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Capnocytophaga canimorsis a cause of septicaemia following a dog bite: A case review
Australian Critical Care (2011) 24, 93—99
CASE STUDY
Capnocytophaga canimorsis a cause of septicaemia following a dog bite: A case review Geraldine A. O’Rourke RN Dip Health Sci(Nurs), B(Nurs), Grad Dip Crit Care, MClinNurs a,∗, Rob Rothwell BSc(Hons), Grad Dip Appl Sci(Nurs), Post Basic Nurs Certif Intens Care, BMed b,1 a
Clinical Nurse Level Two Critical Care Services, Calvary Healthcare Tasmania, PO Box 50, North Hobart, TAS 7008, Australia b Clinical Nurse Educator Level Three Critical Care Services, Calvary Healthcare Tasmania, GPO 524 Hobart TAS 7000, PO Box 524, North Hobart, TAS 7001, Australia Received 28 December 2009 ; received in revised form 9 October 2010; accepted 7 December 2010
KEYWORDS Capnocytophaga canimorsus; Sepsis; Dog bite; Case study
∗ 1
Summary Described in this study is the case of a 53-year-old woman who developed a life-threatening infection caused by the bacterium Capnocytophaga canimorsus (C. canimorsus), subsequent to being bitten by a dog. The patient presented to an Emergency Department with a 24-h history of diarrhoea and vomiting with dehydration but within 36 h of presentation developed an overwhelming severe sepsis with septic shock, disseminated intravascular coagulation, acute renal failure, metabolic acidosis and threatened acute respiratory failure requiring urgent intensive care intervention. At subsequent questioning her husband volunteered that she had been bitten on the wrist by the family dog 24 h prior to the onset of symptoms; this bite had been extremely minor, requiring no treatment at the time and leaving only a very superficial wound. The causative organism was finally identified two weeks later as C. canimorsus, a common commensal in the oral flora of dogs. C. canimorsus has been reported as a rare cause of severe infection in susceptible individuals; however this case is of particular interest as there were no apparent predisposing factors conferring risk of severe infection. This case also raised significant practice issues for the treating hospital. © 2010 Australian College of Critical Care Nurses Ltd. Published by Elsevier Australia (a division of Reed International Books Australia Pty Ltd). All rights reserved.
Corresponding author. Tel.: +61 418889519. E-mail addresses: [email protected] (G.A. O’Rourke), [email protected] (R. Rothwell). Tel.: +61 414851261.
1036-7314/ $ — see front matter © 2010 Australian College of Critical Care Nurses Ltd. Published by Elsevier Australia (a division of Reed International Books Australia Pty Ltd). All rights reserved.
doi:10.1016/j.aucc.2010.12.002
94
Introduction Capnocytophaga canimorsus is a commensal bacterium found in the saliva of dogs and cats and has been implicated in a variety of disorders including sepsis, meningitis and endocarditis. This previously unidentified Gram-negative bacillus was isolated by the Centres for Disease Control (CDC) Atlanta, GA, USA in 1976 from the spinal fluid and blood of a patient who had sustained a dog bite. A review of cases found 17 patients with similar organisms dating back to 1961 which could not be identified by the existing systems and was given the vernacular; Centres for Disease Control Dysgonic Fermenter-2 due to its slow growing, fermentative and poor bacterial cultural growth features.5,7 In 1989 this bacterium was named C. canimorsus. The genus Capnocytophaga consists of five species, all of which are common to human and canine flora, although of these only C. canimorsus is recognised as a significant potential pathogen. Infection by C. canimorsus has a propensity to cause a local or systemic inflammatory response, with complications including septic shock, disseminated intravascular coagulation (DIC), gangrene, acute renal failure and respiratory failure.1,10 Australia has a canine population of about 3.75—4 million. It is estimated that around 63% of Australian households own some type of pet, with 53% owning a cat or a dog. It has been projected that each year more than 100,000 Australians are attacked by dogs, causing injuries of varying degrees of severity. The Emergency Departments of Australia’s public hospitals treat between 12,000 and 14,000 people for dog bite injuries and almost 1400 of those have injuries that are serious enough to warrant hospitalisation. Between 4 and 25% of dog bite wounds become infected. The median time to presentation with the first symptoms of infection is 24 h.17,18
Case history A 53-year-old woman presented to an Emergency Department (ED) at 08:00-h with a 24-h history of diarrhoea and vomiting. She was initially ascribed an Australian triage scale category of three requiring an urgent review within 30 min.19 She had experienced sudden onset of profuse, watery diarrhoea which had persisted throughout the previous day and night. There was some initial vomiting but this had subsided and the patient was left feeling nauseated, feverish and lethargic with a persis-
G.A. O’Rourke, R. Rothwell tent head and neck ache, no rash was evident. She was alert with clear sensorium and walked into the ED. She had no previous significant medical history including overseas travel or consumption of food or fluids different to her family. She was previously well as were her latest contacts. No mention of a dog bite was made by either the patient or her husband. Her vital signs at admission were heart rate 137 beats per minute (bpm) sinus tachycardia, blood pressure (BP) 56/29 mm Hg, pulse oximetry (SpO2 ) 96% breathing room air and temperature 37.7 ◦ C. Her respiratory rate was not recorded. Serum biochemistry was consistent with moderate dehydration with a systemic inflammatory response (elevated C-reactive protein) but was otherwise unremarkable (see Table 1). Initial treatment in the ED comprised intravenous (IV) fluid resuscitation (4 L crystalloid plus 0.5 L colloid over 7 h) and antiemetic therapy; after which her vital signs were heart rate 102 bpm, BP 76/42 mm Hg, temperature 38.1 ◦ C and SpO2 98% breathing room air. The patient was then admitted to a general medical ward under the care of a specialist gastroenterologist. Her condition deteriorated over the next 21 h, her temperature peaking 40.2 ◦ C at which time blood cultures were taken. IV fluids continued at a rate of 125—250 mL/h. Her heart rate gradually increased to 130 bpm and respiratory rate from 16 to 40 breaths per minute. The profuse diarrhoea persisted and she experienced increasing difficulty maintaining oral intake of fluids or food, due partly to nausea but also developing dyspnoea. During this time her urine output was not known due to a lack of an in-dwelling urinary catheter and inaccurate fluid balance documentation. She was reviewed by the gastroenterologist at 13:00-h the next afternoon. The nursing notes indicate rising concern about her condition and, although she met the criteria for referral to the Medical Emergency Team (MET) of respiratory rate greater than 36 breaths per minute and a person causing ‘‘serious concern’’, no such referral was made. Following medical review the patient was urgently referred to the intensive care specialist and a haematologist. Prior to transfer to the Intensive Care Unit (ICU) arterial blood gases (ABGs) showed a severe metabolic acidosis with raised serum lactate and partial respiratory compensation (see Table 2). A stat dose of ciprofloxacin 200 mg IV was given. Blood was drawn for urea and electrolytes, creatinine, full blood count, liver function tests, coagulation studies and a second set of blood cultures including aerobic and anaerobic and fungal studies.
Capnocytophaga canimorsis a cause of septicaemia following a dog bite: A case review Table 1
95
Serum biochemistry, haematology and coagulation studies days 1 and 2.
Parameter
Day 1
Day 2
[Na+ ] (mmol/L) [K+ ] (mmol/L) [Cl− ] (mmol/L) [Urea] (mmol/L) [Creatinine] (micromol/L) [Bicarbonate] (mmol/L) Estimated glomerular filtration rate (mL/min) C-reactive protein (mg/L) Erythrocyte sedimentation rate (mm/h) Gamma-glutamyl transferase (U/L) Alkaline phosphatase (U/L) Alanine aminotransferase (U/L) Corrected [Ca2+ ] (mmol/L) [Mg2+ ] (mmol/L) INR Activated partial thromboplastin time (s) Haemoglobin (g/L) Platelets (×109 /L) White cell count (×109 /L) Neutrophils (×109 /L) Fibrinogen (g/L)
135 3.9 111 13.6 135 26 38 38 14 30 19 41 1.83 0.60 Not requested Not requested Not requested Not requested Not requested Not requested Not requested
140 3.9 117 13.6 226 5 21 340 Not requested 53 115 77 1.68 0.53 1.9 110 105 98 12.7 10.9 0.9
On transfer to the ICU she was distressed but alert and co-operative. Vital signs showed a heart rate 130 bpm, sinus tachycardia, blood pressure 130/80 mm Hg, a respiratory rate of 40 breaths per minute, pulse oximetry 100% with supplemental oxygen at 4 L/min via nasal cannulae and temperature 37.6 ◦ C. Further antibiotics administered were gentamicin 240 mg IV as a single dose, ticarcillin 3 g plus clavulanate 500 mg IV 6hourly and metronidazole 500 mg IV 8-hourly. On examination she exhibited marked diaphoresis and peripheral hypoperfusion, dry mucous membranes and reduced tissue turgor. Jugular venous pressure was not visible. Her breath sounds were clear; her abdomen was soft and non tender with no organomegaly. Bowel sounds were present. There was no rash or lymphadenopathy. A central venous catheter, intra-arterial catheter and vascular access catheter for renal replacement therapy were inserted — these all required multiple attempts due to the severely depleted intravascular volume. Repeat ABGs showed increasing metabolic acidosis with worsening pH despite increasing respiratory compensation (see Table 2). Sodium bicarbonate 8.4% was administered (100 mL plus ongoing infusion). Fluid resuscitation initially comprised crystalloid 2 L plus colloid 0.5 L then ongoing crystalloid at 1 L/h. Serum biochemistry, haematology and coagulation studies were consistent with severe dehydration with marked renal impairment, increased
inflammatory response and an incipient disseminated intravascular coagulation with coagulopathy and thrombocytopaenia. Subsequent pathological findings were an elevated D-dimer, a decreased fibrinogen and a moderate neutrophilia. Insertion of an indwelling urinary catheter revealed a residual urine volume of 10 mL and ongoing anuria consistent with acute renal failure. She was electively intubated at 16:00-h and ventilated due to threatened respiratory failure secondary to her extreme work of breathing. At this point, 28 h post admission; the patient began to show evidence of a purpuric discolouration of digits, nose and ears. Also noticeable was a petechial rash originating in the peripheries and spreading rapidly to central locations. Continued deterioration in her haemodynamic status was evident with a sinus tachycardia of 155 bpm and BP decreasing to 65/35 mm Hg. Further crystalloid and colloid fluid resuscitation was administered along with the commencement of a noradrenaline infusion to achieve a mean arterial pressure of 70 mm Hg. Over the next 8 h the noradrenaline requirements escalated to 50 g/min. The decision was made to administer hydrocortisone 50 mg every 6 h and commence a vasopressin infusion. Her clinical condition continued to rapidly deteriorate with peripheral purpura and associated bleeding from mouth, nose and puncture sites from line insertions. The petechial rash began to expand over her face, chest and abdomen with
96 distal ischaemia becoming evident. The haematologist conveyed to the intensivist that the blood films showed large numbers of Gram-negative rods clearly visible ‘swarming’ over slides. A differential diagnosis of a possible meningococcal disease was made and further antibiotic therapy was administered (ceftriaxone 2 g). Activated protein C was commenced and continued as an infusion for the next 96 h. At this point an Infectious Disease Physician was consulted to review the patient’s clinical course and avenues for continued therapy. Further antibiotic therapy was administered in the form of meropenem, moxifloxacin and repeated doses of metronidazole. A computed tomography (CT) scan was performed to eliminate any abdominal disease and to help exclude an overwhelming clostridial sepsis. Blood products, including Fresh Frozen Plasma (FFP), cryoprecipitate, platelets, and packed red blood cells suspended in saline—adenine—glucose—mannitol (SAG-M) were available within the next 5 h and were administered to the patient. The CT scan of the chest and abdomen was essentially normal, effectively excluding any infective sources requiring surgical intervention but an aetiological diagnosis remained unclear. Meningococcal disease was now thought unlikely on the basis of history, pathology investigations and medical imaging. Continuous renal replacement therapy (CRRT) was commenced, specifically continuous venovenous haemodiafiltration (CVVHDF) for five days then continuous venovenous haemofiltration (CVVH) for the next ten days. CRRT was ceased when the patient’s urea was 9.9 mmol/L and a creatinine of 181 mmol/L. Adequate amounts of urine were being produced but not in large quantities. The CRRT circuit was initially anticoagulated with heparin; however a persistent thrombocytopaenia raised concerns regarding the possible development of heparin-induced thrombocytopaenia syndrome which, in addition to ongoing DIC, indicated changing to citrate anticoagulation.8 The patient exhibited ongoing DIC with thrombocytopenia, coagulopathy and anaemia and received multiple transfusions of FFP, cryoprecipitate, platelets and packed red blood cells across the course of her illness. On the day following admission to ICU, further discussion with the patient’s husband revealed that she had been bitten on the arm by the family dog 24 h prior to her illness becoming evident. On examination, two shallow tooth marks were noted over the ulnar styloid process. These were not obviously infected and the patient herself had not mentioned this when she presented to the ED.
G.A. O’Rourke, R. Rothwell The widespread vascular rash, which was attributed primarily to DIC and secondarily to vasopressor use, proved extensive and resulted in partial thickness skin loss at the tip of the nose and the ear lobes which were treated with chloramphenicol ointment and healed well. Dermal lesions with blistering of the right forearm and bilateral thighs became evident over time with deeper blistering on the lateral aspects of both thighs. All dermal lesions were treated with third-daily dressings of a silver impregnated barrier dressing and all healed well. The digits of all limbs became necrotic although the thumbs and big toes were relatively spared. The fingertips were allowed to auto-amputate. The tips of all four smaller toes of each foot were surgically amputated after demarcation had occurred. The patient spent a total of twenty-four days in intensive care, was referred to medical and rehabilitation wards and discharged home thirty-two days post admission to hospital. Five days after admission it was reported that a bacterium isolated from blood cultures was provisionally identified as C. canimorsus. Two weeks after admission this was confirmed by the Institute of Clinical Pathology and Medical Research, Westmead, Sydney, Australia following gene sequencing of the isolate.
Data/results Data and results Tables 1 and 2.
in
detail
are
shown
in
Discussion The patient’s case was extremely unusual among cases of C. canimorsus infection in that it initially presented as severe diarrhoea (the resulting dehydration predisposing to multi-organ failure), and that it became overwhelming in an otherwise healthy person with no identifiable risk factors. This case also raises issues regarding her management, in that it may be argued that the severity of her illness was not identified, that she was underresuscitated and subsequently under-monitored. By the time aggressive treatment was commenced she was deteriorating rapidly to the extent that her condition was life-threatening.
Diarrhoea in systemic illness The initial evaluation of a patient with acute diarrhoea needs to include any relevant past history, accurate understanding of the duration of
Capnocytophaga canimorsis a cause of septicaemia following a dog bite: A case review Table 2
97
Arterial blood gases on ward and on admission to CCU.
Parameter
On ward (13:50 h day 2)
On admission to ICU (15:20 h day 2)
pH PaCO2 (mm Hg) [HCO3 − ] (mmol/L) PaO2 (mm Hg)
7.23 14 6 87 (room air)
[Lactate] (mmol/L) [Glucose] (mmol/L Haemoglobin (g/L) [Na+ ] (mmol/L) [K+ ] (mmol/L)
5.7 5.6 129 138 3.5
7.15 12 5 140 (oxygen 4 L/min via nasal cannulae) 7.6 5.3 132 136 3.4
the symptoms and the frequency and consistency of the associated stool. Further clinical evaluation includes monitoring for extracellular volume depletion (urine output, blood pressure and skin turgor), fever, pain and pathological investigations to exclude any invasive enteric pathogens.19 This case presentation had masqueraded itself as an acute gastroenteritis that, in-part, diagnostically misled the clinicians. This patient’s acute illness from diarrhoea, concurrently under treatment, proved near fatal.19
Bacteraemia The genus Capnocytophaga comprises five species of Gram-negative, oxidase-positive, catalasepositive, thin, non-spore forming motile rods 1—3 m in length with tapered or spindle shaped ends. Flagella are not present and a gliding motility is exhibited on microscopy. C. canimorsus is a fastidious slow-growing bacterium, taking from 1 to 14 days to appear in both aerobic and non-aerobic blood culture mediums. C. canimorsus’ growth is enhanced in a CO2 enriched atmosphere; the colonies are smooth, circular, convex or flat and are moist yellow, tan or pinkish in colour.1—4 Differential diagnoses may include C. canimorsus bacteraemia from blood films on demonstration of Gram-negative bacilli within neutrophils (suggesting high level bacteraemia), however a definitive diagnosis cannot be made until at least five days of culture in a laboratory.7,9 C. canimorsus is an opportunistic pathogen which may cause systemic bacteraemia resulting in severe systemic and local inflammatory responses. Complications may include DIC, gangrene and multiple organ failure including acute renal failure, acute respiratory failure and septic shock. Severe infections caused by C. canimorsus are generally associated with identifiable predispos-
ing factors, such as immuno-compromise, previous splenectomy or chronic alcohol abuse.3,6,7,11 It is particularly notable that there were no obvious factors predisposing the patient to this infection; in fact she was an extremely healthy and fit individual.
Sepsis Severe Gram-negative sepsis may lead to the Systemic Inflammatory Response Syndrome and multi-organ failure by several mechanisms, including shock due to profound vasodilation, myocardial depression, diffuse endothelial injury, tissue hypoperfusion and disseminated intravascular coagulation (DIC). Septic shock is defined as hypoperfusion and increased microvascular permeability due to severe sepsis with associated organ dysfunction with hypotension that is unresponsive to adequate fluid resuscitation. Septic shock may lead to multiorgan failure including acute lung injury, metabolic acidosis, renal hypoperfusion and acute renal failure and altered brain function.12 Inhibition of coagulation during Gramnegative sepsis is manifested in critical illness as inflammation-induced coagulation, namely DIC, leading to microvascular ischaemia and associated multiple organ failure.10 DIC is an alteration in the pro-coagulant-anticoagulant balance within the body. There is an overall increase in the pro-coagulant factors and a decrease in the anticoagulant factors resulting in the formation of micro-vascular thrombi and end-organ injury and ultimately dysfunction.12,14 Organ dysfunction with sepsis occurs when the host’s defence to invading organisms and infection are inadequate. The underpinning objective in the treatment of sepsis is to support and manage cardiovascular collapse with fluid resuscitation, inotropic and vasopressor medications, and the implementation of lung-protective ventilation, early introduction
98 of broad spectrum antibiotics, renal replacement therapy and the use of corticosteroids and activated protein C.12,14,15 Gram-negative sepsis may interfere with the body’s coagulation processes and inflammatory process. Local antibacterial defences are dependent on pro-inflammatory cytokines (tumour necrosis factor, interleukin-1, 2 and 6) anti-inflammatory cytokines (interleukin-4 and 10) and soluble inhibitors of cytokines. However a systemic influx of these mediators may lead to tissue toxicity and harm the host.10,14
Activated protein C Activated protein C, or drotrecogin alfa (activated), has antithrombotic, anti-inflammatory and profibrinolytic properties. The PROWESS (recombinant human activated protein C worldwide evaluation in severe sepsis) trial in the use of activated protein C in sepsis showed an inhibition of the activation of thrombin, which leads to decreased levels of platelets, recruitment of neutrophils and degranulation of mast cells with an overall decrease in the inflammatory process.13,14 The use of activated protein C is only approved for use in patients with sepsis and multi-organ failure with a high chance of death according to the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.16
Vasopressin Another complication of septic shock is arterial vasodilatation with accompanying lowered arterial blood pressure which can contribute to endorgan failure. Pressor medication delivery in sepsis related vasodilatory-shock may help in the maintenance of an effective blood pressure. Noradrenaline (NA) is the primary drug used to maintain and sustain a mean arterial pressure (typically greater than 65 mm Hg). If the doses of NA needed to maintain the required blood pressure become excessive then the introduction of another agent may be considered.15,16 Vasopressin arginine may be effective in raising blood pressure in a patient refractory to other vasopressors, and the current dose supported by the literature is at 0.03 U/min.16 Higher doses of vasopressin have been associated with cardiac, digital and splanchnic ischemia and should be reserved for situations where alternative vasopressors have failed.15,16
Management issues The rapid deterioration of this patient was in part attributable to initial under-resuscitation and
G.A. O’Rourke, R. Rothwell under monitoring. There are several identifiable points where more aggressive treatment and monitoring might have been initiated. When the patient presented to the ED she was ascribed a triage category of three, presumably on the grounds her presenting complaint of diarrhoea did not warrant a higher category. It is likely she did not seem particularly unwell as she walked into the ED and retained a clear sensorium. However, it was subsequently apparent that a blood pressure of 56/29 mm Hg demanded a more aggressive response, including early referral to intensive care. Her urine output was not monitored on the ward as she had no urinary catheter and the diarrhoea masked her oliguria. It is striking that no referral was made to the Medical Emergency Team, despite delayed review by the specialist and a high level of concern among nursing staff.20,21 The reasons for this remain unclear. Factors which may have contributed to her inadequate response may include: i. Absence of clear history. ii. Unusual presentation. iii. Good pre-existing health masking the severity of her illness. It is arguable that her good health and fitness allowed her to compensate physiologically for her illness for some time until her compensatory mechanisms failed and she rapidly deteriorated.
Conclusion The potential for dog bites to transmit lifethreatening organisms to humans is clearly evident although rare. It is notable that systemic infections may present in a wide range of ways, including as in this case, severe diarrhoea. C. canimorsus infections are rare and often not severe, although severe infections do occur, especially in susceptible individuals with identifiable predisposing factors. This patient became severely unwell despite the absence of identifiable predisposing factors. It is arguable that her management was compromised by inadequate resuscitation and monitoring and that this was almost disastrous. Ultimately her survival may be attributed to her previous good health and fitness and a rapid response to correct her deterioration once it had been correctly identified.
References 1. Cooley L. Capnocytophaga canimorsus: a serious infection masquerading as a serious infection. Victorian Infectious Disease Bulletin 2001;4(3):37—8.
Capnocytophaga canimorsis a cause of septicaemia following a dog bite: A case review 2. Ehrbar HU, Gubler J, Harbarth S, Hirschel B. Capnocytophaga canimorsus sepsis complicated by myocardial infarction in two patients with normal coronary arteries. Clinical Infectious Diseases 1996;23(2):335—6. 3. Lion C, Escande F, Burdin JC. Capnocytophaga canimorsus infections in human: review of the literature and cases report. European Journal of Epidemiology 1996;12(October (5)):521—33. 4. Blanche P, Sicard D, Meyniard O, Ratovohery D, Brun T, Paul G. Capnocytophaga canimorsus lymphocytic meningitis in an immunocompetent man who was bitten by a dog. Clinical Infectious Diseases 1994;18(4):654—5. 5. Brenner DJ, Hollis DG, Fanning GR, Weaver RE. Capnocytophaga canimorsus sp. nov. (formerly CDC group DF-2), a cause of septicemia following dog bite and C. cynodegmia sp. nov., a cause of localized wound infection following dog bite. Journal of Clinical Microbiology 1989;27(2): 231—5. 6. Le Moal G, Landron C, Grollier G, Robert R, Burucoa C. Meningitis due to Capnocytophaga canimorsus after receipt of a dog bite: case report and review of the literature. Clinical Infectious Diseases 2003;36(3):e42—46. 7. Pers C, Gahrn-Hansen B, Frederiksen W. Capnocytophaga canimorsus septicemia in Denmark, 1982—1995: review of 39 cases. Clinical Infectious Diseases 1996;23: 71—5. 8. Davies H, Morgan D, Leslie G. A regional citrate anticoagulation protocol for pre-dilutional CVVHDf: the ‘modified Alabama protocol’. Australian Critical Care 2008;21:154—66. 9. Mellor D, Bhandari S, Kerr K, Bodenham A. Man’s best friend: life threatening sepsis after minor dog bite. British Medical Journal 1997;314:129—30. 10. Schoenmakers SHHF, Reitsma PH, Spek CA. Blood coagulation factors as inflammatory mediators. Blood Cells, Molecules, and Diseases 2005;34(1):30—7.
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11. Oehler R, Velez A, Mizrachi M, Lamarche J, Gompf S. Bite related and septic syndromes caused by cats and dogs. Lancet Infectious Diseases 2009;9:439—47. 12. Russell J. Management of sepsis. New England Journal of Medicine 2006;355(16):1699—713. 13. Bernard GR, Vincent JL, Laterre PF, LaRosa S, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. New England Journal of Medicine 2001;344(10): 699—709. 14. Hotchkiss R, Karl IE. The pathophysiology and treatment of sepsis. New England Journal of Medicine 2003;348(2):138—50. 15. Schrier R, Wang W. Acute renal failure and sepsis. New England Journal of Medicine 2004;351(2):159—69. 16. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock 2008. Intensive Care Medicine 2008;34: 17—60. 17. Australian Companion Animal Inc. Contribution of the pet care industry to the Australian economy. Sydney: BIS Shrapnel; 2006. 18. Dendle C, Looke D. Review article: animal bites: an update for management with a focus on infections. Emergency Medicine Australasia 2008;20(6):458—67. 19. Thielman NM, Guerrant RL. Clinical practice. Acute infectious diarrhoea. The New England Journal of Medicine 2004:350—438. 20. Tee A, Calzavacca E, Licari E, Goldsmith D, Bellomo R. Bench-to-bedside review: the MET syndrome — the challenges of researching and adopting medical emergency teams. Critical Care 2008;12(1):205—11. 21. Cooper J, Buist M. Vitalness of vital signs, and medical emergency teams. The Medical Journal of Australia 2008;188(11):630—1.
Available online at www.sciencedirect.com
CASE STUDY
Capnocytophaga canimorsis a cause of septicaemia following a dog bite: A case review Geraldine A. O’Rourke RN Dip Health Sci(Nurs), B(Nurs), Grad Dip Crit Care, MClinNurs a,∗, Rob Rothwell BSc(Hons), Grad Dip Appl Sci(Nurs), Post Basic Nurs Certif Intens Care, BMed b,1 a
Clinical Nurse Level Two Critical Care Services, Calvary Healthcare Tasmania, PO Box 50, North Hobart, TAS 7008, Australia b Clinical Nurse Educator Level Three Critical Care Services, Calvary Healthcare Tasmania, GPO 524 Hobart TAS 7000, PO Box 524, North Hobart, TAS 7001, Australia Received 28 December 2009 ; received in revised form 9 October 2010; accepted 7 December 2010
KEYWORDS Capnocytophaga canimorsus; Sepsis; Dog bite; Case study
∗ 1
Summary Described in this study is the case of a 53-year-old woman who developed a life-threatening infection caused by the bacterium Capnocytophaga canimorsus (C. canimorsus), subsequent to being bitten by a dog. The patient presented to an Emergency Department with a 24-h history of diarrhoea and vomiting with dehydration but within 36 h of presentation developed an overwhelming severe sepsis with septic shock, disseminated intravascular coagulation, acute renal failure, metabolic acidosis and threatened acute respiratory failure requiring urgent intensive care intervention. At subsequent questioning her husband volunteered that she had been bitten on the wrist by the family dog 24 h prior to the onset of symptoms; this bite had been extremely minor, requiring no treatment at the time and leaving only a very superficial wound. The causative organism was finally identified two weeks later as C. canimorsus, a common commensal in the oral flora of dogs. C. canimorsus has been reported as a rare cause of severe infection in susceptible individuals; however this case is of particular interest as there were no apparent predisposing factors conferring risk of severe infection. This case also raised significant practice issues for the treating hospital. © 2010 Australian College of Critical Care Nurses Ltd. Published by Elsevier Australia (a division of Reed International Books Australia Pty Ltd). All rights reserved.
Corresponding author. Tel.: +61 418889519. E-mail addresses: [email protected] (G.A. O’Rourke), [email protected] (R. Rothwell). Tel.: +61 414851261.
1036-7314/ $ — see front matter © 2010 Australian College of Critical Care Nurses Ltd. Published by Elsevier Australia (a division of Reed International Books Australia Pty Ltd). All rights reserved.
doi:10.1016/j.aucc.2010.12.002
94
Introduction Capnocytophaga canimorsus is a commensal bacterium found in the saliva of dogs and cats and has been implicated in a variety of disorders including sepsis, meningitis and endocarditis. This previously unidentified Gram-negative bacillus was isolated by the Centres for Disease Control (CDC) Atlanta, GA, USA in 1976 from the spinal fluid and blood of a patient who had sustained a dog bite. A review of cases found 17 patients with similar organisms dating back to 1961 which could not be identified by the existing systems and was given the vernacular; Centres for Disease Control Dysgonic Fermenter-2 due to its slow growing, fermentative and poor bacterial cultural growth features.5,7 In 1989 this bacterium was named C. canimorsus. The genus Capnocytophaga consists of five species, all of which are common to human and canine flora, although of these only C. canimorsus is recognised as a significant potential pathogen. Infection by C. canimorsus has a propensity to cause a local or systemic inflammatory response, with complications including septic shock, disseminated intravascular coagulation (DIC), gangrene, acute renal failure and respiratory failure.1,10 Australia has a canine population of about 3.75—4 million. It is estimated that around 63% of Australian households own some type of pet, with 53% owning a cat or a dog. It has been projected that each year more than 100,000 Australians are attacked by dogs, causing injuries of varying degrees of severity. The Emergency Departments of Australia’s public hospitals treat between 12,000 and 14,000 people for dog bite injuries and almost 1400 of those have injuries that are serious enough to warrant hospitalisation. Between 4 and 25% of dog bite wounds become infected. The median time to presentation with the first symptoms of infection is 24 h.17,18
Case history A 53-year-old woman presented to an Emergency Department (ED) at 08:00-h with a 24-h history of diarrhoea and vomiting. She was initially ascribed an Australian triage scale category of three requiring an urgent review within 30 min.19 She had experienced sudden onset of profuse, watery diarrhoea which had persisted throughout the previous day and night. There was some initial vomiting but this had subsided and the patient was left feeling nauseated, feverish and lethargic with a persis-
G.A. O’Rourke, R. Rothwell tent head and neck ache, no rash was evident. She was alert with clear sensorium and walked into the ED. She had no previous significant medical history including overseas travel or consumption of food or fluids different to her family. She was previously well as were her latest contacts. No mention of a dog bite was made by either the patient or her husband. Her vital signs at admission were heart rate 137 beats per minute (bpm) sinus tachycardia, blood pressure (BP) 56/29 mm Hg, pulse oximetry (SpO2 ) 96% breathing room air and temperature 37.7 ◦ C. Her respiratory rate was not recorded. Serum biochemistry was consistent with moderate dehydration with a systemic inflammatory response (elevated C-reactive protein) but was otherwise unremarkable (see Table 1). Initial treatment in the ED comprised intravenous (IV) fluid resuscitation (4 L crystalloid plus 0.5 L colloid over 7 h) and antiemetic therapy; after which her vital signs were heart rate 102 bpm, BP 76/42 mm Hg, temperature 38.1 ◦ C and SpO2 98% breathing room air. The patient was then admitted to a general medical ward under the care of a specialist gastroenterologist. Her condition deteriorated over the next 21 h, her temperature peaking 40.2 ◦ C at which time blood cultures were taken. IV fluids continued at a rate of 125—250 mL/h. Her heart rate gradually increased to 130 bpm and respiratory rate from 16 to 40 breaths per minute. The profuse diarrhoea persisted and she experienced increasing difficulty maintaining oral intake of fluids or food, due partly to nausea but also developing dyspnoea. During this time her urine output was not known due to a lack of an in-dwelling urinary catheter and inaccurate fluid balance documentation. She was reviewed by the gastroenterologist at 13:00-h the next afternoon. The nursing notes indicate rising concern about her condition and, although she met the criteria for referral to the Medical Emergency Team (MET) of respiratory rate greater than 36 breaths per minute and a person causing ‘‘serious concern’’, no such referral was made. Following medical review the patient was urgently referred to the intensive care specialist and a haematologist. Prior to transfer to the Intensive Care Unit (ICU) arterial blood gases (ABGs) showed a severe metabolic acidosis with raised serum lactate and partial respiratory compensation (see Table 2). A stat dose of ciprofloxacin 200 mg IV was given. Blood was drawn for urea and electrolytes, creatinine, full blood count, liver function tests, coagulation studies and a second set of blood cultures including aerobic and anaerobic and fungal studies.
Capnocytophaga canimorsis a cause of septicaemia following a dog bite: A case review Table 1
95
Serum biochemistry, haematology and coagulation studies days 1 and 2.
Parameter
Day 1
Day 2
[Na+ ] (mmol/L) [K+ ] (mmol/L) [Cl− ] (mmol/L) [Urea] (mmol/L) [Creatinine] (micromol/L) [Bicarbonate] (mmol/L) Estimated glomerular filtration rate (mL/min) C-reactive protein (mg/L) Erythrocyte sedimentation rate (mm/h) Gamma-glutamyl transferase (U/L) Alkaline phosphatase (U/L) Alanine aminotransferase (U/L) Corrected [Ca2+ ] (mmol/L) [Mg2+ ] (mmol/L) INR Activated partial thromboplastin time (s) Haemoglobin (g/L) Platelets (×109 /L) White cell count (×109 /L) Neutrophils (×109 /L) Fibrinogen (g/L)
135 3.9 111 13.6 135 26 38 38 14 30 19 41 1.83 0.60 Not requested Not requested Not requested Not requested Not requested Not requested Not requested
140 3.9 117 13.6 226 5 21 340 Not requested 53 115 77 1.68 0.53 1.9 110 105 98 12.7 10.9 0.9
On transfer to the ICU she was distressed but alert and co-operative. Vital signs showed a heart rate 130 bpm, sinus tachycardia, blood pressure 130/80 mm Hg, a respiratory rate of 40 breaths per minute, pulse oximetry 100% with supplemental oxygen at 4 L/min via nasal cannulae and temperature 37.6 ◦ C. Further antibiotics administered were gentamicin 240 mg IV as a single dose, ticarcillin 3 g plus clavulanate 500 mg IV 6hourly and metronidazole 500 mg IV 8-hourly. On examination she exhibited marked diaphoresis and peripheral hypoperfusion, dry mucous membranes and reduced tissue turgor. Jugular venous pressure was not visible. Her breath sounds were clear; her abdomen was soft and non tender with no organomegaly. Bowel sounds were present. There was no rash or lymphadenopathy. A central venous catheter, intra-arterial catheter and vascular access catheter for renal replacement therapy were inserted — these all required multiple attempts due to the severely depleted intravascular volume. Repeat ABGs showed increasing metabolic acidosis with worsening pH despite increasing respiratory compensation (see Table 2). Sodium bicarbonate 8.4% was administered (100 mL plus ongoing infusion). Fluid resuscitation initially comprised crystalloid 2 L plus colloid 0.5 L then ongoing crystalloid at 1 L/h. Serum biochemistry, haematology and coagulation studies were consistent with severe dehydration with marked renal impairment, increased
inflammatory response and an incipient disseminated intravascular coagulation with coagulopathy and thrombocytopaenia. Subsequent pathological findings were an elevated D-dimer, a decreased fibrinogen and a moderate neutrophilia. Insertion of an indwelling urinary catheter revealed a residual urine volume of 10 mL and ongoing anuria consistent with acute renal failure. She was electively intubated at 16:00-h and ventilated due to threatened respiratory failure secondary to her extreme work of breathing. At this point, 28 h post admission; the patient began to show evidence of a purpuric discolouration of digits, nose and ears. Also noticeable was a petechial rash originating in the peripheries and spreading rapidly to central locations. Continued deterioration in her haemodynamic status was evident with a sinus tachycardia of 155 bpm and BP decreasing to 65/35 mm Hg. Further crystalloid and colloid fluid resuscitation was administered along with the commencement of a noradrenaline infusion to achieve a mean arterial pressure of 70 mm Hg. Over the next 8 h the noradrenaline requirements escalated to 50 g/min. The decision was made to administer hydrocortisone 50 mg every 6 h and commence a vasopressin infusion. Her clinical condition continued to rapidly deteriorate with peripheral purpura and associated bleeding from mouth, nose and puncture sites from line insertions. The petechial rash began to expand over her face, chest and abdomen with
96 distal ischaemia becoming evident. The haematologist conveyed to the intensivist that the blood films showed large numbers of Gram-negative rods clearly visible ‘swarming’ over slides. A differential diagnosis of a possible meningococcal disease was made and further antibiotic therapy was administered (ceftriaxone 2 g). Activated protein C was commenced and continued as an infusion for the next 96 h. At this point an Infectious Disease Physician was consulted to review the patient’s clinical course and avenues for continued therapy. Further antibiotic therapy was administered in the form of meropenem, moxifloxacin and repeated doses of metronidazole. A computed tomography (CT) scan was performed to eliminate any abdominal disease and to help exclude an overwhelming clostridial sepsis. Blood products, including Fresh Frozen Plasma (FFP), cryoprecipitate, platelets, and packed red blood cells suspended in saline—adenine—glucose—mannitol (SAG-M) were available within the next 5 h and were administered to the patient. The CT scan of the chest and abdomen was essentially normal, effectively excluding any infective sources requiring surgical intervention but an aetiological diagnosis remained unclear. Meningococcal disease was now thought unlikely on the basis of history, pathology investigations and medical imaging. Continuous renal replacement therapy (CRRT) was commenced, specifically continuous venovenous haemodiafiltration (CVVHDF) for five days then continuous venovenous haemofiltration (CVVH) for the next ten days. CRRT was ceased when the patient’s urea was 9.9 mmol/L and a creatinine of 181 mmol/L. Adequate amounts of urine were being produced but not in large quantities. The CRRT circuit was initially anticoagulated with heparin; however a persistent thrombocytopaenia raised concerns regarding the possible development of heparin-induced thrombocytopaenia syndrome which, in addition to ongoing DIC, indicated changing to citrate anticoagulation.8 The patient exhibited ongoing DIC with thrombocytopenia, coagulopathy and anaemia and received multiple transfusions of FFP, cryoprecipitate, platelets and packed red blood cells across the course of her illness. On the day following admission to ICU, further discussion with the patient’s husband revealed that she had been bitten on the arm by the family dog 24 h prior to her illness becoming evident. On examination, two shallow tooth marks were noted over the ulnar styloid process. These were not obviously infected and the patient herself had not mentioned this when she presented to the ED.
G.A. O’Rourke, R. Rothwell The widespread vascular rash, which was attributed primarily to DIC and secondarily to vasopressor use, proved extensive and resulted in partial thickness skin loss at the tip of the nose and the ear lobes which were treated with chloramphenicol ointment and healed well. Dermal lesions with blistering of the right forearm and bilateral thighs became evident over time with deeper blistering on the lateral aspects of both thighs. All dermal lesions were treated with third-daily dressings of a silver impregnated barrier dressing and all healed well. The digits of all limbs became necrotic although the thumbs and big toes were relatively spared. The fingertips were allowed to auto-amputate. The tips of all four smaller toes of each foot were surgically amputated after demarcation had occurred. The patient spent a total of twenty-four days in intensive care, was referred to medical and rehabilitation wards and discharged home thirty-two days post admission to hospital. Five days after admission it was reported that a bacterium isolated from blood cultures was provisionally identified as C. canimorsus. Two weeks after admission this was confirmed by the Institute of Clinical Pathology and Medical Research, Westmead, Sydney, Australia following gene sequencing of the isolate.
Data/results Data and results Tables 1 and 2.
in
detail
are
shown
in
Discussion The patient’s case was extremely unusual among cases of C. canimorsus infection in that it initially presented as severe diarrhoea (the resulting dehydration predisposing to multi-organ failure), and that it became overwhelming in an otherwise healthy person with no identifiable risk factors. This case also raises issues regarding her management, in that it may be argued that the severity of her illness was not identified, that she was underresuscitated and subsequently under-monitored. By the time aggressive treatment was commenced she was deteriorating rapidly to the extent that her condition was life-threatening.
Diarrhoea in systemic illness The initial evaluation of a patient with acute diarrhoea needs to include any relevant past history, accurate understanding of the duration of
Capnocytophaga canimorsis a cause of septicaemia following a dog bite: A case review Table 2
97
Arterial blood gases on ward and on admission to CCU.
Parameter
On ward (13:50 h day 2)
On admission to ICU (15:20 h day 2)
pH PaCO2 (mm Hg) [HCO3 − ] (mmol/L) PaO2 (mm Hg)
7.23 14 6 87 (room air)
[Lactate] (mmol/L) [Glucose] (mmol/L Haemoglobin (g/L) [Na+ ] (mmol/L) [K+ ] (mmol/L)
5.7 5.6 129 138 3.5
7.15 12 5 140 (oxygen 4 L/min via nasal cannulae) 7.6 5.3 132 136 3.4
the symptoms and the frequency and consistency of the associated stool. Further clinical evaluation includes monitoring for extracellular volume depletion (urine output, blood pressure and skin turgor), fever, pain and pathological investigations to exclude any invasive enteric pathogens.19 This case presentation had masqueraded itself as an acute gastroenteritis that, in-part, diagnostically misled the clinicians. This patient’s acute illness from diarrhoea, concurrently under treatment, proved near fatal.19
Bacteraemia The genus Capnocytophaga comprises five species of Gram-negative, oxidase-positive, catalasepositive, thin, non-spore forming motile rods 1—3 m in length with tapered or spindle shaped ends. Flagella are not present and a gliding motility is exhibited on microscopy. C. canimorsus is a fastidious slow-growing bacterium, taking from 1 to 14 days to appear in both aerobic and non-aerobic blood culture mediums. C. canimorsus’ growth is enhanced in a CO2 enriched atmosphere; the colonies are smooth, circular, convex or flat and are moist yellow, tan or pinkish in colour.1—4 Differential diagnoses may include C. canimorsus bacteraemia from blood films on demonstration of Gram-negative bacilli within neutrophils (suggesting high level bacteraemia), however a definitive diagnosis cannot be made until at least five days of culture in a laboratory.7,9 C. canimorsus is an opportunistic pathogen which may cause systemic bacteraemia resulting in severe systemic and local inflammatory responses. Complications may include DIC, gangrene and multiple organ failure including acute renal failure, acute respiratory failure and septic shock. Severe infections caused by C. canimorsus are generally associated with identifiable predispos-
ing factors, such as immuno-compromise, previous splenectomy or chronic alcohol abuse.3,6,7,11 It is particularly notable that there were no obvious factors predisposing the patient to this infection; in fact she was an extremely healthy and fit individual.
Sepsis Severe Gram-negative sepsis may lead to the Systemic Inflammatory Response Syndrome and multi-organ failure by several mechanisms, including shock due to profound vasodilation, myocardial depression, diffuse endothelial injury, tissue hypoperfusion and disseminated intravascular coagulation (DIC). Septic shock is defined as hypoperfusion and increased microvascular permeability due to severe sepsis with associated organ dysfunction with hypotension that is unresponsive to adequate fluid resuscitation. Septic shock may lead to multiorgan failure including acute lung injury, metabolic acidosis, renal hypoperfusion and acute renal failure and altered brain function.12 Inhibition of coagulation during Gramnegative sepsis is manifested in critical illness as inflammation-induced coagulation, namely DIC, leading to microvascular ischaemia and associated multiple organ failure.10 DIC is an alteration in the pro-coagulant-anticoagulant balance within the body. There is an overall increase in the pro-coagulant factors and a decrease in the anticoagulant factors resulting in the formation of micro-vascular thrombi and end-organ injury and ultimately dysfunction.12,14 Organ dysfunction with sepsis occurs when the host’s defence to invading organisms and infection are inadequate. The underpinning objective in the treatment of sepsis is to support and manage cardiovascular collapse with fluid resuscitation, inotropic and vasopressor medications, and the implementation of lung-protective ventilation, early introduction
98 of broad spectrum antibiotics, renal replacement therapy and the use of corticosteroids and activated protein C.12,14,15 Gram-negative sepsis may interfere with the body’s coagulation processes and inflammatory process. Local antibacterial defences are dependent on pro-inflammatory cytokines (tumour necrosis factor, interleukin-1, 2 and 6) anti-inflammatory cytokines (interleukin-4 and 10) and soluble inhibitors of cytokines. However a systemic influx of these mediators may lead to tissue toxicity and harm the host.10,14
Activated protein C Activated protein C, or drotrecogin alfa (activated), has antithrombotic, anti-inflammatory and profibrinolytic properties. The PROWESS (recombinant human activated protein C worldwide evaluation in severe sepsis) trial in the use of activated protein C in sepsis showed an inhibition of the activation of thrombin, which leads to decreased levels of platelets, recruitment of neutrophils and degranulation of mast cells with an overall decrease in the inflammatory process.13,14 The use of activated protein C is only approved for use in patients with sepsis and multi-organ failure with a high chance of death according to the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.16
Vasopressin Another complication of septic shock is arterial vasodilatation with accompanying lowered arterial blood pressure which can contribute to endorgan failure. Pressor medication delivery in sepsis related vasodilatory-shock may help in the maintenance of an effective blood pressure. Noradrenaline (NA) is the primary drug used to maintain and sustain a mean arterial pressure (typically greater than 65 mm Hg). If the doses of NA needed to maintain the required blood pressure become excessive then the introduction of another agent may be considered.15,16 Vasopressin arginine may be effective in raising blood pressure in a patient refractory to other vasopressors, and the current dose supported by the literature is at 0.03 U/min.16 Higher doses of vasopressin have been associated with cardiac, digital and splanchnic ischemia and should be reserved for situations where alternative vasopressors have failed.15,16
Management issues The rapid deterioration of this patient was in part attributable to initial under-resuscitation and
G.A. O’Rourke, R. Rothwell under monitoring. There are several identifiable points where more aggressive treatment and monitoring might have been initiated. When the patient presented to the ED she was ascribed a triage category of three, presumably on the grounds her presenting complaint of diarrhoea did not warrant a higher category. It is likely she did not seem particularly unwell as she walked into the ED and retained a clear sensorium. However, it was subsequently apparent that a blood pressure of 56/29 mm Hg demanded a more aggressive response, including early referral to intensive care. Her urine output was not monitored on the ward as she had no urinary catheter and the diarrhoea masked her oliguria. It is striking that no referral was made to the Medical Emergency Team, despite delayed review by the specialist and a high level of concern among nursing staff.20,21 The reasons for this remain unclear. Factors which may have contributed to her inadequate response may include: i. Absence of clear history. ii. Unusual presentation. iii. Good pre-existing health masking the severity of her illness. It is arguable that her good health and fitness allowed her to compensate physiologically for her illness for some time until her compensatory mechanisms failed and she rapidly deteriorated.
Conclusion The potential for dog bites to transmit lifethreatening organisms to humans is clearly evident although rare. It is notable that systemic infections may present in a wide range of ways, including as in this case, severe diarrhoea. C. canimorsus infections are rare and often not severe, although severe infections do occur, especially in susceptible individuals with identifiable predisposing factors. This patient became severely unwell despite the absence of identifiable predisposing factors. It is arguable that her management was compromised by inadequate resuscitation and monitoring and that this was almost disastrous. Ultimately her survival may be attributed to her previous good health and fitness and a rapid response to correct her deterioration once it had been correctly identified.
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