio-economic and ethnic differences in the complications and mortality of appendicitis, again reflecting difficulties in accessing surgical care20. The mortality rate from peritonitis due to typhoid ileal perforation similarly varies, but is everywhere high, ranging from 23% in Tanzania21 to 13% in Nigeria22. Many centres report an improvement in mortality over time but identify late presentation as the principal cause of treatment failure23,24.

Whilst the

recognition of the importance of pre-operative resuscitation and the evolution of surgical techniques may have contributed greatly to the improved outlook for typhoid patients, mortality is likely to remain high until this element is effectively addressed. Chronic peritonitis is seen frequently in children undergoing continuing ambulatory peritoneal dialysis (CAPD)25 and is commonly seen in children with abdominal tuberculosis. This latter group has increased in regions severely affected by the HIV pandemic26. Tuberculous peritonitis may be one component of widespread extrapulmonary tuberculosis or may arise de novo27. Clinical clues to the diagnosis of tuberculous peritonitis may be found by inspection of the umbilicus28. but tuberculosis should be suspected in any patient with ascites, abdominal discomfort and weight loss. Primary peritonitis in rich countries is seen in children with cirrhosis or nephrotic syndrome who are being treated with steroids29 and patients in this clinical situation can confidently be treated initially nonoperatively. In poor countries the condition is usually seen in otherwise well children making it more difficult to suspect and diagnose. The migration of people from developing countries to Europe and America suggests that it would be unwise for surgeons in the developed world to ignore patterns of disease seen in poor countries.

Principles of management of peritonitis in children Acute peritonitis is a potentially lethal condition and should always be treated as an emergency. In children the suspicion of peritonitis mandates close observation and an early decision on intervention. The diagnosis of peritonitis is clinical and based on the findings of abdominal pain and tenderness, toxaemia with resultant tachycardia and pyrexia, frequently an associated ileus and evidence of a fluid deficit. Laboratory tests such as C-reactive protein, procalcitonin, serum lactate etc.30, and radiological studies, may be indicative of inflammatory or ischaemic pathology, and may direct resuscitation efforts, but can never, of themselves, make a diagnosis. This remains a clinical responsibility. Peritonitis is an evolving pathology that worsens with time31 and awareness of the inevitable progression forms the rationale for a policy of frequent repeated observations by the same observer when critical decisions, such as the need for surgery, must be made.

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Recognition that the removal of a normal appendix in adults in whom a clinical diagnosis of appendicitis had been entertained is associated with a higher mortality than ruptured appendicitis16.has driven the expansion of radiological investigation of patients presenting with abdominal pain. It must be remembered that in many patients investigation is neither necessary nor desirable as clinical signs and symptoms are diagnostic. Scoring systems are of little practical help32 but may be used to select patients for further investigation, particularly those who present with non-diagnostic scores on either the Alvarado or Samuel’s scoring system33. Ultrasound is the most frequently used aid with reported accuracy of 7197%34 but is limited by being operator dependent and not freely available. Computerized tomography is even less widely available but has a reported diagnostic accuracy of 93-98%34 although it is potentially hazardous in children. Each CT scan exposes the patient to approximately the equivalent of 250 chest radiographs35 and whilst modern scan protocols might reduce this exposure36 formal clinical practice guidelines can make up to 80% of the investigations unnecessary37

Magnetic resonance imaging has

been proposed for children and pregnant women but is no more able to differentiate simple from complicated appendicitis than ultrasound38. Of course in much of the world none of these modalities are available and reliance must be placed on clinical findings and serial review of patients in whom there is diagnostic doubt. Clinical diagnosis in most centres has an accuracy of between 85-95%39 The neonate can be very difficult to assess particularly in an ICU situation where mechanical ventilation, paralysis or deep sedation may impact on the precision of clinical diagnosis. Trends in levels of inflammatory markers such as pro-calcitonin or C-reactive protein, may assist in reaching a decision40 but under such circumstances it is often expedient to open the abdomen to confirm or refute the diagnosis. Awaiting objective signs such as abdominal wall erythema in small babies allows the pathology to progress and may increase the risk of multi-organ dysfunction. With the exception of children in whom primary peritonitis has been confidently diagnosed the definitive management of acute bacterial peritonitis requires surgical ablation of the source of the peritoneal insult31. Prior to surgery all patients benefit from a period of resuscitation, restoration of intravascular volume, relief of abdominal distension with a nasogastric tube, antibiotic therapy and analgesia. Fluid resuscitation may require large volumes of balanced salt solution guided by the clinical response in terms of both urinary output and peripheral perfusion. Patients presenting in septic shock may additionally benefit from inotropic support with dopamine and/or epinephrine and mechanical ventilation. Pain relief should be given intravenously, or if available trans-mucosally41, even in patients in whom a decision to operate has been deferred and who are being observed for clinical progression. Intravenous opiates will reduce the symptom of pain without masking the sign of tenderness42. Antibiotics should be given pre-operatively and include anaerobic as well as gram negative cover. In the circumstance of a

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child with generalized peritonitis the drugs are given with therapeutic intent, not prophylactically. Patients with peritonitis occurring during a programme of CAPD are usually treated with intraperitoneal antibiotics in addition to systemic therapy43

Surgical Approach Source control in complicated intra-abdominal infection implies surgical intervention. Whilst antibiotic therapy alone may be effective in the treatment of early, uncomplicated infection such as early appendicitis without peritonitis, surgery is still the management of choice44. Whenever the possibility of treating simple appendicitis non-surgically is raised there is always suspicion about the accuracy of the diagnosis. Certainly imaging, whether ultrasound, CT or MRI, has severe limitations in the diagnosis of appendicitis and in distinguishing simple appendicitis from more advanced disease38, yet this is the basis for all studies45. A French randomized trial concluded that antibiotic therapy for acute appendicitis in adults was not inferior to emergency appendicectomy46. There are serious concerns about the ethics of non-inferiority trials47 but there appears little doubt that some patients in whom a clinical diagnosis of acute appendicitis is made, supported by CT scans to confirm the uncomplicated nature of the disease, respond to antibiotic treatment48. Selecting patients for this treatment is a poorly defined art and the regimen should still be regarded as experimental and only be employed as part of a formal assessment protocol. Throughout most of the world where advanced disease is more common and the radiological resources to corroborate the clinical diagnosis do not exist the clinical diagnosis of acute appendicitis is followed by appendicectomy and most centres would accept a diagnostic error rate of 5-10%. Nearly all abdominal operations can be done laparoscopically given the necessary facilities and expertise; that is not to say that they should be. Laparoscopic appendicectomy has become commonplace in centres with the requisite equipment and has comparable outcomes to open appendicectomy in children, although at a greater cost49,50, however open appendicectomy still appears to be the most frequently used approach even in well-equipped centres in the developed world51. Diagnostic laparoscopy is a usual precursor to any laparoscopic procedure and may identify factors that define the optimal surgical approach. Laparoscopy has also been used in the initial assessment of blunt abdominal trauma

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and in

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the diagnosis of tuberculous peritionitis , however in most parts of the world treatment of generalized peritonitis mandates a laparotomy. In each and every circumstance the surgeon must be aware of the support structures upon which his management depends. In many parts of the world anaesthetic resources are limited54, blood transfusion may be dangerous or not available55, mechanical ventilation may be impossible56, TPN unavailable57, and

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drug choices limited by supply chain limitations etc. and he must learn to cut his suit according to his cloth.

Source control Fundamental to all surgical strategies in the management of intraperitoneal sepsis is “source control”. How this can be best achieved is dependent upon the nature of the source, the facilities available and the skills and experience of the surgeon. Mortality is lowest when operations are performed in daylight by experienced surgeons, however this may not always be practicable58

Damage Control Surgery in Peritonitis The original concept of damage control surgery arose in relation to trauma victims and the need to prevent the vicious cycle of shock, hypothermia, coagulopathy, bleeding and shock which invariably led to a high mortality59. At the same time the recognition of abdominal compartment syndromes led to the widespread use of the open abdomen as a preventative strategy. However these concepts are applicable to any situation in which an unstable patient requires surgical intervention60. In paediatric surgery the exemplar is the neonate with necrotizing enterocolitis(NEC) who has been maximally resuscitated in the intensive care unit (ICU) but whose clinical condition mandates laparotomy. All surgeons recognize the futility of attempting definitive surgery under these circumstances and several strategies have emerged to avoid this. Clearly resecting necrotic bowel which is the perceived source of the instability is common to all strategies61. Simple peritoneal drainage is regarded as an aid to resuscitation rather than a definitive surgical option and with few exceptions following relief of tension pneumoperitoneum surgical exploration will be required62. In patients undergoing intestinal resection for NEC considerations of bowel length become important and to avoid the unnecessary resection of bowel that has the potential for recovery, yet is sub-optimally perfused making anastomosis risky, a policy of “damage control” meaning emergency “source control” using a conservative resection followed by a second look after 24-48 hours, is a pragmatic approach. Many surgeons create a proximal stoma to protect bowel of dubious viability or following intestinal resection in the belief that at review surgery an anastomosis can be more safely achieved with preservation of bowel length63, however this entrains management of a high output fistula that may tax

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the resources of many centres. Despite this drawback resection with stoma creation is regarded as the gold standard against which other strategies must be weighed64. The technique of “clip and drop”, wherein the bowel ends after resection of non-viable segments are simply clipped or ligated and replaced in the abdomen, a procedure that can be performed quickly, has found wide application65. At a second look some time later, usually at 48-72 hours, any further diseased segments can be resected or anastomoses achieved66. The common thread running through all these techniques is; rapid control of the primary source of peritoneal contamination, terminate the procedure at this point, resuscitate the patient then, after a delay of 2- 3 days, complete the definitive surgery. Underlying these strategies is the understanding that there is no point in operating the patient to death in an attempt to complete the operation at one sitting and that it is more sensible to stabilize the situation and return to fight another day.

Intra-abdominal pressure Whether the abdomen should be closed or left open to minimize the risk of abdominal compartment syndrome (ACS) is moot. Similarly there is no consensus on the performance of re-laparotomy as either a planned procedure or only when indicated by deterioration of the patient’s condition. The heterogeneity of the patient cohort makes randomized trials difficult to design and conduct leading to a paucity of evidence to guide practice. However it is known that the open abdomen is well tolerated by children and neonates. Experience with large numbers of neonates with gastroschisis treated with an open abdomen has made paediatric surgeons familiar with the principles involved. Intravesical pressure monitoring is a validated technique for the assessment of intra-abdominal pressures67 however no norms exist for infants and children and no critical levels have been defined. Abdominal compartment syndrome must occur at different intra-abdominal pressures depending upon the age, clinical status and size of the patient. Absolute numbers in terms of mmHg are therefore generally not helpful diagnostically and reliance is placed upon recognizing a trend from repeated measurements68 Negative pressure wound management is also well tolerated by neonates and infants if the pressure is controlled appropriately69 When abdominal decompression is required either therapeutically or as a preventative strategy plastic sheeting sutured to the fascial layer represents a cheap and satisfactory procedure.

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Peritoneal lavage Most surgeons would accept the need for a mechanical toilet of the peritoneal cavity after completing “source control” surgery for peritonitis. The debridement of necrotic tissue, the removal of vegetable matter, the drainage of contaminated fluid all seem reasonable and appropriate steps prior to abdominal closure. Considerable debate revolves around the desirability for peritoneal lavage thereafter although nearly all surgeons do it, including a reported 97% of UK surgeons70. Proponents stress the need to dilute any toxins and organisms related to the primary pathology but are divided between those who lavage with an isotonic solution and those who add antibiotics or antiseptics. Antagonists stress the potential to spread regionalized disease throughout the peritoneal cavity as well as damage to the mesothelial cell lining with a possible increase in post-operative adhesions. The debate continues because there are no well-controlled clinical trials to guide us and the practice appears to be based on bias and dogma rather than evidence. There are few data to support the use of drains in generalized peritonitis and their use has largely been abandoned71. Peritonitis is a progressive pathology and it is naïve to assume that bacterial proliferation ceases upon initial source control at laparotomy. Indeed, adequate control may require a second, and sometimes subsequent, exploration. Whether these subsequent re-explorations should be performed as planned procedures or only if the patient’s condition demands it has been the subject of debate. There are few trials to shed light on the issue72. A trial in adult patients showed no statistically significant differences in outcome between the two strategies although there was a trend in favour of on-demand re-laparotomy73. However caution must be exercised when applying the results of adult trials to a paediatric population where the diseases differ and the margins for error are smaller All surgeons have in their mind an anticipated path to recovery for each individual patient and deviation from this trajectory requires investigation and action. Clinical evaluation of children in the intensive care environment is notoriously difficult and where radiological investigation is not available and an intraabdominal source of continuing sepsis cannot be excluded, it is often prudent to reopen the abdomen to drain further peritoneal effusion and ensure that no abscesses remain74. Having a low threshold for intervention has economic advantages as well75 and there is no such thing as a negative laparotomy. In some circumstances where damage control surgery has been performed a repeat operation is inevitable and should be a planned procedure.

Primary Peritonitis in children In the vast majority of patients with peritonitis the peritoneal disease is secondary to an identifiable primary pathology, or source, in the alimentary or genito-urinary tracts and surgery is aimed at dealing

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with this primary pathology. Primary peritonitis conversely occurs in the absence of any intra-abdominal primary pathology and surgery is rarely therapeutic but may be necessary to confirm the diagnosis. Radiological studies are rarely sufficiently discriminatory to prevent abdominal exploration76 The disease can be seen at all ages but the typical patient is a girl between six and twelve years of age who presents with high fever, abdominal pain and the clinical signs of peritonitis77 In secondary peritonitis there is a polymicrobial insult involving gastro-intestinal organisms, both aerobic and anaerobic. In primary peritonitis there is usually a monoculture, most frequently of Streptococcus spp or Escherischia coli

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and anaerobes are not involved, thus the pus within the peritoneal cavity is non-

odorous. The common finding of a streptococcal monoculture gave rise to the hypothesis that primary peritonitis results from a primary upper respiratory infection79 and the reduction in the incidence of primary peritonitis in the developed world is coincident with the widespread use of antibiotics in the treatment of upper respiratory infection, and more recently the use of pneumococcal vaccines. The fact that girls are more frequently affected raises the possibility of an ascending genito-urinary infection as the initiating insult80 although a study in Ghana failed to confirm this route as important in their patients81. In the developing world, and in cohorts with an identifiable defect in immunoprotection such as diabetics, patients with hepatic cirrhosis, those on steroids, with or without nephrotic syndrome82, there is an increased incidence although the female predominance is maintained. In patients without an overt predisposing condition the diagnosis is difficult and many patients are diagnosed only at laparotomy77, however when suspected the diagnosis can be confirmed by peritoneal aspirates that reveal gram positive cocci or a pure smear of gram negative rods83 Thereafter a trial of antibiotic therapy, not extended beyond 12 hours, may allow the patient to avoid an operation. In high risk communities such a trial is more easily justified.

Intra-peritoneal abscesses Abscesses within the peritoneal cavity commonly occur in the sub-diaphragmatic spaces, the pelvis or between loops of bowel. Visceral abscesses are not considered here. Usually such abscesses result from the successful localization of an intraperitoneal source infection, such as appendicitis or a leaking intestinal anastamosis, and their site depends upon the source and the position of the patient which directs infected fluid into the lowest peritoneal recess. In the stable patient the identification and localization of intraperitoneal infection is best achieved by CT scanning but in the

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unstable patient who cannot be moved from the ICU ultrasound scanning must suffice84. abscesses are due to low-virulence organisms such as the bacteroides group

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Many

and many are

polymicrobial and may include fungi. In parts of the world where access to microbiology reporting is not available malodorous pus should be taken as an indication to include anti-anaerobic antimicrobials. In selected individuals it may be possible to treat intraperitoneal abscesses conservatively86 but most are best treated by drainage. Nearly all pelvic and subdiaphragmatic abscesses are amenable to percutaneous drainage under imaging control87. Appendix abscess is particularly well-suited to this form of drainage

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, or to per-rectal drainage when a deep pelvic abscess presents89 but when fungal infection

occurs the results of percutaneous drainage seem to be poorer90. Interloop abscesses may be more safely drained at laparotomy.

Conclusions Peritonitis is a common problem that is usually secondary to a primary disease within the peritoneal cavity. The nature of this primary disease varies around the world and at different ages. Mortality rates in poor countries remain high and reflect resource deficiency and delayed presentation. As the disease is potentially fatal all patients with peritonitis should be treated as emergencies with initial fluid resuscitation, analgesia and antibiotics. Peritonitis is generally a polymicrobial infection justifying the empirical use of broad spectrum antibiotics. Control of the source of the infection usually requires surgery. How this is done is unimportant and is usually determined by the skills and resources available. Patients presenting with advanced disease, MODS or shock may require intotropic and ventilator support prior to operation and then may benefit from “damage control” surgery with a view to definitive management after a period of further stabilization. The abdominal compartment syndrome is occasionally seen after such endeavours and monitoring of IAP is essential. Primary peritonitis is seen with greater frequency in poor countries and is frequently diagnosed at laparotomy. Patients with cirrhosis or nephrotic syndrome are at high risk and in such patients a trial of conservative treatment may be justified. Chronic peritonitis is seen in patients on CAPD and in some patients with tuberculosis. Abscesses resulting from the successful localization of sepsis within the peritoneal cavity are often amenable to percutaneous drainage. Interloop abscesses are more safely approached by laparotomy.

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