Advertisement

Pyometra in Small Animals

      Keywords

      Key points

      • Pyometra foremost affects middle-aged to older intact bitches and queens, usually within 4 months after estrus.
      • Hormonal and bacterial factors are involved in the pathogenesis, and progesterone plays a key role.
      • Cystic endometrial hyperplasia (CEH) is a predisposing factor, but pyometra and CEH can develop independently.
      • Pyometra induces endotoxemia and sepsis, and early diagnosis and treatment increase the chances of survival.
      • Diagnosis is based on clinical signs and findings on physical examination, hematology and biochemistry laboratory tests, and diagnostic imaging identifying intrauterine fluid.
      • Surgical ovariohysterectomy is the safest and most effective treatment, as the source of infection is removed and recurrence prevented. Medical treatment can be an alternative in young and otherwise healthy breeding animals with open cervix and without other uterine or ovarian pathologies.
      Video content accompanies this article at http://www.vetsmall.theclinics.com.

      Introduction

      Pyometra, literally meaning “pus-filled uterus,” is a common illness in adult intact female dogs and cats and a less frequent diagnosis in other small animal species.
      • Egenvall A.
      • Hagman R.
      • Bonnett B.N.
      • et al.
      Breed risk of pyometra in insured dogs in Sweden.
      • Hagman R.
      • Strom Holst B.
      • Moller L.
      • et al.
      Incidence of pyometra in Swedish insured cats.
      The disease is characterized by an acute or chronic suppurative bacterial infection of the uterus post estrum with accumulation of inflammatory exudate in the uterine lumen and a variety of clinical and pathologic manifestations, locally and systemically.
      • Dow C.
      The cystic hyperplasia-pyometra complex in the bitch.
      The disease develops during the luteal phase, and progesterone plays a key role for the establishment of infection with ascending opportunistic bacteria. The pathogen most often isolated from pyometra uteri is Escherichia coli.
      • Hagman R.
      • Greko C.
      Antimicrobial resistance in Escherichia coli isolated from bitches with pyometra and from urine samples from other dogs.
      • Sandholm M.
      • Vasenius H.
      • Kivisto A.K.
      Pathogenesis of canine pyometra.
      • Wadås B.
      • Kuhn I.
      • Lagerstedt A.S.
      • et al.
      Biochemical phenotypes of Escherichia coli in dogs: comparison of isolates isolated from bitches suffering from pyometra and urinary tract infection with isolates from faeces of healthy dogs.
      A wide range of clinical signs are associated with the disease, which can be life-threatening in severe cases. It is important to seek immediate veterinary care when pyometra is suspected because a patient’s status may deteriorate rapidly and early intervention increases chances of survival. The diagnosis is generally straightforward but can be challenging when there is no vaginal discharge and obscure clinical signs. Surgical ovariohysterectomy (OHE) is the safest and most efficient treatment, but purely medical alternatives may be an option in some cases.

      Epidemiology and risk factors

      Pyometra is an important disease, particularly in countries where elective neutering of healthy dogs and cats is not generally performed.
      • Egenvall A.
      • Hagman R.
      • Bonnett B.N.
      • et al.
      Breed risk of pyometra in insured dogs in Sweden.
      • Hagman R.
      • Strom Holst B.
      • Moller L.
      • et al.
      Incidence of pyometra in Swedish insured cats.
      • Jitpean S.
      • Hagman R.
      • Strom Holst B.
      • et al.
      Breed variations in the incidence of pyometra and mammary tumours in Swedish dogs.
      In Sweden, in average 20% of all bitches are diagnosed before 10 years of age and more than 50% in certain high-risk breeds. The disease generally affects middle-aged to older bitches, with a mean age at diagnosis of 7 years, and has been reported in dogs from 4 months to 18 years of age. The overall incidence rate is 199 per 10,000 dog-years at risk.
      • Jitpean S.
      • Hagman R.
      • Strom Holst B.
      • et al.
      Breed variations in the incidence of pyometra and mammary tumours in Swedish dogs.
      In cats, pyometra is not as common, which is believed to depend on less progesterone dominance due to seasonality and induced ovulation. In queens, 2.2% are diagnosed with the disease before 13 years of age, with an incidence rate of 17 cats per 10,000 cat-years at risk.
      • Hagman R.
      • Strom Holst B.
      • Moller L.
      • et al.
      Incidence of pyometra in Swedish insured cats.
      The mean age at diagnosis is 5.6 years, with an age range of 10 months to 20 years, and the incidence increases with age and markedly over 7 years of age.
      • Hagman R.
      • Strom Holst B.
      • Moller L.
      • et al.
      Incidence of pyometra in Swedish insured cats.
      • Davidson A.P.
      • Feldman E.C.
      • Nelson R.W.
      Treatment of pyometra in cats, using prostaglandin F2 alpha: 21 cases (1982-1990).
      • Kenney K.J.
      • Matthiesen D.T.
      • Brown N.O.
      • et al.
      Pyometra in cats: 183 cases (1979-1984).
      • Hagman R.
      • Karlstam E.
      • Persson S.
      • et al.
      Plasma PGF 2 alpha metabolite levels in cats with uterine disease.
      A higher incidence in some dog and cat breeds indicates that they may have a genetic predisposition.
      • Egenvall A.
      • Hagman R.
      • Bonnett B.N.
      • et al.
      Breed risk of pyometra in insured dogs in Sweden.
      • Hagman R.
      • Strom Holst B.
      • Moller L.
      • et al.
      Incidence of pyometra in Swedish insured cats.
      • Jitpean S.
      • Hagman R.
      • Strom Holst B.
      • et al.
      Breed variations in the incidence of pyometra and mammary tumours in Swedish dogs.
      • Kenney K.J.
      • Matthiesen D.T.
      • Brown N.O.
      • et al.
      Pyometra in cats: 183 cases (1979-1984).
      Exogenous treatment with steroid hormones, such as progestogens, or estrogen compounds that increase the response to progesterone, are associated with increased risk of the disease.
      • Niskanen M.
      • Thrusfield M.V.
      Associations between age, parity, hormonal therapy and breed, and pyometra in Finnish dogs.
      • Von Berky A.G.
      • Townsend W.L.
      The relationship between the prevalence of uterine lesions and the use of medroxyprogesterone acetate for canine population control.
      Pregnancy is slightly protective in dogs, an effect that is also influenced by breed.
      • Hagman R.
      • Lagerstedt A.S.
      • Hedhammar A.
      • et al.
      A breed-matched case-control study of potential risk-factors for canine pyometra.
      Cystic endometrial hyperplasia (CEH) is believed to increase the uterine susceptibility for infection.
      • Cox J.E.
      Progestagens in bitches: a review.
      • England G.C.
      • Moxon R.
      • Freeman S.L.
      Delayed uterine fluid clearance and reduced uterine perfusion in bitches with endometrial hyperplasia and clinical management with postmating antibiotic.
      In cats, little is known about risk factors and protective factors but previous hormone therapy (ie, exogenous progesterone) is associated with an increased risk.
      • Hollinshead F.
      • Krekeler N.
      Pyometra in the queen: to spay or not to spay?.

      Etiology and pathogenesis

      The complex pathogenesis of pyometra is not yet completely understood but involves both hormonal and bacterial factors. Although most studies have been done in dogs, the development is believed similar in cats. The uterine environment during the luteal phase is suitable for pregnancy but also for microbial growth. Progesterone stimulates growth and proliferation of endometrial glands, increased secretion, cervical closure, and suppression of myometrial contractions.
      • Cox J.E.
      Progestagens in bitches: a review.
      The local leukocyte response and uterine resistance to bacterial infection also become decreased.
      • Wijewardana V.
      • Sugiura K.
      • Wijesekera D.P.
      • et al.
      Effect of ovarian hormones on maturation of dendritic cells from peripheral blood monocytes in dogs.
      • Rowson L.E.
      • Lamming G.E.
      • Fry R.M.
      Influence of ovarian hormones on uterine infection.
      • Hawk H.W.
      • Turner G.D.
      • Sykes J.F.
      The effect of ovarian hormones on the uterine defense mechanism during the early stages of induced infection.
      Circulating concentrations of estrogen and progesterone are not usually abnormally elevated in pyometra, and increased numbers and sensitivity of hormone receptors are believed to initiate an amplified response.
      • Chaffaux S.
      • Thibier M.
      Peripheral plasma concentrations of progesterone in the bitch with pyometra.
      • Prapaiwan N.
      • Manee-In S.
      • Olanratmanee E.
      • et al.
      Expression of oxytocin, progesterone, and estrogen receptors in the reproductive tract of bitches with pyometra.
      Simultaneous corpora lutea and follicular cysts are more often found in bitches with pyometra, supporting a synergistic hormonal effect.
      • Strom Holst B.
      • Larsson B.
      • Rodriguez-Martinez H.
      • et al.
      Prediction of the oocyte recovery rate in the bitch.
      Progesterone-mediated pathologic proliferation and growth of endometrial glands and formation of cysts (ie, cystic endometrial hyperplasia [CEH]) is believed to predispose for pyometra but the 2 disorders can develop independently (Fig. 1).
      • De Bosschere H.
      • Ducatelle R.
      • Vermeirsch H.
      • et al.
      Cystic endometrial hyperplasia-pyometra complex in the bitch: should the two entities be disconnected?.
      Sterile fluid may accumulate in the uterine lumen, with or without CEH, which is defined as hydrometra or mucometra or, more rarely, hemometra, depending on the type of fluid and its mucin content. Clinical signs are generally subclinical or mild when there is no bacterial infection of the uterus.
      • Dow C.
      The cystic hyperplasia-pyometra complex in the bitch.
      • Fransson B.A.
      • Karlstam E.
      • Bergstrom A.
      • et al.
      C-reactive protein in the differentiation of pyometra from cystic endometrial hyperplasia/mucometra in dogs.
      • Hagman R.
      • Kindahl H.
      • Fransson B.A.
      • et al.
      Differentiation between pyometra and cystic endometrial hyperplasia/mucometra in bitches by prostaglandin F2alpha metabolite analysis.
      Figure thumbnail gr1
      Fig. 1Images of histologic examination findings in uterine tissues examples from dogs with CEH/pyometra. (A) CEH; (B) larger magnification of (A); (C) CEH–endometritis; (D) pyometra; (E) larger magnification of (D); (F) pyometra–atrophic endometrium.
      E coli is the predominant pathogen isolated from pyometra uteri, but other species may also occur (Table 1).
      • Hagman R.
      • Greko C.
      Antimicrobial resistance in Escherichia coli isolated from bitches with pyometra and from urine samples from other dogs.
      • Børresen B.
      • Naess B.
      Microbial immunological and toxicological aspects of canine pyometra.
      • Coggan J.A.
      • Melville P.A.
      • de Oliveira C.M.
      • et al.
      Microbiological and histopathological aspects of canine pyometra.
      • Fransson B.
      • Lagerstedt A.S.
      • Hellmen E.
      • et al.
      Bacteriological findings, blood chemistry profile and plasma endotoxin levels in bitches with pyometra or other uterine diseases.
      • Grindlay M.
      • Renton J.P.
      • Ramsay D.H.
      O-groups of Escherichia coli associated with canine pyometra.
      More than 1 bacterial species can be involved, and cultures are sometimes negative.
      • Fransson B.
      • Lagerstedt A.S.
      • Hellmen E.
      • et al.
      Bacteriological findings, blood chemistry profile and plasma endotoxin levels in bitches with pyometra or other uterine diseases.
      • Grindlay M.
      • Renton J.P.
      • Ramsay D.H.
      O-groups of Escherichia coli associated with canine pyometra.
      Emphysematous pyometra is caused by gas-producing bacteria.
      • Hernandez J.L.
      • Besso J.G.
      • Rault D.N.
      • et al.
      Emphysematous pyometra in a dog.
      A healthy uterus eliminates bacteria that have entered during cervical opening, but the clearance capacity varies depending on the estrus cycle stage. Experimental E coli infection during the luteal phase more often leads to CEH/pyometra compared with in other estrus cycle stages.
      • Nomura K.
      • Yoshida K.
      • Funahashi H.
      • et al.
      The possibilities of uterine infection of Escherichia coli inoculated into the vagina and development of endometritis in bitches.
      The infection is most likely ascending because the same strains are present in the gastrointestinal tract, but hematogenic spread could possibly also occur.
      • Wadås B.
      • Kuhn I.
      • Lagerstedt A.S.
      • et al.
      Biochemical phenotypes of Escherichia coli in dogs: comparison of isolates isolated from bitches suffering from pyometra and urinary tract infection with isolates from faeces of healthy dogs.
      • Agostinho J.M.
      • de Souza A.
      • Schocken-Iturrino R.P.
      • et al.
      Escherichia coli strains isolated from the uteri horn, mouth, and rectum of bitches suffering from pyometra: virulence factors, antimicrobial susceptibilities, and clonal relationships among strains.
      • Hagman R.
      • Kuhn I.
      Escherichia coli strains isolated from the uterus and urinary bladder of bitches suffering from pyometra: comparison by restriction enzyme digestion and pulsed-field gel electrophoresis.
      E coli are natural inhabitants of the vaginal flora
      • Watts J.R.
      • Wright P.J.
      • Whithear K.C.
      Uterine, cervical and vaginal microflora of the normal bitch throughout the reproductive cycle.
      and have an increased ability to adhere to specific receptors in a progesterone-stimulated endometrium.
      • Sandholm M.
      • Vasenius H.
      • Kivisto A.K.
      Pathogenesis of canine pyometra.
      Certain serotypes of E coli are more common and often exhibit the same virulence traits as isolates from urinary tract infections.
      • Mateus L.
      • Henriques S.
      • Merino C.
      • et al.
      Virulence genotypes of Escherichia coli canine isolates from pyometra, cystitis and fecal origin.
      • Siqueira A.K.
      • Ribeiro M.G.
      • Leite Dda S.
      • et al.
      Virulence factors in Escherichia coli strains isolated from urinary tract infection and pyometra cases and from feces of healthy dogs.
      • Chen Y.M.
      • Wright P.J.
      • Lee C.S.
      • et al.
      Uropathogenic virulence factors in isolates of Escherichia coli from clinical cases of canine pyometra and feces of healthy bitches.
      The same bacterial clone can frequently be isolated from the uterus and the urinary bladder in pyometra.
      • Sandholm M.
      • Vasenius H.
      • Kivisto A.K.
      Pathogenesis of canine pyometra.
      • Wadås B.
      • Kuhn I.
      • Lagerstedt A.S.
      • et al.
      Biochemical phenotypes of Escherichia coli in dogs: comparison of isolates isolated from bitches suffering from pyometra and urinary tract infection with isolates from faeces of healthy dogs.
      • Hagman R.
      • Kuhn I.
      Escherichia coli strains isolated from the uterus and urinary bladder of bitches suffering from pyometra: comparison by restriction enzyme digestion and pulsed-field gel electrophoresis.
      Table 1Bacterial species isolated from the uterus in bitches and queens with pyometra
      Data from Refs.
      • Hagman R.
      • Greko C.
      Antimicrobial resistance in Escherichia coli isolated from bitches with pyometra and from urine samples from other dogs.
      • Sandholm M.
      • Vasenius H.
      • Kivisto A.K.
      Pathogenesis of canine pyometra.
      • Davidson A.P.
      • Feldman E.C.
      • Nelson R.W.
      Treatment of pyometra in cats, using prostaglandin F2 alpha: 21 cases (1982-1990).
      • Kenney K.J.
      • Matthiesen D.T.
      • Brown N.O.
      • et al.
      Pyometra in cats: 183 cases (1979-1984).
      • Hagman R.
      • Karlstam E.
      • Persson S.
      • et al.
      Plasma PGF 2 alpha metabolite levels in cats with uterine disease.
      • Fransson B.
      • Lagerstedt A.S.
      • Hellmen E.
      • et al.
      Bacteriological findings, blood chemistry profile and plasma endotoxin levels in bitches with pyometra or other uterine diseases.
      • Hernandez J.L.
      • Besso J.G.
      • Rault D.N.
      • et al.
      Emphysematous pyometra in a dog.
      • Børresen B.
      Pyometra in the dog. II.–A pathophysiological investigation. II. Anamnestic, clinical and reproductive aspects.
      • Vandeplassche M.
      • Coryn M.
      • De Schepper J.
      Pyometra in the bitch: cytological, bacterial, histological and endocrinological characteristics.
      • Hardy R.M.
      • Osborne C.A.
      Canine pyometra: pathophysiology, diagnosis and treatment of uterine and extra-genital lesions.
      • Maddens B.
      • Heiene R.
      • Smets P.
      • et al.
      Evaluation of kidney injury in dogs with pyometra based on proteinuria, renal histomorphology, and urinary biomarkers.
      • Jitpean S.
      • Pettersson A.
      • Hoglund O.V.
      • et al.
      Increased concentrations of Serum amyloid A in dogs with sepsis caused by pyometra.
      OrganismProportion in Bitches (%)Proportion in Queens (%)
      Escherichia coli65–9071
      Staphylococcus spp2–158
      Streptococcus spp4–2319
      Pseudomonas spp1–8
      Proteus spp1–4
      Enterobacter spp1–3
      Nocardia spp10
      Pasteurella spp1–2<1
      Klebsiella spp2–14<1
      Mixed culture4–16
      No growth10–2620
      Mycoplasma spp, Enterococcus spp, Clostridium perfringens, Corynebacterium spp, Citrobacter spp, Moraxella spp, Edwardsiella spp, and others<1<1
      Bacteria and bacterial products are potent inducers of local and systemic inflammation. Endotoxin, lipopolysaccharide components of Gram-negative bacteria, such as E coli, are released into the circulation during bacterial disintegration and induces fever, lethargy, tachycardia, and tachypnea.
      • Van Miert A.S.J.
      • Frens J.
      The reaction of different animal species to bacterial pyrogens.
      Higher endotoxin concentrations may cause fatal shock, disseminated intravascular coagulation, and generalized organ failure.
      • McAnulty J.F.
      Septic shock in the dog: a review.
      • Okano S.
      • Tagawa M.
      • Takase K.
      Relationship of the blood endotoxin concentration and prognosis in dogs with pyometra.
      Pyometra has been associated with endotoxemia
      • Okano S.
      • Tagawa M.
      • Takase K.
      Relationship of the blood endotoxin concentration and prognosis in dogs with pyometra.
      • Hagman R.
      • Kindahl H.
      • Lagerstedt A.S.
      Pyometra in bitches induces elevated plasma endotoxin and prostaglandin F2alpha metabolite levels.
      and bacteremia,
      • Karlsson I.
      • Wernersson S.
      • Ambrosen A.
      • et al.
      Increased concentrations of C-reactive protein but not high-mobility group box 1 in dogs with naturally occurring sepsis.
      and disseminated infection may affect various organs.
      • Marretta S.M.
      • Matthiesen D.T.
      • Nichols R.
      Pyometra and its complications.
      • Wheaton L.G.
      • Johnson A.L.
      • Parker A.J.
      • et al.
      Results and complications of surgical treatment of pyometra: a review of 80 cases.
      Approximately 60% of bitches and 86% of queens with pyometra suffer from sepsis (ie, life-threatening organ dysfunction caused by a dysregulated host response to an infectious process).
      • Singer M.
      The new sepsis consensus definitions (Sepsis-3): the good, the not-so-bad, and the actually-quite-pretty.
      • Brady C.A.
      • Otto C.M.
      • Van Winkle T.J.
      • et al.
      Severe sepsis in cats: 29 cases (1986-1998).
      The illness is considered a medical emergency and it is important to seek immediate veterinary care because a patient’s health status may deteriorate rapidly.

      Clinical presentation

      Typically, middle-aged to older animals are presented up to 2 months to 4 months after estrus with a history of various signs associated with the genital tract and systemic illness (Table 2). A continuous or intermittent mucopurulent to hemorrhagic vaginal discharge is often present but can be absent if the cervix is closed.
      • Børresen B.
      Pyometra in the dog. II.–A pathophysiological investigation. II. Anamnestic, clinical and reproductive aspects.
      The systemic illness is often more severe if the cervix is closed, and the uterus may become severely distended.
      • Jitpean S.
      • Ambrosen A.
      • Emanuelson U.
      • et al.
      Closed cervix is associated with more severe illness in dogs with pyometra.
      Classic systemic signs are anorexia, depression/lethargy, polydipsia, polyuria, tachycardia, tachypnea, weak pulse quality, and abnormal visible mucous membranes. Fever, dehydration, vomiting, abdominal pain on palpation, anorexia, gait abnormalities, and diarrhea are present in approximately 15% to 30% of bitches with the disease.
      • Børresen B.
      Pyometra in the dog. II.–A pathophysiological investigation. II. Anamnestic, clinical and reproductive aspects.
      • Jitpean S.
      • Strom-Holst B.
      • Emanuelson U.
      • et al.
      Outcome of pyometra in female dogs and predictors of peritonitis and prolonged postoperative hospitalization in surgically treated cases.
      The most common clinical signs in queens are vaginal discharge, lethargy, and gastrointestinal disturbances, such as anorexia, vomiting, and diarrhea (Fig. 2).
      • Davidson A.P.
      • Feldman E.C.
      • Nelson R.W.
      Treatment of pyometra in cats, using prostaglandin F2 alpha: 21 cases (1982-1990).
      • Hagman R.
      • Karlstam E.
      • Persson S.
      • et al.
      Plasma PGF 2 alpha metabolite levels in cats with uterine disease.
      Vaginal discharge may absent or concealed by fastidious cleaning habits in up to 40% of affected queens.
      • Kenney K.J.
      • Matthiesen D.T.
      • Brown N.O.
      • et al.
      Pyometra in cats: 183 cases (1979-1984).
      Weight loss, dehydration, polydipsia/polyuria, tachycardia, tachypnea, abdominal pain on palpation, abnormal mucous membranes (pale, hyperemic, or toxic), and unkept appearance are other findings associated with feline pyometra.
      Table 2History data and clinical signs in bitches with pyometra
      Data from Refs.
      • Fransson B.A.
      • Karlstam E.
      • Bergstrom A.
      • et al.
      C-reactive protein in the differentiation of pyometra from cystic endometrial hyperplasia/mucometra in dogs.
      • Hagman R.
      • Kindahl H.
      • Fransson B.A.
      • et al.
      Differentiation between pyometra and cystic endometrial hyperplasia/mucometra in bitches by prostaglandin F2alpha metabolite analysis.
      • Jitpean S.
      • Ambrosen A.
      • Emanuelson U.
      • et al.
      Closed cervix is associated with more severe illness in dogs with pyometra.
      • Jitpean S.
      • Strom-Holst B.
      • Emanuelson U.
      • et al.
      Outcome of pyometra in female dogs and predictors of peritonitis and prolonged postoperative hospitalization in surgically treated cases.
      • Hardy R.M.
      • Osborne C.A.
      Canine pyometra: pathophysiology, diagnosis and treatment of uterine and extra-genital lesions.
      • Jitpean S.
      • Pettersson A.
      • Hoglund O.V.
      • et al.
      Increased concentrations of Serum amyloid A in dogs with sepsis caused by pyometra.
      • Nelson R.W.
      • Feldman E.C.
      Pyometra.
      Case History and Clinical SignsIn Percentage (%)
      Vaginal discharge
      Usually in greater than 50% of the bitches.
      57–88
      Lethargy/depression
      Usually in greater than 50% of the bitches.
      63–100
      Inappetence/anorexia
      Usually in greater than 50% of the bitches.
      42–87
      Polydipsia
      Usually in greater than 50% of the bitches.
      28–89
      Polyuria
      Usually in greater than 50% of the bitches.
      34–73
      Vomiting13–38
      Diarrhea0–27
      Abnormal mucous membranes16–76
      Dehydration15–94
      Palpable enlarged uterus19–40
      Pain on abdominal palpation23–80
      Lameness16
      Distended abdomen5
      Fever32–50
      Hypothermia3–10
      Tachycardia23–28
      Tachypnea32–40
      Systemic inflammatory response syndrome57–61
      a Usually in greater than 50% of the bitches.
      Figure thumbnail gr2
      Fig. 2Purulent vaginal discharge in a queen with open cervix pyometra.

      Diagnosis

      The disease is easy to recognize in classic cases but can be more challenging when there is no vaginal discharge (ie, closed cervix), and the history and clinical picture are obscure. Pyometra should be a differential diagnosis in bitches and queens admitted with signs of illness after estrus, but the disease can occur at any time during the estrus cycle. The preliminary diagnosis is based on history and findings on physical and gynecologic examinations, hematology and blood biochemistry analyses, and ultrasonography and/or radiography of the abdomen. Bacteriologic culturing of the vaginal discharge is not helpful for the diagnosis because the same microbes are present in the vagina in healthy animals.
      • Bjurstrom L.
      Aerobic bacteria occurring in the vagina of bitches with reproductive disorders.
      Careful abdominal palpation, to avoid rupture of a fragile uterus, may identify an enlarged uterus. Diagnostic imaging is valuable for determining the uterine size and to rule out other causes of uterine enlargement (Fig. 3A–G ). Radiography frequently identifies a large tubular structure in the caudoventral abdomen. Ultrasonography has the advantage of detecting intrauterine fluid, even when the uterine diameter is within the normal range, and of revealing additional pathologic changes of the uterine tissue and ovaries, such as ovarian cysts or CEH, which may affect the outcome of medical treatment negatively (Fig. 4, Video 1). More advanced diagnostic imaging techniques are seldom necessary. Differential diagnoses include mucometra, hydrometra, and hemometra that may have similar clinical presentation and ultrasonography findings.
      • Bigliardi E.
      • Parmigiani E.
      • Cavirani S.
      • et al.
      Ultrasonography and cystic hyperplasia-pyometra complex in the bitch.
      Vaginal cytology usually shows severe leukocyte degeneration, neutrophils and some macrophages, plasmacytes, and lymphocytes but bacterial phagocytosis is not always visible.
      • Vandeplassche M.
      • Coryn M.
      • De Schepper J.
      Pyometra in the bitch: cytological, bacterial, histological and endocrinological characteristics.
      Vaginoscopy is helpful for determining the origin of a vaginal discharge and to exclude other pathologies but is usually not performed in the emergent clinical setting. The diagnosis pyometra is verified by postoperative macroscopic and histologic examination of the uterus and ovaries, and microbiological examination of the uterine content.
      Figure thumbnail gr3
      Fig. 3(A) Uterine enlargement in a cat; diagnosis: pyometra. Tubular structures of soft tissue/fluid opacity (arrows). (B) Uterine enlargement in a dog; diagnosis: CEH. Tubular structures of soft tissue/fluid opacity (arrows). (C) Ultrasound images of CEH in a dog. Thickening of the uterine wall with multiple anechoic cystic structures, no intraluminal fluid. Uterine diameter was 2 cm. Cervix located between double-headed arrow. (D) CEH and pyometra—thickening of the uterine wall with multiple anechoic cystic structures; the intraluminal fluid was purulent. Both images in (D) are of the same uterus. The uterine diameter was 2 cm. (E) CEH in a rabbit. (F) Atrophic wall pyometra: enlarged uterus with a thin wall and echogenic intraluminal fluid. (G) Uterus or small intestines of the same diameter (radiograph to the left). Uterus between white double-headed arrows, CEH. Small intestine with typical layered appearance between black double-headed arrows.
      Figure thumbnail gr4
      Fig. 4Canine uterus with CEH and purulent appearance of the fluid in some cysts.

      Clinicopathologic testing—laboratory parameters

      Hematology and biochemistry parameter abnormalities are generally investigated,
      • Jitpean S.
      • Strom-Holst B.
      • Emanuelson U.
      • et al.
      Outcome of pyometra in female dogs and predictors of peritonitis and prolonged postoperative hospitalization in surgically treated cases.
      • Hardy R.M.
      • Osborne C.A.
      Canine pyometra: pathophysiology, diagnosis and treatment of uterine and extra-genital lesions.
      with additional tests performed depending on the health status (Table 3). Leukocytosis, with neutrophilia and left shift, and monocytosis are characteristic findings in pyometra together with normocytic, normochromic regenerative anemia. Renal dysfunction is common, to which endotoxemia, glomerular dysfunction, renal tubular damage and decreased response to antidiuretic hormone contribute.
      • Maddens B.
      • Heiene R.
      • Smets P.
      • et al.
      Evaluation of kidney injury in dogs with pyometra based on proteinuria, renal histomorphology, and urinary biomarkers.
      • Asheim A.
      Renal function in dogs with pyometra. 8. Uterine infection and the pathogenesis of the renal dysfunction.
      Concomitant cystitis and proteinuria usually resolve after treatment of the pyometra, but severe proteinuria that remains may predispose for renal failure.
      • Maddens B.
      • Heiene R.
      • Smets P.
      • et al.
      Evaluation of kidney injury in dogs with pyometra based on proteinuria, renal histomorphology, and urinary biomarkers.
      Circulating inflammatory mediators and acute phase proteins are generally increased.
      • Dabrowski R.
      • Kostro K.
      • Lisiecka U.
      • et al.
      Usefulness of C-reactive protein, serum amyloid A component, and haptoglobin determinations in bitches with pyometra for monitoring early post-ovariohysterectomy complications.
      A hypercoagulable state is usually present.
      • Dorsey T.I.
      • Rozanski E.A.
      • Sharp C.R.
      • et al.
      Evaluation of thromboelastography in bitches with pyometra.
      Table 3Laboratory findings in bitches with pyometra
      Data from Refs.
      • Fransson B.A.
      • Karlstam E.
      • Bergstrom A.
      • et al.
      C-reactive protein in the differentiation of pyometra from cystic endometrial hyperplasia/mucometra in dogs.
      • Jitpean S.
      • Strom-Holst B.
      • Emanuelson U.
      • et al.
      Outcome of pyometra in female dogs and predictors of peritonitis and prolonged postoperative hospitalization in surgically treated cases.
      • Maddens B.
      • Heiene R.
      • Smets P.
      • et al.
      Evaluation of kidney injury in dogs with pyometra based on proteinuria, renal histomorphology, and urinary biomarkers.
      AbnormalityIn No. of Bitches (%)
      Leukopenia4
      Leukocytosis61
      Neutropenia4
      Neutrophilia55
      Monocytopenia3
      Monocytosis60
      Anemia55
      Band neutrophils40
      Band neutrophils >3%83
      Trombocytopenia37
      Toxic changes present9
      Increased ALAT22
      Hypoalbuminemia33
      Decreased ALP49
      Increased ALP37
      Increased AST64
      Cholesterolemia74
      Hypernatremia29
      Hypochloremia2
      Hypochloremia33
      Azotemia5
      BUN decreased10
      BUN increased5
      Bile acids increased21
      Hypoglycemia6
      Hyperglycemia4
      Hypokalemia4
      Hypercalcemia6
      Hypokalemia25
      Hyperlactatemia10
      Urine enzymes increased42
      Bacteruria25
      Abbreviations: ALAT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate transaminase; BUN, blood urea nitrogen.

      Treatment alternatives

      Surgical treatment, OHE, is safest and most effective because the source of infection and bacterial products are removed and recurrence prevented.
      • Hardy R.M.
      • Osborne C.A.
      Canine pyometra: pathophysiology, diagnosis and treatment of uterine and extra-genital lesions.
      Laparoscopically assisted techniques have been developed but are not commonly used and only in mild cases.
      • Becher-Deichsel A.
      • Aurich J.E.
      • Schrammel N.
      • et al.
      A surgical glove port technique for laparoscopic-assisted ovariohysterectomy for pyometra in the bitch.
      Medical management (solely pharmacologic) may be possible in young and otherwise healthy breeding animals or in a patient for which anesthesia and surgery is hazardous. In patients with serious illness or when complications, such as peritonitis or organ dysfunctions, are present or the cervix is closed, medical treatment is not recommended and surgery is the treatment of choice. Candidates for medical treatment need to be carefully selected for best prognosis for recovery and subsequent fertility.
      • Fieni F.
      • Topie E.
      • Gogny A.
      Medical treatment for pyometra in dogs.
      Microbiological culturing and sensitivity testing are prerequisites for optimal selection of antimicrobial therapy, for which samples are obtained from the cranial vagina or postoperatively from the uterus.

      Surgical treatment

      Prior to surgery, the patient is stabilized with adequate intravenous fluid therapy to correct hypotension, hypoperfusion, shock, dehydration, acid-base balance and electrolyte abnormalities, coagulation disturbances, and organ dysfunctions.
      • Fantoni D.
      • Shih A.C.
      Perioperative fluid therapy.
      Monitoring and intervention in critically ill patients following parameters according to the “rule of 20” is recommended.
      • Kirby R.
      An introduction to SIRS and the rule of 20.
      In moderately severely and severely ill patients, or if sepsis or serious complications are identified, intravenous broad-spectrum bactericidal antimicrobials are administered to prevent systemic effects of bacteremia and sepsis.
      • DeClue A.
      Sepsis and the systemic inflammatory response syndrome.
      The initial choice of antimicrobial drug should be effective against the most common pathogen E coli and adjusted after culture and sensitivity results to a narrow-spectrum alternative.
      • DeClue A.
      Sepsis and the systemic inflammatory response syndrome.
      The drug should not be nephrotoxic, and the dose, route, and frequency of administration adjusted to ascertain optimal effect. In 1 study, 90% of E coli pyometra isolates were sensitive to ampicillin.
      • Hagman R.
      • Greko C.
      Antimicrobial resistance in Escherichia coli isolated from bitches with pyometra and from urine samples from other dogs.
      The frequency of antimicrobial resistance, however, may differ by geographic location, which needs to be considered, and national regulations concerning restriction of antimicrobial usage in pets should be followed.
      • Coggan J.A.
      • Melville P.A.
      • de Oliveira C.M.
      • et al.
      Microbiological and histopathological aspects of canine pyometra.
      • Agostinho J.M.
      • de Souza A.
      • Schocken-Iturrino R.P.
      • et al.
      Escherichia coli strains isolated from the uteri horn, mouth, and rectum of bitches suffering from pyometra: virulence factors, antimicrobial susceptibilities, and clonal relationships among strains.
      In life-threatening peritonitis, severe sepsis, or septic shock, a combination of antimicrobials is usually recommended for covering a wider range of pathogens.
      • DeClue A.
      Sepsis and the systemic inflammatory response syndrome.
      If the health status is close to normal or only mildly depressed and without complications or concurrent diseases, OHE is curative for pyometra per se, and antimicrobials not included in the perioperative supportive treatment.
      Removal of the infection is key, and surgery should not be unnecessarily delayed due to the risk of endotoxemia and sepsis when the uterus remains in situ. Anesthesia and perioperative management are focused on maintaining hemodynamic function, gastrointestinal function and protection, pain management, cellular oxygenation, nutrition, and nursing care.
      • Devey J.J.
      Surgical considerations in the emergent small animal patient.
      Certain drugs may alleviate the inflammatory response.
      • Liao P.Y.
      • Chang S.C.
      • Chen K.S.
      • et al.
      Decreased postoperative C-reactive protein production in dogs with pyometra through the use of low-dose ketamine.
      A standard OHE is performed with some modifications.
      • Hollinshead F.
      • Krekeler N.
      Pyometra in the queen: to spay or not to spay?.
      • Tobias K.M.
      • Wheaton L.G.
      Surgical management of pyometra in dogs and cats.
      The uterus may be large, friable, and prone to rupture, and it is important to handle the tissues carefully (Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9). The abdominal cavity should be protected from accidental leakage of pus via uterine laceration or the fallopian tubes/ovarian bursa opening by packing off the uterus with moistened laparotomy swabs (see Fig. 9). Vessels in the broad ligament are usually ligated. Purulent material is completely removed from the remaining cervical tissue stump, which is not oversewn. Urine for bacterial culturing can be obtained by cystocentesis when the bladder is exposed. The abdomen is routinely closed but if contaminated with pus this should be removed and the abdomen rinsed with several liters of warmed physiologic saline solution and a closed suction (or open) drainage considered.
      • Devey J.J.
      Surgical considerations in the emergent small animal patient.
      • Tobias K.M.
      • Wheaton L.G.
      Surgical management of pyometra in dogs and cats.
      Samples for bacterial culturing are acquired before abdominal closure if needed. For verification of the diagnosis, macroscopic and histopathologic examination of the uterus and ovaries is performed.
      Figure thumbnail gr9
      Fig. 9Canine pyometra uterus with rupture and leakage of pus showing at the tip of the clamp.
      Intensive postoperative monitoring is essential, and in uncomplicated cases 1 day to 2 days of postoperative hospitalization is usually sufficient. The need for continued supportive care and antimicrobial therapy is evaluated several times daily on a case-by-case basis.
      • Jitpean S.
      • Strom-Holst B.
      • Emanuelson U.
      • et al.
      Outcome of pyometra in female dogs and predictors of peritonitis and prolonged postoperative hospitalization in surgically treated cases.
      Antimicrobial therapy is discontinued as soon as possible. The overall health status and most laboratory abnormalities improve rapidly after surgery and often normalize within 2 weeks.
      • Dabrowski R.
      • Kostro K.
      • Lisiecka U.
      • et al.
      Usefulness of C-reactive protein, serum amyloid A component, and haptoglobin determinations in bitches with pyometra for monitoring early post-ovariohysterectomy complications.
      • Bartoskova A.
      • Vitasek R.
      • Leva L.
      • et al.
      Hysterectomy leads to fast improvement of haematological and immunological parameters in bitches with pyometra.
      Considering the seriousness of pyometra, the prognosis for survival is good and mortality rates relatively low, 3% to 20%.
      • Egenvall A.
      • Hagman R.
      • Bonnett B.N.
      • et al.
      Breed risk of pyometra in insured dogs in Sweden.
      • Kenney K.J.
      • Matthiesen D.T.
      • Brown N.O.
      • et al.
      Pyometra in cats: 183 cases (1979-1984).
      • Jitpean S.
      • Strom-Holst B.
      • Emanuelson U.
      • et al.
      Outcome of pyometra in female dogs and predictors of peritonitis and prolonged postoperative hospitalization in surgically treated cases.
      • Feldman E.C.
      • Nelson R.W.
      Cystic endometrial hyperplasia/pyometra complex.
      If more severe systemic illness or complications, such as uterine rupture, peritonitis, or septic shock, develop, however, mortality rates can be considerably higher.
      • Kenney K.J.
      • Matthiesen D.T.
      • Brown N.O.
      • et al.
      Pyometra in cats: 183 cases (1979-1984).
      • DeClue A.
      Sepsis and the systemic inflammatory response syndrome.
      • Fantoni D.T.
      • Auler Junior J.O.
      • Futema F.
      • et al.
      Intravenous administration of hypertonic sodium chloride solution with dextran or isotonic sodium chloride solution for treatment of septic shock secondary to pyometra in dogs.
      In queens with pyometra and uterine rupture, a mortality rate of 57% has been reported.
      • Davidson A.P.
      • Feldman E.C.
      • Nelson R.W.
      Treatment of pyometra in cats, using prostaglandin F2 alpha: 21 cases (1982-1990).
      Complications develop in approximately 20% of pyometra patients, the most common peritonitis, in 12%.
      • Kenney K.J.
      • Matthiesen D.T.
      • Brown N.O.
      • et al.
      Pyometra in cats: 183 cases (1979-1984).
      • Marretta S.M.
      • Matthiesen D.T.
      • Nichols R.
      Pyometra and its complications.
      • Wheaton L.G.
      • Johnson A.L.
      • Parker A.J.
      • et al.
      Results and complications of surgical treatment of pyometra: a review of 80 cases.
      • Jitpean S.
      • Strom-Holst B.
      • Emanuelson U.
      • et al.
      Outcome of pyometra in female dogs and predictors of peritonitis and prolonged postoperative hospitalization in surgically treated cases.
      • Fransson B.A.
      • Lagerstedt A.S.
      • Bergstrom A.
      • et al.
      C-reactive protein, tumor necrosis factor alpha, and interleukin-6 in dogs with pyometra and SIRS.
      Other reported complications include uveitis, urinary tract infection, intracranial thromboemboli, bacterial osteomyelitis, pericarditis, myocarditis, septic arthritis, incisional swelling, dehiscence, urethral trauma, recurrent estrus, uterine stump pyometra, fistulous tracts, and urinary incontinence.
      • Marretta S.M.
      • Matthiesen D.T.
      • Nichols R.
      Pyometra and its complications.
      • Wheaton L.G.
      • Johnson A.L.
      • Parker A.J.
      • et al.
      Results and complications of surgical treatment of pyometra: a review of 80 cases.
      • Maddens B.
      • Heiene R.
      • Smets P.
      • et al.
      Evaluation of kidney injury in dogs with pyometra based on proteinuria, renal histomorphology, and urinary biomarkers.

      Medical (nonsurgical) treatment

      For purely medical management, careful patient selection is central to ensure the best possible outcome (ie, resolution of clinical illness and maintained fertility). Suitable candidates are young and otherwise healthy breeding bitches and queens with open cervix and that have no ovarian cysts. It is important that the patients are stable and not critically ill, because it may take up to 48 hours until treatment effect for some drugs used.
      • Fieni F.
      Clinical evaluation of the use of aglepristone, with or without cloprostenol, to treat cystic endometrial hyperplasia-pyometra complex in bitches.
      Contraindications include systemic illness, fever or hypothermia, intrauterine fetal remains, organ dysfunctions, or complications, such as peritonitis or sepsis. Adverse drug effects may occur, and endotoxemia and sepsis can quickly transform a clinically stable pyometra to an emergency. Hospitalization is, therefore, recommended to allow close monitoring, supportive treatments, and rapid intervention. Clinical signs, reduction, and clearing of the vaginal discharge, the uterine size, and laboratory abnormalities gradually normalize in 1 week to 3 weeks.
      • England G.C.
      • Freeman S.L.
      • Russo M.
      Treatment of spontaneous pyometra in 22 bitches with a combination of cabergoline and cloprostenol.
      OHE may be necessary without delay if complications arise or the general health status deteriorates and in refractory cases. Antimicrobials alone for treatment of pyometra may reduce the disease and prevent its progression but does not result in uterine healing.
      The strategies of medical treatment are to minimize effects of progesterone by preventing its production and/or action, eliminate the uterine infection, promote relaxation of the cervix and expulsion of the intraluminal pus, and facilitate uterine healing. Commonly used drugs are natural prostaglandin F (PGF) or its synthetic analog cloprostenol, dopamine agonists (cabergoline and bromocriptine), or progesterone-receptor blockers (aglepristone)
      • Verstegen J.
      • Dhaliwal G.
      • Verstegen-Onclin K.
      Mucometra, cystic endometrial hyperplasia, and pyometra in the bitch: advances in treatment and assessment of future reproductive success.
      (Tables 4 and 5). The available protocols include systemic antimicrobial therapy, often recommended for 2 weeks or more.
      • Lopate C.
      Pyometra, cystic endometrial hyperplasia (hydrometra, mucometra, hematometra).
      The shortest effective duration of adjunctive antimicrobial therapy, however, has not been determined, and 5 days and 6 days were sufficient in 2 studies using aglepristone.
      • Fieni F.
      Clinical evaluation of the use of aglepristone, with or without cloprostenol, to treat cystic endometrial hyperplasia-pyometra complex in bitches.
      • Contri A.
      • Gloria A.
      • Carluccio A.
      • et al.
      Effectiveness of a modified administration protocol for the medical treatment of canine pyometra.
      The antimicrobial drug and administration protocol should be based on bacterial culturing, sensitivity tests, and pharmacokinetics/pharmacodynamics for achieving optimal effect. Additional supportive treatment, including intravenous fluids and electrolyte supplementation, is provided depending on physical examinations and laboratory tests results.
      Table 4Examples of studies of medical treatment protocols for open cervix pyometra in dogs
      DrugNProtocol and DosageOutcome and Side EffectsReference
      Aglepristone24Aglepristone 10 mg/kg SC q 24 h on day 2, 7 and 14Recovery in 100%; recurrence after up to 54 months 12%; fertility in 12% of 17 bitches matedJurka et al,
      • Jurka P.
      • Max A.
      • Hawrynska K.
      • et al.
      Age-related pregnancy results and further examination of bitches after aglepristone treatment of pyometra.
      2010
      Aglepristone28Aglepristone 10 mg/kg SC q 24 h on days 1, 2, 7, 15, and 23, 29 if not curedRecovery in 75% (resolution of clinical signs); recurrence: 48% after up to 6 y; fertility in 69% of 13 mated bitchesRos et al,
      • Ros L.
      • Holst B.S.
      • Hagman R.
      A retrospective study of bitches with pyometra, medically treated with aglepristone.
      2014
      Aglepristone52Aglepristone 10 mg/kg SC q 24 h on days 1, 2, and 7Recovery in 92%; recurrence: 10% after 3 months, 19% in 37 bitches followed up to 1 y; fertility in 83% (5/6 mated bitches)Trasch et al,
      • Trasch K.
      • Wehrend A.
      • Bostedt H.
      Follow-up examinations of bitches after conservative treatment of pyometra with the antigestagen aglepristone.
      2003
      Aglepristone13Aglepristone 10 mg/kg SC q 24 h on days 1, 2, 7, and 14Recovery in 46%Gurbulak et al,
      • Gurbulak K.
      • Pancarci M.
      • Ekici H.
      • et al.
      Use of aglepristone and aglepristone + intrauterine antibiotic for the treatment of pyometra in bitches.
      2005
      Aglepristone20Aglepristone 10 mg/kg SC q 24 h on days 1, 2, and 8 and if not cured on day 15Recovery in 60%Fieni,
      • Fieni F.
      Clinical evaluation of the use of aglepristone, with or without cloprostenol, to treat cystic endometrial hyperplasia-pyometra complex in bitches.
      2006
      Aglepristone + cloprostenol32Aglepristone 10 mg/kg SC q 24 h on days 1, 2, and 8 and if not cured on days 14 and 28 + cloprostenol: 1 μg/kg SC q 24 h on days 3–7Recovery in 84%; no side effect of cloprostenol in 45% of the bitches; in 56% some side effects were noted: loss of appetite, lethargy, vomiting, nausea; 19% recurrence; in closed cervix pyometra cases: recovery in 76.5%, in open cervix pyometra recovery in 74.3%; 1 euthanasia due to declining health, 1 death; Follow-up time: 90 d and up to 2 y in 23 bitches; fertility in 80% (4/5 mated bitches)Fieni,
      • Fieni F.
      Clinical evaluation of the use of aglepristone, with or without cloprostenol, to treat cystic endometrial hyperplasia-pyometra complex in bitches.
      2006
      Aglepristone73Traditional protocol: aglepristone 10 mg/kg SC q 24 h on days 1, 2, and 7 (26 bitches)

      Modified protocol: aglepristone 10 mg/kg SC q 24 h on days 1, 3, 6, and 9 (47 bitches)
      Recovery with traditional protocol in 88%; recurrence: 17%; fertility in 86%

      Resolution of clinical signs of pyometra with modified protocol, in 100%; recurrence: 0%; fertility in 78%

      Follow-up after 2 y
      Contri et al,
      • Contri A.
      • Gloria A.
      • Carluccio A.
      • et al.
      Effectiveness of a modified administration protocol for the medical treatment of canine pyometra.
      2015
      Aglepristone + cloprostenol15
      • Aglepristone 10 mg/kg SC q 24 h on days 1, 3, 8, and 15 (if not cured) + cloprostenol:
        • a.
          1 μg/kg SC q 24 h on days 3 and 8 (N = 8)
        • b.
          1 μg/kg, SC q 24 h on days 3, 5, 8 10, 12, and 15 (N = 7)
      Recovery in 100%, recurrence: 20% by the next estrus cycle (in all 15 bitches); fertility in 100% (1 bitch mated); no side effects reportedGobello et al,
      • Gobello C.
      • Castex G.
      • Klima L.
      • et al.
      A study of two protocols combining aglepristone and cloprostenol to treat open cervix pyometra in the bitch.
      2003
      Cabergoline + cloprostenol29Cabergoline 5 μg/kg PO q 24 h

      + cloprostenol 1 μg/kg SC q 24 h for 7–14 d
      Recovery in 83% by day 14, recurrence: 21%; fertility in 1/2 mated bitches. Mild side effects noted.Corrada et al,
      • Corrada Y.
      • Arias D.
      • Rodriguez R.
      • et al.
      Combination dopamine agonist and prostaglandin agonist treatment of cystic endometrial hyperplasia-pyometra complex in the bitch.
      2006
      Cabergoline + cloprostenol22Cabergoline 5 μg/kg PO q 24 h

      + cloprostenol 5 μg/kg every third day SC for 7–13 d
      Recovery in 90.5% by day 13; recurrence: 20%; fertility in 64% of 11 bitches mated; side effects: retching, vomiting, mild abdominal straining, diarrhea, and panting up to 60 min after administrationEngland et al,
      • England G.C.
      • Freeman S.L.
      • Russo M.
      Treatment of spontaneous pyometra in 22 bitches with a combination of cabergoline and cloprostenol.
      2007
      All protocols combined with and systemic antimicrobial therapy. See the original reference for the most accurate information and more details.
      Abbreviations: N, number of bitches; PO, per os; PG, prostaglandin; recovery, resolution of pyometra; SC, subcutaneous.
      Table 5Selected studies of medical treatment protocols for open cervix pyometra in cats
      DrugNProtocol and DosageOutcome and Side EffectsReference
      PGF (natural)210.1 mg/kg SC q 12–24 h for 3–5 d (6 queens); 0.25 mg/kg was used in 15 queens but was not more effectiveResolution of signs of pyometra and return to cyclicity in 95%; treatment was repeated in 1 queen; fertility in 81%; no difference between the 2 different dosages (ie, the lower dosage recommended); transient side effects observed in 76%: vocalization, panting, restlessness, grooming, tenesmus, salivation, diarrhea, kneading, mydriasis, emesis, urination, and lordosis lasting up to 60 min. Recurrence of pyometra in 14% (3 cats)Davidson et al,
      • Davidson A.P.
      • Feldman E.C.
      • Nelson R.W.
      Treatment of pyometra in cats, using prostaglandin F2 alpha: 21 cases (1982-1990).
      1992
      Prostaglandin F (synthetic analog cloprostenol)55 μg/kg SC q 24 h for 3 consecutive daysResolution of signs of pyometra in 100%; no recurrence after 1 y; fertility in 40%; transient side effects: diarrhea, vomiting, vocalizationGarcia Mitacek et al,
      • Garcia Mitacek M.C.
      • Stornelli M.C.
      • Tittarelli C.M.
      • et al.
      Cloprostenol treatment of feline open-cervix pyometra.
      2014
      Progesterone receptor blocker (aglepristone)1010 mg/kg SC q 24 h on days 1, 2, and 7 and on day 14 (if not cured)Resolution of signs of pyometra in 90%; no recurrence after 2-y follow-up; no side effects observedNak et al,
      • Nak D.
      • Nak Y.
      • Tuna B.
      Follow-up examinations after medical treatment of pyometra in cats with the progesterone-antagonist aglepristone.
      2009
      See the original reference for the most accurate information and more details.
      Abbreviations: IM, intramuscular administration; q, every; N, number of cats; PO, oral administration; SC, subcutaneous administration.
      PGF is luteolytic and uterotonic and stimulates smooth musculature. Side effects, such as hypothermia, frequent defecation, diarrhea, salivation, vomiting, restlessness, shivering, and depression, are common and dose dependent and may last for approximately 1 hour after administration.
      • Davidson A.
      Female and male infertility and subfertility.
      PGF should be administrated far from feeding to reduce the risk of vomiting. Treatment with metoclopramide or walking the bitch for 15 minutes to 20 minutes after administration has been suggested to lessen nausea and vomiting.
      • Verstegen J.
      • Dhaliwal G.
      • Verstegen-Onclin K.
      Mucometra, cystic endometrial hyperplasia, and pyometra in the bitch: advances in treatment and assessment of future reproductive success.
      • Greer M.
      Canine reproduction and neonatology - a practical guide for veterinarians, veterinary staff and breeders.
      Serious adverse effects of the drug (PGF), such as death, shock, and ventricular tachycardia, have been reported and the therapeutic window is narrow, which is why dosage calculations should be done meticulously. It is therefore very important to chose the lowest possible effective dose and hospitalize patients during treatment for monitoring and immediate intervention if severe side-effects develop. Brachycephalic breeds may be predisposed to bronchospasm, making PGF contraindicated.
      • Lopate C.
      Pyometra, cystic endometrial hyperplasia (hydrometra, mucometra, hematometra).
      • Greer M.
      Canine reproduction and neonatology - a practical guide for veterinarians, veterinary staff and breeders.
      Owner consent, with information of potential risks, is necessary to obtain prior to extralabel drug usage. Several protocols are still considered experimental, because efficiency and optimal dosages have not yet been established. For natural PGF, ie, dinoprost tromethamine, subcutaneous administration of 0.1 mg/kg every 12 hours to 24 hours until resolution is the dose generally recommended in bitches and queens. Despite at the lower end of the recommended range and administered once daily, this dose is associated with many undesired side effects (the recommended range includes higher doses, following evaluation of the effect of a lower dose), which is why other lower dose alternatives and drug combinations are becoming more commonly used.
      • Davidson A.
      Female and male infertility and subfertility.
      Other authors suggest starting by giving 10 μg/kg subcutaneously 5 times on the first day, gradually increasing the dose to 25 μg/kg 5 times on the second day, and reaching 50 μg/kg by day 3. Doses of 50 μg/kg were then given 3 times to 5 times daily from day 3 and onward over the treatment period, a regime resulting in side effects in 15% of treated bitches.
      • Verstegen J.
      • Dhaliwal G.
      • Verstegen-Onclin K.
      Mucometra, cystic endometrial hyperplasia, and pyometra in the bitch: advances in treatment and assessment of future reproductive success.
      A dose of 100 µg/kg natural PGF administered subcutaneously once daily for 7 days resulted in recovery in 7 bitches, but many side-effects were observed and lower doses are preferable.
      • Jena B.
      • Rao K.S.
      • Reddy K.C.S.
      • et al.
      Comparative efficacy or various therapeutic protocols in the treatment of pyometra in bitches.
      Natural PGF, 20 μg/kg, was given intramuscularly 3 times daily on up to 8 consecutive days in 1 study, and 30 μg/kg was given subcutaneously twice daily for 8 days in another study, resulting in resolution of the illness in 70% of 10 bitches and in 100% of 7 bitches, respectively, and no side effects.
      • Arnold S.
      • Hubler M.
      • Casal M.
      • et al.
      Use of low dose prostaglandin for the treatment of canine pyometra.
      • Sridevi P.
      • Balasubramanian S.
      • Devanathan T.
      • et al.
      Low dose prostaglandin F2 alpha therapy in treatment of canine pyometra.
      More recent low dose protocols, recommend subcutaneous administration of natural PGF at a dose of 10-50µg/kg every 4-6 hours.
      • Lopate C.
      Pyometra, cystic endometrial hyperplasia (hydrometra, mucometra, hematometra).
      The synthetic PGF analog cloprostenol is administered at a notably lower dose than for natural PGF,
      • Jena B.
      • Rao K.S.
      • Reddy K.C.S.
      • et al.
      Comparative efficacy or various therapeutic protocols in the treatment of pyometra in bitches.
      and accurate calculations are crucial to avoid serious side-effects or fatalities. For cloprostenol, subcutaneous administration of 1 μg/kg to 3 μg/kg every 12 hours to 24 hours to resolution/effect is the recommended dose for bitches and queens.
      • Davidson A.
      Female and male infertility and subfertility.
      Subcutaneous administration of low-dose cloprostenol, 1 μg/kg, once daily was effective in 100% of 7 bitches in 1 study but with a high recurrence rate, 85%, and subsequent fertility rate of 14%.
      • Jena B.
      • Rao K.S.
      • Reddy K.C.S.
      • et al.
      Comparative efficacy or various therapeutic protocols in the treatment of pyometra in bitches.
      The dopamine agonists cabergoline and bromocriptine are effectively luteolytic from day 25 after estrus because of their antiprolactin effects and have been used together with PGF for augmented treatment of pyometra.
      • England G.C.
      • Freeman S.L.
      • Russo M.
      Treatment of spontaneous pyometra in 22 bitches with a combination of cabergoline and cloprostenol.
      • Verstegen J.
      • Dhaliwal G.
      • Verstegen-Onclin K.
      Mucometra, cystic endometrial hyperplasia, and pyometra in the bitch: advances in treatment and assessment of future reproductive success.
      Cabergoline usually causes less vomiting than bromocriptine, which is an advantage.
      • Verstegen J.
      • Dhaliwal G.
      • Verstegen-Onclin K.
      Mucometra, cystic endometrial hyperplasia, and pyometra in the bitch: advances in treatment and assessment of future reproductive success.
      • Lopate C.
      Pyometra, cystic endometrial hyperplasia (hydrometra, mucometra, hematometra).
      • Greer M.
      Canine reproduction and neonatology - a practical guide for veterinarians, veterinary staff and breeders.
      Cabergoline combined with a low dose of cloprostenol led to resolution of the illness in 90.5% of 22 treated bitches with pyometra in 1 study.
      • England G.C.
      • Freeman S.L.
      • Russo M.
      Treatment of spontaneous pyometra in 22 bitches with a combination of cabergoline and cloprostenol.
      In another study using cabergoline and cloprostenol, 83% of 29 bitches recovered from the illness.
      • Corrada Y.
      • Arias D.
      • Rodriguez R.
      • et al.
      Combination dopamine agonist and prostaglandin agonist treatment of cystic endometrial hyperplasia-pyometra complex in the bitch.
      This combination was also shown the most effective compared with only low-dose cloprostenol or natural PGF.
      • Jena B.
      • Rao K.S.
      • Reddy K.C.S.
      • et al.
      Comparative efficacy or various therapeutic protocols in the treatment of pyometra in bitches.
      For treatment of pyometra in cats, no clinical studies have been published on cabergoline and bromocriptine, but similar doses and regimes as for dogs have been suggested.
      • Hollinshead F.
      • Krekeler N.
      Pyometra in the queen: to spay or not to spay?.
      The progesterone blocker aglepristone is commonly used in Europe for treatment of pyometra (see Tables 4 and 5) but is not currently approved for use in North America. Aglepristone binds to progesterone receptors effectively and competitively and without stimulating any of the hormone’s effects. Side effects are usually rare and not severe, and cervical relaxation induced within 48 hours.
      • Fieni F.
      Clinical evaluation of the use of aglepristone, with or without cloprostenol, to treat cystic endometrial hyperplasia-pyometra complex in bitches.
      • Contri A.
      • Gloria A.
      • Carluccio A.
      • et al.
      Effectiveness of a modified administration protocol for the medical treatment of canine pyometra.
      • Gurbulak K.
      • Pancarci M.
      • Ekici H.
      • et al.
      Use of aglepristone and aglepristone + intrauterine antibiotic for the treatment of pyometra in bitches.
      • Trasch K.
      • Wehrend A.
      • Bostedt H.
      Follow-up examinations of bitches after conservative treatment of pyometra with the antigestagen aglepristone.
      • Jurka P.
      • Max A.
      • Hawrynska K.
      • et al.
      Age-related pregnancy results and further examination of bitches after aglepristone treatment of pyometra.
      • Ros L.
      • Holst B.S.
      • Hagman R.
      A retrospective study of bitches with pyometra, medically treated with aglepristone.
      According to the recommended protocol, 10 mg/kg aglepristone is administered subcutaneously once daily on days 1, 2, and 7 or 8 and on days 14 and 28 if not cured. This protocol results in success rates of 46% to 100%, recurrence rates 0% to 48% and subsequent fertility rates of 69% to 85%.
      • Gogny A.
      • Fieni F.
      Aglepristone: a review on its clinical use in animals.
      Aglepristone was administered more frequently (on days 1, 3, 6, and 9) in a modified protocol, which resulted in resolution of the illness in all 47 treated bitches and with no reported recurrence for up to 2 years.
      • Contri A.
      • Gloria A.
      • Carluccio A.
      • et al.
      Effectiveness of a modified administration protocol for the medical treatment of canine pyometra.
      Treatment with aglepristone resulted in resolution of pyometra in 9 of 10 queens, with no recurrence reported after 2 years and no side effects observed (see Table 5).
      • Nak D.
      • Nak Y.
      • Tuna B.
      Follow-up examinations after medical treatment of pyometra in cats with the progesterone-antagonist aglepristone.
      Local treatment methods of pyometra have been shown effective but are not yet commonly used in clinical practice in bitches and have not been reported in cats.
      • Lagerstedt A.-S.
      • Obel N.
      • Stavenborn M.
      Uterine drainage in the bitch for treatment of pyometra refractory to prostaglandin F2α.
      Intravaginal infusion of prostaglandins and antimicrobials yielded successful result in 15 of 17 treated bitches, without side effects or recurrence after 12 months.
      • Gabor G.
      • Siver L.
      • Szenci O.
      Intravaginal prostaglandin F2 alpha for the treatment of metritis and pyometra in the bitch.
      Aglepristone in combination with intrauterine antimicrobials was successful in 9 of 11 bitches.
      • Gurbulak K.
      • Pancarci M.
      • Ekici H.
      • et al.
      Use of aglepristone and aglepristone + intrauterine antibiotic for the treatment of pyometra in bitches.
      Intrauterine drainage through transcervical catheters may facilitate recovery in refractory cases.
      • Lagerstedt A.-S.
      • Obel N.
      • Stavenborn M.
      Uterine drainage in the bitch for treatment of pyometra refractory to prostaglandin F2α.
      Surgical drainage and intrauterine lavage resulted in fertility in 100% of 8 treated bitches.
      • De Cramer K.G.
      Surgical uterine drainage and lavage as treatment for canine pyometra.
      Whether prostaglandin E2, administered intravaginally or orally, gives a cervical relaxation that is beneficial in medical treatment protocols remains to be studied.
      • Lopate C.
      Pyometra, cystic endometrial hyperplasia (hydrometra, mucometra, hematometra).
      • Greer M.
      Canine reproduction and neonatology - a practical guide for veterinarians, veterinary staff and breeders.

      Prognosis after medical treatment

      The prognosis for survival and fertility is considered guarded to good. Breeding on the subsequent estrus cycle is consistently recommended after medical treatment, to avoid recurrence. The mean reported long-term success (resolution of clinical illness) of medical treatment is approximately 86% (range 46%–100%) in dogs
      • Feldman E.C.
      • Nelson R.W.
      Cystic endometrial hyperplasia/pyometra complex.
      • Fieni F.
      Clinical evaluation of the use of aglepristone, with or without cloprostenol, to treat cystic endometrial hyperplasia-pyometra complex in bitches.
      • England G.C.
      • Freeman S.L.
      • Russo M.
      Treatment of spontaneous pyometra in 22 bitches with a combination of cabergoline and cloprostenol.
      • Contri A.
      • Gloria A.
      • Carluccio A.
      • et al.
      Effectiveness of a modified administration protocol for the medical treatment of canine pyometra.
      • Jena B.
      • Rao K.S.
      • Reddy K.C.S.
      • et al.
      Comparative efficacy or various therapeutic protocols in the treatment of pyometra in bitches.
      • Corrada Y.
      • Arias D.
      • Rodriguez R.
      • et al.
      Combination dopamine agonist and prostaglandin agonist treatment of cystic endometrial hyperplasia-pyometra complex in the bitch.
      • Gurbulak K.
      • Pancarci M.
      • Ekici H.
      • et al.
      Use of aglepristone and aglepristone + intrauterine antibiotic for the treatment of pyometra in bitches.
      • Trasch K.
      • Wehrend A.
      • Bostedt H.
      Follow-up examinations of bitches after conservative treatment of pyometra with the antigestagen aglepristone.
      • Ros L.
      • Holst B.S.
      • Hagman R.
      A retrospective study of bitches with pyometra, medically treated with aglepristone.
      • Gobello C.
      • Castex G.
      • Klima L.
      • et al.
      A study of two protocols combining aglepristone and cloprostenol to treat open cervix pyometra in the bitch.
      and in cats 95% (range 90%–100%)
      • Davidson A.P.
      • Feldman E.C.
      • Nelson R.W.
      Treatment of pyometra in cats, using prostaglandin F2 alpha: 21 cases (1982-1990).
      • Nak D.
      • Nak Y.
      • Tuna B.
      Follow-up examinations after medical treatment of pyometra in cats with the progesterone-antagonist aglepristone.
      • Garcia Mitacek M.C.
      • Stornelli M.C.
      • Tittarelli C.M.
      • et al.
      Cloprostenol treatment of feline open-cervix pyometra.
      (see Tables 4 and 5). The prognosis for fertility after medical treatment is generally considered good, with a mean fertility rate of 70% (range 14%–100%) reported in dogs and of 60% in cats. The mean recurrence rate reported in dogs is 29% (range 0%–85%), and 0% to 14% in cats. Fertility rates after aglepristone treatment are higher in younger (<5 years) bitches and those that have no other uterine or ovarian pathology.
      • Jurka P.
      • Max A.
      • Hawrynska K.
      • et al.
      Age-related pregnancy results and further examination of bitches after aglepristone treatment of pyometra.
      • Ros L.
      • Holst B.S.
      • Hagman R.
      A retrospective study of bitches with pyometra, medically treated with aglepristone.

      Predictive markers

      Of clinical and laboratory parameters investigated, leukopenia has been associated with both presence of peritonitis and increased postoperative hospitalization in surgically treated bitches with pyometra.
      • Jitpean S.
      • Strom-Holst B.
      • Emanuelson U.
      • et al.
      Outcome of pyometra in female dogs and predictors of peritonitis and prolonged postoperative hospitalization in surgically treated cases.
      Concentrations of the acute-phase proteins, C-reactive protein and serum amyloid A, are increased in sepsis.
      • Fransson B.A.
      • Lagerstedt A.S.
      • Bergstrom A.
      • et al.
      C-reactive protein, tumor necrosis factor alpha, and interleukin-6 in dogs with pyometra and SIRS.
      • Jitpean S.
      • Pettersson A.
      • Hoglund O.V.
      • et al.
      Increased concentrations of Serum amyloid A in dogs with sepsis caused by pyometra.
      Concentrations of C-reactive protein and PGF have been linked with length of postoperative hospitalization.
      • Hagman R.
      • Kindahl H.
      • Fransson B.A.
      • et al.
      Differentiation between pyometra and cystic endometrial hyperplasia/mucometra in bitches by prostaglandin F2alpha metabolite analysis.
      • Fransson B.A.
      • Lagerstedt A.S.
      • Bergstrom A.
      • et al.
      C-reactive protein, tumor necrosis factor alpha, and interleukin-6 in dogs with pyometra and SIRS.
      Acute-phase proteins concentrations decrease gradually during postoperative recovery, and maintained or increased concentrations may indicate complications.
      • Dabrowski R.
      • Kostro K.
      • Lisiecka U.
      • et al.
      Usefulness of C-reactive protein, serum amyloid A component, and haptoglobin determinations in bitches with pyometra for monitoring early post-ovariohysterectomy complications.
      Persistent proteinuria and urinary protein-creatinine indicate renal disease that requires special attention.
      • Maddens B.
      • Heiene R.
      • Smets P.
      • et al.
      Evaluation of kidney injury in dogs with pyometra based on proteinuria, renal histomorphology, and urinary biomarkers.
      Central venous oxygen saturation and base-deficit and lactate levels were valuable for determining outcome in bitches with pyometra and sepsis.
      • Conti-Patara A.
      • de Araujo Caldeira J.
      • de Mattos-Junior E.
      • et al.
      Changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization at admission to ICU and the relation to outcome.
      Band neutrophil concentrations, lymphopenia and monocytosis, blood urea nitrogen greater than 30 mg/dL, and creatinine concentrations greater than 1.5 mg/dL have been associated with death.
      • Kuplulu S.
      • Vural M.R.
      • Demirel A.
      • et al.
      The comparative evaluation of serum biochemical, haematological, bacteriological and clinical findings of dead and recovered bitches with pyometra in the postoperative process.
      Certain inflammatory variables may be clinically useful for prognostication if cageside tests become available.
      • Hagman R.
      Diagnostic and prognostic markers for uterine diseases in dogs.
      In queens, white blood cell counts, neutrophils, band neutrophils, monocytes, and the percentage band neutrophils were positively, and albumin concentrations negatively, associated with postoperative hospitalization.
      • Hagman R.
      • Karlstam E.
      • Persson S.
      • et al.
      Plasma PGF 2 alpha metabolite levels in cats with uterine disease.

      Differentiation of pyometra and mucometra or hydrometra

      Fluid in the uterine lumen is present in both pyometra and mucometra/hydrometra, and their clinical manifestations can be similar. In pyometra, however, life-threatening complications may develop because of the bacterial infection, and differentiation of these disorders is thus important to optimize treatments. Ultrasonographic examination of the uterus illustrating the fluid echogenicity and hemodynamic parameters may be helpful in some cases but is not diagnostic.
      • Bigliardi E.
      • Parmigiani E.
      • Cavirani S.
      • et al.
      Ultrasonography and cystic hyperplasia-pyometra complex in the bitch.
      The health status is more depressed and lethargy and gastrointestinal disturbances more frequently observed in pyometra. More than 3 clinical signs of illness and a more pronounced inflammatory response are also indicative of pyometra as opposed to mucometra/hydrometra.
      • Fransson B.A.
      • Karlstam E.
      • Bergstrom A.
      • et al.
      C-reactive protein in the differentiation of pyometra from cystic endometrial hyperplasia/mucometra in dogs.
      • Hagman R.
      • Kindahl H.
      • Fransson B.A.
      • et al.
      Differentiation between pyometra and cystic endometrial hyperplasia/mucometra in bitches by prostaglandin F2alpha metabolite analysis.

      Prevention

      To diagnose and treat CEH and pyometra early is favorable, and noninvasive diagnostic methods are warranted.
      • Mir F.
      • Fontaine E.
      • Albaric O.
      • et al.
      Findings in uterine biopsies obtained by laparotomy from bitches with unexplained infertility or pregnancy loss: an observational study.
      • Christensen B.W.
      • Schlafer D.H.
      • Agnew D.W.
      • et al.
      Diagnostic value of transcervical endometrial biopsies in domestic dogs compared with full-thickness uterine sections.
      Elective OHE has the advantage of being performed in a healthy animal and preventing pyometra and other uterine diseases. Because there are many negative side effects of spaying, all pros and cons of such intervention, need to be thoroughly evaluated in each individual.
      • Artl S.
      • Wehrend A.
      • Reichler I.M.
      Kastration der Hundin - neue und alte Erkenntnisse zu Vor- und nachteilen.
      If breeding on the first estrus after medical treatment is not possible, close monitoring is advisable to rule out abnormalities that may emerge during the luteal phase. Progesterone receptor blockers or prostaglandins may prevent the development of pyometra in high-risk patients.
      • Mir F.
      • Fontaine E.
      • Albaric O.
      • et al.
      Findings in uterine biopsies obtained by laparotomy from bitches with unexplained infertility or pregnancy loss: an observational study.
      Some investigators recommend postponing the subsequent estrus after medical treatment of pyometra, to promote uterine healing.
      • Verstegen J.
      • Dhaliwal G.
      • Verstegen-Onclin K.
      Mucometra, cystic endometrial hyperplasia, and pyometra in the bitch: advances in treatment and assessment of future reproductive success.

      Stump pyometra

      A stump pyometra is when pyometra develops in residual uterine tissue in incompletely spayed bitches and queens, most often because of hormone-producing ovarian remnants.
      • Ball R.L.
      • Birchard S.J.
      • May L.R.
      • et al.
      Ovarian remnant syndrome in dogs and cats: 21 cases (2000-2007).
      The clinical presentation is similar, except for a history of previous spay. Ultrasonography usually shows areas of local fluid accumulation at the tissue stump, but it may be difficult to localize the ovarian remnant tissue unless follicles are present (Fig. 10). Incomplete resection is the leading cause, but ectopic or revascularized ovarian tissue separated from the ovary during surgery have also been proposed.
      • Ball R.L.
      • Birchard S.J.
      • May L.R.
      • et al.
      Ovarian remnant syndrome in dogs and cats: 21 cases (2000-2007).
      Treatment includes surgical resection of remaining uterine and ovarian tissue, in combination with supportive treatments and antimicrobials, if indicated.
      Figure thumbnail gr10
      Fig. 10Stump pyometra due to ovarian remnant.
      Pyometra has been described in many other small animals, such as rabbits (see Fig. 3), rodents, guinea pigs, hamsters, gerbils, ferrets, and chipmunks.
      • Kondert L.
      • Mayer J.
      Reproductive medicine in guinea pigs, chinchillas and degus.
      • Martorell J.
      Reproductive disorders in pet rodents.
      • Mancinelli E.
      • Lord B.
      Urogenital system and reproductive disease.
      • Heap R.B.
      Prostaglandins in pyometrial fluid from the cow, bitch and ferret.
      The causative microbes often differ from isolates in dogs and cats with the disease. Ultrasonography and cytology are helpful to confirm a presumptive diagnosis based on clinical signs and physical examination, and the preferred treatment is OHE. Aglepristone combined with antibiotics has been used successfully for medical treatment in a golden hamster and a guinea pig.
      • Engelhardt A.B.
      Behandlung des Endometritis/Pyometrakomplexes eines Meerschweinchens - ein Fallbericht.
      • Pisu M.C.
      • Andolfatto A.
      • Veronesi M.C.
      Pyometra in a six-month-old nulliparous golden hamster (Mesocricetus auratus) treated with aglepristone.

      Acknowledgments

      The author is very grateful for the following experts’ contributions: Dr Fredrik Södersten, DVM, PhD, Swedish University of Agricultural Sciences, performed histopathology examinations and provided the images in Fig. 1. Dr George Mantziaras, DVM, PhD, VetRepro, Athens, Greece, provided the ultrasonography Video 1 supplementary files and the stump pyometra ultrasonography image for Fig. 10. Associate Professor, Kerstin Hansson, DVM, PhD, Diplomate ECVDI, Swedish University of Agricultural Sciences and the University Animal Hospital, Swedish University of Agricultural Sciences provided the diagnostic imaging and text in Fig. 3.

      Supplementary data

      References

        • Egenvall A.
        • Hagman R.
        • Bonnett B.N.
        • et al.
        Breed risk of pyometra in insured dogs in Sweden.
        J Vet Intern Med. 2001; 15: 530-538
        • Hagman R.
        • Strom Holst B.
        • Moller L.
        • et al.
        Incidence of pyometra in Swedish insured cats.
        Theriogenology. 2014; 82: 114-120
        • Dow C.
        The cystic hyperplasia-pyometra complex in the bitch.
        J Comp Pathol. 1959; 69: 237-250
        • Hagman R.
        • Greko C.
        Antimicrobial resistance in Escherichia coli isolated from bitches with pyometra and from urine samples from other dogs.
        Vet Rec. 2005; 157: 193-196
        • Sandholm M.
        • Vasenius H.
        • Kivisto A.K.
        Pathogenesis of canine pyometra.
        J Am Vet Med Assoc. 1975; 167: 1006-1010
        • Wadås B.
        • Kuhn I.
        • Lagerstedt A.S.
        • et al.
        Biochemical phenotypes of Escherichia coli in dogs: comparison of isolates isolated from bitches suffering from pyometra and urinary tract infection with isolates from faeces of healthy dogs.
        Vet Microbiol. 1996; 52: 293-300
        • Jitpean S.
        • Hagman R.
        • Strom Holst B.
        • et al.
        Breed variations in the incidence of pyometra and mammary tumours in Swedish dogs.
        Reprod Domest Anim. 2012; 47: 347-350
        • Davidson A.P.
        • Feldman E.C.
        • Nelson R.W.
        Treatment of pyometra in cats, using prostaglandin F2 alpha: 21 cases (1982-1990).
        J Am Vet Med Assoc. 1992; 200: 825-828
        • Kenney K.J.
        • Matthiesen D.T.
        • Brown N.O.
        • et al.
        Pyometra in cats: 183 cases (1979-1984).
        J Am Vet Med Assoc. 1987; 191: 1130-1132
        • Hagman R.
        • Karlstam E.
        • Persson S.
        • et al.
        Plasma PGF 2 alpha metabolite levels in cats with uterine disease.
        Theriogenology. 2009; 72: 1180-1187
        • Niskanen M.
        • Thrusfield M.V.
        Associations between age, parity, hormonal therapy and breed, and pyometra in Finnish dogs.
        Vet Rec. 1998; 143: 493-498
        • Von Berky A.G.
        • Townsend W.L.
        The relationship between the prevalence of uterine lesions and the use of medroxyprogesterone acetate for canine population control.
        Aust Vet J. 1993; 70: 249-250
        • Hagman R.
        • Lagerstedt A.S.
        • Hedhammar A.
        • et al.
        A breed-matched case-control study of potential risk-factors for canine pyometra.
        Theriogenology. 2011; 75: 1251-1257
        • Cox J.E.
        Progestagens in bitches: a review.
        J Small Anim Pract. 1970; 11: 759-778
        • England G.C.
        • Moxon R.
        • Freeman S.L.
        Delayed uterine fluid clearance and reduced uterine perfusion in bitches with endometrial hyperplasia and clinical management with postmating antibiotic.
        Theriogenology. 2012; 78: 1611-1617
        • Hollinshead F.
        • Krekeler N.
        Pyometra in the queen: to spay or not to spay?.
        J Feline Med Surg. 2016; 18: 21-33
        • Wijewardana V.
        • Sugiura K.
        • Wijesekera D.P.
        • et al.
        Effect of ovarian hormones on maturation of dendritic cells from peripheral blood monocytes in dogs.
        J Vet Med Sci. 2015; 77: 771-775
        • Rowson L.E.
        • Lamming G.E.
        • Fry R.M.
        Influence of ovarian hormones on uterine infection.
        Nature. 1953; 171: 749-750
        • Hawk H.W.
        • Turner G.D.
        • Sykes J.F.
        The effect of ovarian hormones on the uterine defense mechanism during the early stages of induced infection.
        Am J Vet Res. 1960; 21: 644-648
        • Chaffaux S.
        • Thibier M.
        Peripheral plasma concentrations of progesterone in the bitch with pyometra.
        Ann Rech Vet. 1978; 9: 587-592
        • Prapaiwan N.
        • Manee-In S.
        • Olanratmanee E.
        • et al.
        Expression of oxytocin, progesterone, and estrogen receptors in the reproductive tract of bitches with pyometra.
        Theriogenology. 2017; 89: 131-139
        • Strom Holst B.
        • Larsson B.
        • Rodriguez-Martinez H.
        • et al.
        Prediction of the oocyte recovery rate in the bitch.
        J Vet Med A Physiol Pathol Clin Med. 2001; 48: 587-592
        • De Bosschere H.
        • Ducatelle R.
        • Vermeirsch H.
        • et al.
        Cystic endometrial hyperplasia-pyometra complex in the bitch: should the two entities be disconnected?.
        Theriogenology. 2001; 55: 1509-1519
        • Fransson B.A.
        • Karlstam E.
        • Bergstrom A.
        • et al.
        C-reactive protein in the differentiation of pyometra from cystic endometrial hyperplasia/mucometra in dogs.
        J Am Anim Hosp Assoc. 2004; 40: 391-399
        • Hagman R.
        • Kindahl H.
        • Fransson B.A.
        • et al.
        Differentiation between pyometra and cystic endometrial hyperplasia/mucometra in bitches by prostaglandin F2alpha metabolite analysis.
        Theriogenology. 2006; 66: 198-206
        • Børresen B.
        • Naess B.
        Microbial immunological and toxicological aspects of canine pyometra.
        Acta Vet Scand. 1977; 18: 569-571
        • Coggan J.A.
        • Melville P.A.
        • de Oliveira C.M.
        • et al.
        Microbiological and histopathological aspects of canine pyometra.
        Braz J Microbiol. 2008; 39: 477-483
        • Fransson B.
        • Lagerstedt A.S.
        • Hellmen E.
        • et al.
        Bacteriological findings, blood chemistry profile and plasma endotoxin levels in bitches with pyometra or other uterine diseases.
        Zentralbl Veterinarmed A. 1997; 44: 417-426
        • Grindlay M.
        • Renton J.P.
        • Ramsay D.H.
        O-groups of Escherichia coli associated with canine pyometra.
        Res Vet Sci. 1973; 14: 75-77
        • Hernandez J.L.
        • Besso J.G.
        • Rault D.N.
        • et al.
        Emphysematous pyometra in a dog.
        Vet Radiol Ultrasound. 2003; 44: 196-198
        • Nomura K.
        • Yoshida K.
        • Funahashi H.
        • et al.
        The possibilities of uterine infection of Escherichia coli inoculated into the vagina and development of endometritis in bitches.
        Japanese Journal of Reproduction. 1988; 34: 199-203
        • Agostinho J.M.
        • de Souza A.
        • Schocken-Iturrino R.P.
        • et al.
        Escherichia coli strains isolated from the uteri horn, mouth, and rectum of bitches suffering from pyometra: virulence factors, antimicrobial susceptibilities, and clonal relationships among strains.
        Int J Microbiol. 2014; 2014: 979584
        • Hagman R.
        • Kuhn I.
        Escherichia coli strains isolated from the uterus and urinary bladder of bitches suffering from pyometra: comparison by restriction enzyme digestion and pulsed-field gel electrophoresis.
        Vet Microbiol. 2002; 84: 143-153
        • Watts J.R.
        • Wright P.J.
        • Whithear K.C.
        Uterine, cervical and vaginal microflora of the normal bitch throughout the reproductive cycle.
        J Small Anim Pract. 1996; 37: 54-60
        • Mateus L.
        • Henriques S.
        • Merino C.
        • et al.
        Virulence genotypes of Escherichia coli canine isolates from pyometra, cystitis and fecal origin.
        Vet Microbiol. 2013; 166: 590-594
        • Siqueira A.K.
        • Ribeiro M.G.
        • Leite Dda S.
        • et al.
        Virulence factors in Escherichia coli strains isolated from urinary tract infection and pyometra cases and from feces of healthy dogs.
        Res Vet Sci. 2009; 86: 206-210
        • Chen Y.M.
        • Wright P.J.
        • Lee C.S.
        • et al.
        Uropathogenic virulence factors in isolates of Escherichia coli from clinical cases of canine pyometra and feces of healthy bitches.
        Vet Microbiol. 2003; 94: 57-69
        • Van Miert A.S.J.
        • Frens J.
        The reaction of different animal species to bacterial pyrogens.
        Zentralbl Veterinarmed A. 1968; 15: 532-543
        • McAnulty J.F.
        Septic shock in the dog: a review.
        J Am Anim Hosp Assoc. 1983; 19: 827-836
        • Okano S.
        • Tagawa M.
        • Takase K.
        Relationship of the blood endotoxin concentration and prognosis in dogs with pyometra.
        J Vet Med Sci. 1998; 60: 1265-1267
        • Hagman R.
        • Kindahl H.
        • Lagerstedt A.S.
        Pyometra in bitches induces elevated plasma endotoxin and prostaglandin F2alpha metabolite levels.
        Acta Vet Scand. 2006; 47: 55-67
        • Karlsson I.
        • Wernersson S.
        • Ambrosen A.
        • et al.
        Increased concentrations of C-reactive protein but not high-mobility group box 1 in dogs with naturally occurring sepsis.
        Vet Immunol Immunopathol. 2013; 156: 64-72
        • Marretta S.M.
        • Matthiesen D.T.
        • Nichols R.
        Pyometra and its complications.
        Probl Vet Med. 1989; 1: 50-62
        • Wheaton L.G.
        • Johnson A.L.
        • Parker A.J.
        • et al.
        Results and complications of surgical treatment of pyometra: a review of 80 cases.
        J Am Anim Hosp Assoc. 1987; 25: 563-568
        • Singer M.
        The new sepsis consensus definitions (Sepsis-3): the good, the not-so-bad, and the actually-quite-pretty.
        Intensive Care Med. 2016; 42: 2027-2029
        • Brady C.A.
        • Otto C.M.
        • Van Winkle T.J.
        • et al.
        Severe sepsis in cats: 29 cases (1986-1998).
        J Am Vet Med Assoc. 2000; 217: 531-535
        • Børresen B.
        Pyometra in the dog. II.–A pathophysiological investigation. II. Anamnestic, clinical and reproductive aspects.
        Nord Vet Med. 1979; 31: 251-257
        • Jitpean S.
        • Ambrosen A.
        • Emanuelson U.
        • et al.
        Closed cervix is associated with more severe illness in dogs with pyometra.
        BMC Vet Res. 2017; 13: 11
        • Jitpean S.
        • Strom-Holst B.
        • Emanuelson U.
        • et al.
        Outcome of pyometra in female dogs and predictors of peritonitis and prolonged postoperative hospitalization in surgically treated cases.
        BMC Vet Res. 2014; 10: 6
        • Bjurstrom L.
        Aerobic bacteria occurring in the vagina of bitches with reproductive disorders.
        Acta Vet Scand. 1993; 34: 29-34
        • Bigliardi E.
        • Parmigiani E.
        • Cavirani S.
        • et al.
        Ultrasonography and cystic hyperplasia-pyometra complex in the bitch.
        Reprod Domest Anim. 2004; 39: 136-140
        • Vandeplassche M.
        • Coryn M.
        • De Schepper J.
        Pyometra in the bitch: cytological, bacterial, histological and endocrinological characteristics.
        Vlaams Diergeneeskd Tijdschr. 1991; 60: 207-211
        • Hardy R.M.
        • Osborne C.A.
        Canine pyometra: pathophysiology, diagnosis and treatment of uterine and extra-genital lesions.
        J Am Anim Hosp Assoc. 1974; 10: 245-267
        • Maddens B.
        • Heiene R.
        • Smets P.
        • et al.
        Evaluation of kidney injury in dogs with pyometra based on proteinuria, renal histomorphology, and urinary biomarkers.
        J Vet Intern Med. 2011; 25: 1075-1083
        • Asheim A.
        Renal function in dogs with pyometra. 8. Uterine infection and the pathogenesis of the renal dysfunction.
        Acta Pathol Microbiol Scand. 1964; 60: 99-107
        • Dabrowski R.
        • Kostro K.
        • Lisiecka U.
        • et al.
        Usefulness of C-reactive protein, serum amyloid A component, and haptoglobin determinations in bitches with pyometra for monitoring early post-ovariohysterectomy complications.
        Theriogenology. 2009; 72: 471-476
        • Dorsey T.I.
        • Rozanski E.A.
        • Sharp C.R.
        • et al.
        Evaluation of thromboelastography in bitches with pyometra.
        J Vet Diagn Invest. 2018; 30: 165-168
        • Becher-Deichsel A.
        • Aurich J.E.
        • Schrammel N.
        • et al.
        A surgical glove port technique for laparoscopic-assisted ovariohysterectomy for pyometra in the bitch.
        Theriogenology. 2016; 86: 619-625
        • Fieni F.
        • Topie E.
        • Gogny A.
        Medical treatment for pyometra in dogs.
        Reprod Domest Anim. 2014; 49: 28-32
        • Fantoni D.
        • Shih A.C.
        Perioperative fluid therapy.
        Vet Clin North Am Small Anim Pract. 2017; 47: 423-434
        • Kirby R.
        An introduction to SIRS and the rule of 20.
        in: Kirby R. Linklater A. Monitoring and intervention for the critically ill small animal. Wiley Blackwell, Ames (IA)2017: 1-8
        • DeClue A.
        Sepsis and the systemic inflammatory response syndrome.
        in: Ettinger S.J. Feldman E.C. Cote E. Textbook of veterinary internal medicine: diseases of the dogs and cat. 8th edition. Elsevier, St Louis (MO)2016: 554-560
        • Devey J.J.
        Surgical considerations in the emergent small animal patient.
        Vet Clin North Am Small Anim Pract. 2013; 43: 899-914
        • Liao P.Y.
        • Chang S.C.
        • Chen K.S.
        • et al.
        Decreased postoperative C-reactive protein production in dogs with pyometra through the use of low-dose ketamine.
        J Vet Emerg Crit Care (San Antonio). 2014; 24: 286-290
        • Tobias K.M.
        • Wheaton L.G.
        Surgical management of pyometra in dogs and cats.
        Semin Vet Med Surg (Small Anim). 1995; 10: 30-34
        • Bartoskova A.
        • Vitasek R.
        • Leva L.
        • et al.
        Hysterectomy leads to fast improvement of haematological and immunological parameters in bitches with pyometra.
        J Small Anim Pract. 2007; 48: 564-568
        • Feldman E.C.
        • Nelson R.W.
        Cystic endometrial hyperplasia/pyometra complex.
        in: Feldman E.C. Nelson R.W. Endocrinology and reproduction. 3rd edition. Saunders, St Louis (MO)2004: 852-867
        • Fantoni D.T.
        • Auler Junior J.O.
        • Futema F.
        • et al.
        Intravenous administration of hypertonic sodium chloride solution with dextran or isotonic sodium chloride solution for treatment of septic shock secondary to pyometra in dogs.
        J Am Vet Med Assoc. 1999; 215: 1283-1287
        • Fransson B.A.
        • Lagerstedt A.S.
        • Bergstrom A.
        • et al.
        C-reactive protein, tumor necrosis factor alpha, and interleukin-6 in dogs with pyometra and SIRS.
        J Vet Emerg Crit Care. 2007; 17: 373-381
        • Fieni F.
        Clinical evaluation of the use of aglepristone, with or without cloprostenol, to treat cystic endometrial hyperplasia-pyometra complex in bitches.
        Theriogenology. 2006; 66: 1550-1556
        • England G.C.
        • Freeman S.L.
        • Russo M.
        Treatment of spontaneous pyometra in 22 bitches with a combination of cabergoline and cloprostenol.
        Vet Rec. 2007; 160: 293-296
        • Verstegen J.
        • Dhaliwal G.
        • Verstegen-Onclin K.
        Mucometra, cystic endometrial hyperplasia, and pyometra in the bitch: advances in treatment and assessment of future reproductive success.
        Theriogenology. 2008; 70: 364-374
        • Lopate C.
        Pyometra, cystic endometrial hyperplasia (hydrometra, mucometra, hematometra).
        in: Greco D.S. Davidson A.P. Blackwell’s five-minute veterinary consult clinical companion, small animal endocrinology and reproduction. Wiley-Blackwell, Hoboken (NJ)2017: 53-62
        • Contri A.
        • Gloria A.
        • Carluccio A.
        • et al.
        Effectiveness of a modified administration protocol for the medical treatment of canine pyometra.
        Vet Res Commun. 2015; 39: 1-5
        • Davidson A.
        Female and male infertility and subfertility.
        in: Nelson R.W. Couto C.G. Small Animal Internal Medicine. 5th edition. Elsevier, St Louis (MO)2014: 951-965
        • Greer M.
        Canine reproduction and neonatology - a practical guide for veterinarians, veterinary staff and breeders.
        Teton Newmedia, Jackson (WY)2015
      1. BSAVA small animal formulary. 8th edition. British Small Animal Veterinary Association, Gloucester (United Kingdom)2014
        • Jena B.
        • Rao K.S.
        • Reddy K.C.S.
        • et al.
        Comparative efficacy or various therapeutic protocols in the treatment of pyometra in bitches.
        Vet Med. 2013; 58: 271-276
        • Arnold S.
        • Hubler M.
        • Casal M.
        • et al.
        Use of low dose prostaglandin for the treatment of canine pyometra.
        J Small Anim Pract. 1988; 29: 303-308
        • Sridevi P.
        • Balasubramanian S.
        • Devanathan T.
        • et al.
        Low dose prostaglandin F2 alpha therapy in treatment of canine pyometra.
        Indian Vet J. 2000; 77: 889-890
        • Corrada Y.
        • Arias D.
        • Rodriguez R.
        • et al.
        Combination dopamine agonist and prostaglandin agonist treatment of cystic endometrial hyperplasia-pyometra complex in the bitch.
        Theriogenology. 2006; 66: 1557-1559
        • Gurbulak K.
        • Pancarci M.
        • Ekici H.
        • et al.
        Use of aglepristone and aglepristone + intrauterine antibiotic for the treatment of pyometra in bitches.
        Acta Vet Hung. 2005; 53: 249-255
        • Trasch K.
        • Wehrend A.
        • Bostedt H.
        Follow-up examinations of bitches after conservative treatment of pyometra with the antigestagen aglepristone.
        J Vet Med A Physiol Pathol Clin Med. 2003; 50: 375-379
        • Jurka P.
        • Max A.
        • Hawrynska K.
        • et al.
        Age-related pregnancy results and further examination of bitches after aglepristone treatment of pyometra.
        Reprod Domest Anim. 2010; 45: 525-529
        • Ros L.
        • Holst B.S.
        • Hagman R.
        A retrospective study of bitches with pyometra, medically treated with aglepristone.
        Theriogenology. 2014; 82: 1281-1286
        • Gogny A.
        • Fieni F.
        Aglepristone: a review on its clinical use in animals.
        Theriogenology. 2016; 85: 555-566
        • Nak D.
        • Nak Y.
        • Tuna B.
        Follow-up examinations after medical treatment of pyometra in cats with the progesterone-antagonist aglepristone.
        J Feline Med Surg. 2009; 11: 499-502
        • Lagerstedt A.-S.
        • Obel N.
        • Stavenborn M.
        Uterine drainage in the bitch for treatment of pyometra refractory to prostaglandin F2α.
        J Small Anim Pract. 1987; 28: 215-222
        • Gabor G.
        • Siver L.
        • Szenci O.
        Intravaginal prostaglandin F2 alpha for the treatment of metritis and pyometra in the bitch.
        Acta Vet Hung. 1999; 47: 103-108
        • De Cramer K.G.
        Surgical uterine drainage and lavage as treatment for canine pyometra.
        J S Afr Vet Assoc. 2010; 81: 172-177
        • Gobello C.
        • Castex G.
        • Klima L.
        • et al.
        A study of two protocols combining aglepristone and cloprostenol to treat open cervix pyometra in the bitch.
        Theriogenology. 2003; 60: 901-908
        • Garcia Mitacek M.C.
        • Stornelli M.C.
        • Tittarelli C.M.
        • et al.
        Cloprostenol treatment of feline open-cervix pyometra.
        J Feline Med Surg. 2014; 16: 177-179
        • Jitpean S.
        • Pettersson A.
        • Hoglund O.V.
        • et al.
        Increased concentrations of Serum amyloid A in dogs with sepsis caused by pyometra.
        BMC Vet Res. 2014; 10: 273
        • Conti-Patara A.
        • de Araujo Caldeira J.
        • de Mattos-Junior E.
        • et al.
        Changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization at admission to ICU and the relation to outcome.
        J Vet Emerg Crit Care (San Antonio). 2012; 22: 409-418
        • Kuplulu S.
        • Vural M.R.
        • Demirel A.
        • et al.
        The comparative evaluation of serum biochemical, haematological, bacteriological and clinical findings of dead and recovered bitches with pyometra in the postoperative process.
        Acta Veterinaria-Beograd. 2009; 59: 193-204
        • Hagman R.
        Diagnostic and prognostic markers for uterine diseases in dogs.
        Reprod Domest Anim. 2014; 49: 16-20
        • Mir F.
        • Fontaine E.
        • Albaric O.
        • et al.
        Findings in uterine biopsies obtained by laparotomy from bitches with unexplained infertility or pregnancy loss: an observational study.
        Theriogenology. 2013; 79: 312-322
        • Christensen B.W.
        • Schlafer D.H.
        • Agnew D.W.
        • et al.
        Diagnostic value of transcervical endometrial biopsies in domestic dogs compared with full-thickness uterine sections.
        Reprod Domest Anim. 2012; 47: 342-346
        • Artl S.
        • Wehrend A.
        • Reichler I.M.
        Kastration der Hundin - neue und alte Erkenntnisse zu Vor- und nachteilen.
        Tierärtzliche Praxis Kleintiere. 2017; 45: 253-263
        • Ball R.L.
        • Birchard S.J.
        • May L.R.
        • et al.
        Ovarian remnant syndrome in dogs and cats: 21 cases (2000-2007).
        J Am Vet Med Assoc. 2010; 236: 548-553
        • Kondert L.
        • Mayer J.
        Reproductive medicine in guinea pigs, chinchillas and degus.
        Vet Clin North Am Exot Anim Pract. 2017; 20: 609-628
        • Martorell J.
        Reproductive disorders in pet rodents.
        Vet Clin North Am Exot Anim Pract. 2017; 20: 589-608
        • Mancinelli E.
        • Lord B.
        Urogenital system and reproductive disease.
        BSAVA, Glouchester (United Kingdom)2016
        • Heap R.B.
        Prostaglandins in pyometrial fluid from the cow, bitch and ferret.
        Br J Pharmacol. 1975; 55: 515-518
        • Engelhardt A.B.
        Behandlung des Endometritis/Pyometrakomplexes eines Meerschweinchens - ein Fallbericht.
        Prakt Tierarzt. 2006; 87: 14-16
        • Pisu M.C.
        • Andolfatto A.
        • Veronesi M.C.
        Pyometra in a six-month-old nulliparous golden hamster (Mesocricetus auratus) treated with aglepristone.
        Vet Q. 2012; 32: 179-181
        • Nelson R.W.
        • Feldman E.C.
        Pyometra.
        Vet Clin North Am Small Anim Pract. 1986; 16: 561-576