Peritonitis in peritoneal dialysis patients Dr Cherelle Fitzclarence Renal GP July 2009

Overview Peritoneal Dialysis - principles Anatomy Physiology Pathology Presentations Management Key points

Chronic Kidney Disease Diagnosis End Stage Kidney Disease Diagnosis DIALYSIS HAEMODIALYSIS PERITONEAL DIALYSIS TRANSPLANTATION PALLIATIVE CARE STAGE 1 & 2 Proteinuria plus eGFR 60+ (to determine eGFR over 60, hand calculate GFR using Cockcroft- Gault formula) STAGE 3 eGFR ml/min MODERATE KIDNEY DAMAGE Proteinuria Care plan STAGE 5 eGFR <15 ml/min FAILURE STAGE 4 eGFR ml/min SEVERE KIDNEY DAMAGE CKD Care plan ESKD Care plan GFR = (140 - Age) x wt (kg) se creat (mmol/Lt) Males = GFR x 1.23 Kidney Failure SUPPORTIVE CARE APPROACH

Peritoneal Dialysis A form of renal replacement therapy for patients with end stage kidney disease Endeavours to replace some of the functions of the kidney such as Removing waste products Removing excess fluid Correcting acid/base imbalances Correcting electrolyte imbalances High maintenance form of therapy requiring meticulous compliance and effort on part of patient

IDEAL BODY WEIGHT IBW Normotensive (Good BP)120/70 No signs and symptoms of overload or dehydration Set by: Home Training Staff Royal Perth Hospital Renal Doctor Dialysis Staff KSDC

FLUID ASSESSMENT Blood pressure Weight Chest, SaO2, SOB Oedema Ankles Back Facial JVP Skin tugor Symptoms Nausea, vomiting Diarrhoea Dizziness

FLUID RESTRICTION 800 – 1000 mls per day Weigh patient (will be required daily – SAME SCALES and document which ones) In hospital, remove jug

Peritoneal Dialysis Involves the passage of solutes and water across a membrane that separates two fluid containing compartments-blood and dialysate During dialysis 3 transport processes occur simultaneously Diffusion Ultrafiltration Absorption

Peritoneal Dialysis 2 types CAPD – continuous ambulatory peritoneal dialysis Involves on average 4 dwells per day of 4-8 hours of 2 – 2.5L each APD – automated peritoneal dialysis Involves 3-10 exchanges overnight of varying amounts Usually but not always a daytime dwell

Peritoneal Dialysis Anatomy Serosal membrane lining the gut Thought to be the same as the body surface area – usually 1-2 m 2 in adult 2 parts – visceral peritoneum lining the organs (80% or the peritoneal surface area and the parietal peritoneum lining the walls of the abdominal cavity) Peritoneal blood flow can’t be measured but indirectly estimated to be between mls/min

Peritoneal Dialysis

Horizontal disposition of the peritoneum in the lower part of the abdomen.

Peritoneal Dialysis Visceral peritoneum blood supply is from the superior mesenteric with venous drainage from the portal system Parietal peritoneum blood supply is from the lumbar, intercostal and epigastric arteries while the venous drainage is via the IVC Main lymphatic drainage is via stomata in the diaphragmatic peritoneum which drain into the right lymphatic duct

Three pore model Peritoneal capillary is the critical barrier to peritoneal transport Movement of solute and water movement across the capillary is mediated by pores of three different sizes Large pores nm – protein transport Small pores 4-6nm – small solutes eg urea, creatinine, sodium, potassium, water Ultrapores (aquaporins) <0.8nm – transport of water

Three pore model of peritoneal transport Kidney International ISSN: EISSN: © 2009 International Society of Nephrology

Peritoneal Transport - Diffusion Diffusion – uraemic solutes and potassium diffuse from peritoneal capillary blood into the dialysate. Glucose, lactate, bicarbonate and calcium diffuse in the opposite direction. Diffusion depends on concentration gradient (maximal at the start), effective peritoneal surface area, intrinsic peritoneal membrane resistance, molecular weight of the solute (eg small molecules like urea, diffuse more rapidly than larger molecules such as creatinine)

Diffusion

Peritoneal Transport - Ultrafiltration Occurs as a consequence of the osmotic gradient between the hypertonic dialysate and the relatively hypotonic peritoneal capillary blood Driven by high concentration of glucose in dialysate Depends on; concentration gradient of the osmotic agent (glucose) peritoneal surface area hydraulic conductance of the peritoneal membrane reflection coefficient for the osmotic agent (how effectively the osmotic agent diffuses out of the dialysate into the peritoneal capillaries (0-1 is normal – the lower the value the faster the osmotic gradient is lost. Gluc is 0.3 as opposed to icodextrin which is close to 1)). Hydrostatic pressure gradient – cap press around 20mm versus intraperitoneal pressure around 7mm Hg which favours ultrafiltration

Ultrafiltration

Peritoneal Transport – Ultrafiltration 2 Depends on; Oncotic pressure gradient which acts to keep fluid in blood, opposing ultrafiltration (low in hypoalbuminaemic patients so ultrafiltration tends to be high) Sieving – occurs when solute moves along with water across a semipermeable membrane by convection but some of the solute is held back – sieved. The solute concentration in the ultrafiltrate that has passed through the membrane is lower than the source solution. Different solutes sieve differently ranging from 0 (complete sieving) to 1 (no sieving) Other osmotic agents such as icodextrin with a large reflection coefficient so ultrafiltration is sustained

Ultrafiltration

Peritoneal Transport – Fluid Absorption Occurs via the lymphatics at constant rate Typical values for peritoneal fluid absorption are 1-2 mls/minute Affected by intraperitoneal hydrostatic pressure Effectiveness of lymphatics

Peritonitis Peritoneal Dialysis is a great form of renal replacement therapy Peritonitis is a significant complication Incidence peritonitis episodes varies from 1/9 patient-months to 1/53 patient-months (Grunberg 2005; Kawaguchi 1999)Grunberg 2005Kawaguchi 1999 Our figures pending but are likely to be on the lower end of the scale

Peritonitis in PD pts Risk Factors Diabetes Non caucasian Obesity Temperate climate Depression Possibly the peritoneal dialysis modality but not proven (Huang 2001; Oo 2005).Huang 2001Oo

Peritonitis in PD pts Significant morbidity Some mortality - It is estimated that PD- associated peritonitis results in death in 6% of affected patients (Troidle 2006).Troidle 2006 gymsoap.com

Peritonitis in PD pts Catheter removal may become necessary if pt is not responding to antibiotics or if infection is fungal. May be temporary or permanent Ultrafiltration failure can occur both acutely due to increases in capillary permeability (Ates 2000; Smit 2004) and in the longer term resulting in technique failure (Coles 2000; Davies 1996).Ates 2000Smit 2004Coles 2000Davies 1996

Pathogenesis 1. Potential routes of infection Intraluminal – improper technique; access to bacteria via the catheter lumen Periluminal – bacteria present on skin surface enter the peritoneal cavity via the catheter tract Transmural – bacteria of intestinal origin migrate through the bowel wall Haematogenous – peritoneum seeded via the blood stream Transvaginal - ??

Pathogenesis 2. Bacteria laden plaque – the intraperitoneal portion of the catheter is covered with a bacteria laden plaque - ? Role in pathogenesis of peritonitis 3. Host defences – peritoneal leucocytes critical in combating bacteria that have entered the peritoneum. Affected by A. dialysis solution and ph – hypertonic solution inhibits activity B. Calcium levels – low calcium in dialysate inhibits activity Peritoneal IgG levels – low levels inhibit activity HIV – little known effect

Aetiology Staph aureus Coag neg staph (S.Epidermidis) E coli Pseudomonas Sternotropomonas Candida Atypical TB

Diagnosis 2 of the following 3 conditions Symptoms and signs of peritoneal inflammation (pain, tenderness, guarding, rebound) Cloudy peritoneal fluid with increased white cell count (specifically neutrophils) Demonstration of bacteria on gram stain or culture

Diagnosis – symptoms and signs Abdo pain most common but in a PD pt suspect peritonitis if general malaise, nausea, vomiting or diarrhoea Don’t be blinded by the PD These pts get other pathology EG. Strangulated hernia, withdrawal from steroids (if they stop taking meds suddenly and they happen to be on steroids), ruptured viscus, ulcers, perforations etc EXAMINE THE PATIENT

Diagnosis – symptoms and signs Percentage Symptoms Abdo pain95 Nausea and vomiting30 Fever30 Chills20 Constipation or diarrhoea15 Signs Cloudy peritoneal fluid99 Abdo tenderness80 Rebound tenderness10-50 Increased temperature33 Blood leucocytosis25 CRP100 but can be delayed Daugirdas JT et al 2007 p 419

Diagnosis – peritoneal fluid Cloudiness – when cell count greater than 100 x 10 6 Normal is around 10x10 6 but always less than 50x10 6 Mostly cloudiness means peritonitis but be aware of other causes such as fibrin, blood, malignancy, chyle Don’t write peritonitis off as a diagnosis if everything else fits but the fluid is relatively clear – the changes can lag Must get a WCC (peritoneal fluid) with specific neutrophil count. Neutrophils required as the total number of white cells can vary according to whether patient dry or wet etc. Normally predominant cells are mononuclears and neutrophils are usually less than 15% of total white cell count Be aware of mimickers such as PID, ovulation, recent pelvic examination which may affect the cell counts in the peritoneal fluid

Peritoneal fluid culture Send the whole bag Label it (preferable with texta – label can sweat off) Let the lab know it is coming Ask for urgent gram stain and cell count and ask this to be telephoned to you. Be aware that the gram stain may be negative in 50% of cases of subsequent culture proven peritonitis Also ask for M/C/S and fungal cultures Follow up the culture Do a full septic workup each time – including blood cultures

Peritonitis Common things occur commonly and peritonitis is unfortunately common in our population of PD patients BUT Don’t lose sight of the bigger picture and these patients can suffer from any other pathology – always keep an open mind

Peritonitis Management Broad spectrum coverage Vancomycin (2.5g if more than 60kg / 2 g if 60kg or less) Gentamicin (200mg if more than 60kg / 140mg if 60kg or less) IP is better than IV (confirmed on large Cochrane review April 2009) Await culture. If gram positive, then repeat the vanc dose in 1 week. If gram negative then usually ceftriaxone 1g intraperitoneally daily for 14 days Things to note; if pseudomonas tube is very often lost. May need to consider adding a second antibiotic such as daily ciprofloxacin

Initial symptoms may include; diarrhoea, vomiting, nausea, abdominal pain, mental confusion or feeling unwell PERITONITIS MANAGEMENT COLLECT DRAINED BAG *See additional resources (pink section) for drainage instructions * Send entire bag for urgent MC&S (including WCC differential) and Fungal elements. **** Must ‘cc’ KRSS **** Intraperitoneal (IP) Antibiotics ( see Procedures) Give BOTH Gentamycin – 160mgs if 60kgs or less (gram –ve organisms) 200mg if > 60kgs AND Vancomycin - 2gms if 60kgs or less (gram +ve organisms) 2.5grams if > 60kgs Give both in a 2L 2.3% bag Dwell in the abdomen for minimum 6 hours (Consult microbiologist if Vanc or Gent allergy) must be able to read newspaper print through the bag LOOK FOR OTHER CAUSES Call PD Coordinator or Renal GP ATTENTION: Vanc and Gent provide some coverage while awaiting sensitivities. ****Further antibiotics WILL be required **** If Staph/gram +ve, give IP Vancomicin again on Day 7 If gram negative, refer to sensitivities, but usually 14 days of IP Ceftriaxone 1gm YOU MUST follow up the MC & S 48 hours after initial IP treatment. A WCC > 100 confirms peritonitis. If the patient is not improving within 24 hrs, or any other concerns, contact PD coordinator CLEAR BAG CLOUDY BAG

Peritonitis Mx CAPD/APD Drain abdomen and send bag off with path request as above Change the transfer set completely following usual aseptic techniques Load 2.3% 2 litre dialysate bag (use 1.5% bag if patient hypotensive) with Vancomycin and Gentamicin as per above guideline Infuse bag into peritoneum 6 hour dwell

Peritonitis – fungal infection If fungal organisms are seen on gram stain, or cultured, it is unlikely you will be able to save the tube Once the tube is colonized, the only cure is removal of tube, peritoneal rest (pt on Haemodialysis for a few months) and then start from scratch

Peritonitis If you think that the patient has peritonitis but you think they have life threatening sepsis eg hypotension, tachycardia, fever (or no fever as may not be able to mount an immune response), altered conscious state etc, your patient is likely to require IV broad spectrum antibiotics. Ring the microbiologist on call. Don’t wait to get IP regime in. That can go in while you are making calls and obtaining results. Antibiotics must be given within 1 hour of presentation – it is an emergency. I usually ring SCGH as they maintain a 24 hour consultant micro roster but remember all our patients who require transfer must go to Royal Perth Hospital as they are under the RPH consultant

Peritonitis Patients can have dual pathology Eg it is not uncommon for patients to have peritonitis, delay treatment, splint their abdomen and get pneumonia. This needs to be treated as per the normal guidelines for pneumonia

Peritonitis Additives to bags Vancomycin, aminoglycosides and cephalosporins are safe to mix in the same bag Aminoglycosides are incompatible with penicillins Vancomycin is stable for 28 days in dialysate (normal room temp) Cefazolin is stable for 8 days Gentamicin is stable for 14 days Heparin added decreases duration of stability

Peritonitis Often get formation of fibrin clots which increases risk of catheter block May need to add 500units of heparin to 1 or 2 bags a day until fibrin clots decrease Constipation is common – you may need to stop the calcium based phosphate binders temporarily but better off using aperients early and preventing the need to alter routine meds

Peritonitis Fluid regimes Depends whether patient is overloaded or underloaded Can usually continue normal regime but tailor to patient If BP low, use 1.5% bags x 4 a day If BP high use 2.3% bags, minimum of 4 a day Aim for BP 120/ APD pts can continue on APD or if needed can convert temporarily to CAPD – in Broome with resources this should not be necessary

Peritonitis Can get changes in the permeability of the peritoneal membrane Permeability to water, glucose and proteins is increased Rapid glucose absorption from the dialysis solution reduces amount of ultrafiltration and can result in fluid overload May need high glucose concentration dialysate with shorter dwells Hyperglycaemia is common Protein loss is increased in peritonitis so patients will need high protein supplements

Peritonitis Don’t forget secondary causes of peritonitis Perforated gastric or duodenal ulcer Pancreatitis Appendicitis Diverticulitis PID Talk to the surgeon if you are not sure

Peritonitis You don’t necessarily have to admit the patient Admission dictated by symptoms and distress and often social circumstances up here blogs.southshorenow.ca/louise/ cms.ich.ucl.ac.uk/website/imagebank/images

Peritonitis - bugs Staph – Vancomycin and repeat in 1 week Patients should have nasal carriage treated with mupirocin bd for 5 days and then once a week of bd for 5 days once a month Gram Negs – IP Ceftriaxone for 2 weeks and consider repeating the dose of gentamicin after a week or adding oral ciprofloxacin to the regime Pseudomonas difficult to treat Sternotrophomonas – usually requires 2 antibiotics and usually for 4 weeks Campylobacter not that common – responds to gentamicin

Peritonitis Multiple organisms Have a high index of suspicion for secondary peritonitis If not secondary peritonitis have 60% chance of curing with appropriate antibiotics If one of the organisms is clostridium or bacteroides – likely intra-abdominal abscess or perforated abdominal viscus but exclude appendicitis, perforated ulcer, pancreatitis and any other cause of secondary peritonitis Occurrence of abdominal catastrophe in PD patient has a high mortality Talk to the surgeon Add metronidazole Ship south

Peritonitis Culture negative disease If cell count less than 50 x 10 6 …unlikely to peritonitis If higher white cell count, then repeat empiric therapy Make sure lab is doing cultures for AFB’s and fungus If not improving consider legionella, campylobacter, ureaplama, mycoplasma, enteroviruses, fungus, histoplasma capsulatum

Peritonitis Fungal peritonitis Predisposing factors Prior antibiotic use especially if not full treatment Immunosuppressive therapy HIV Malnutrition Low albumin Diabetes

Peritonitis Fungal peritonitis We tend to try and save the tube by giving antifungals but guidelines recommend prompt removal of catheter, conversion to haemodialysis for a few weeks and then start from scratch Penetration of antifungals to peritoneum other than with IP administration, is poor

Peritonitis Refractory disease Defined as disease that is treated with appropriate antibiotics for 5 days without improvement Catheter removal necessary to reduce morbidity and preserve peritoneum Increased with gram neg bugs

Peritonitis Relapsing disease Peritonitis with the same organism within 4 weeks of stopping therapy Usually Staph epidermidis or a gram negative organism If pseudomonas or gram negatives, remove the catheter If staph, may be able to rescue with repeat vancomycin weekly for a month or may be able to remove the tube and simultaneously insert a new tube (as opposed to any other organism where a 2 month peritoneal rest is required) Sometimes can use urokinase to strip the biofilm (bacteria entrapped in fibrin in the peritoneal membrane) in relapsing disease – last resort but worth a go

Peritonitis 20% of episodes temporally associated with exit site and tunnel infections (Piraino et al 2005) Treat exit site infections if red and purulent Swab it Start Flucloxacillin empirically and change or add ciprofloxacin if gram neg Exit sites are another whole topic

Peritonitis Prevention Good technique Hygiene Mupirocin Exit site care Anchor tape

Cochrane Review 2009 Implications for practice At the present time broad spectrum antibiotics should be initiated at the time a diagnosis of peritonitis is made. When choosing antibiotics the side-effect profile, local drug resistance patterns and previous antibiotic use and infection history in the individual concerned should be considered. In cases of recurrent peritonitis dialysis catheters should be removed rather than using intraperitoneal urokinase. Currently available evidence from RCTs is inadequate in many areas of clinical practice important in the management of PD-associated peritonitis. This is a limiting factor in the provision of definitive treatment guidelines.

Cochrane Review 2009 Implications for research Further studies are required to establish the most effective treatment for peritoneal dialysis- associated peritonitis. An essential feature of such studies is inclusion of enough patients to ensure adequate power to assess meaningful long and short term outcomes. Short term outcomes should extend beyond whether cure is achieved without catheter removal, for example duration of systemic inflammation. Study of long-term outcomes should include permanent transfer to haemodialysis, development of ultrafiltration failure patient death and late recurrent episodes of peritonitis beyond four weeks from the original episode. Specific interventions that would be of value include early versus late catheter removal. Studies designed to study infections due to specific organisms would also be valuable. An example is a study of glycopeptide versus cephalosporin therapy in peritonitis due to coagulase negative Staphylococcal species. The majority of studies have included patients on CAPD rather than APD hence studies designed to test the efficacy of antibiotics in APD are required. This is particularly applicable to studies of intermittent versus continuous dosing when cycler dwell times may well influence pharmacokinetics. Future research should be conducted using standard definitions, with inclusion of information about factors that may influence the response to therapy such as prophylaxis regimens and dialysis solutions used. Current ISPD guidelines provide a comprehensive list of requirements for future studies that should be referred to when designing studies.

Take home points Have a high index of suspicion Use the remote area manual Always let KRSS know of episode Copy all results to KRSS Don’t hesitate to ask if you are not sure – KRSS team, KRSS GP, Renal GP, Nephrologist

Acknowledgements Thanks to Daugirdas et al 2007 – Handbook of dialysis sysrev/articles/CD005284/frame.html

Thank you Questions