Pathogenesis: Canine pyometra is a diestrual disease typical of adult intact bitches whose development is strongly influenced by sequential progestational stimulations (normal diestrus or treatment with progestins) of the uterus. Bitches whelping rarely or never in their lives have a greater chance of developing pyometra with rare or no occurrence of pregnancy. For unknown reasons gestation has a protective action on the canine endometrium, causing pyometra not to develop in areas of the endometrium where placental attachment has occurred (although pyometra can occur in one horn with pregnancy in the opposite horn). During a progestational stimulation the canine endometrium proliferates and starts secreting the so called "uterine milk" while the cervix remains closed and myometrial contractility is inhibited. Fluid accumulates into the endometrial glands which then dilate becoming fairly large (up to 0.3-2.0 cm diameter). The endometrial pattern that develops is referred to as cystic endometrial hyperplasia  which is a prerequisite for the development of pyometra due to the fact that the uterine milk in itself constitutes an inflammatory stimulus as well as an excellent culture media for bacteria which. CEH is a physiological phenomenon whose regression starts during the second half of diestrus. However, with time and number of "open" (non-pregnant) cycles CEH may not entirely disappear from some sections of the endometrium, thus increasing chances of causing endometrial inflammation. Fecal/perineal bacteria (E. coli, Streptococcus spp., Staphylococcus spp., Klebsiella, Proteus and Pseudomonas are the most common ones) often concur to the development of uterine lesions and clinical signs (especially if they cannot be cleared from the uterus prior to onset of the luteal phase), but are not necessary for the clinical manifestation of the disease. E. coli can produce an endotoxin which, upon bacterial death (i.e., following an antibiotic treatment), is released into the uterine lumen and absorbed. The resulting endotoxemia may cause a severe shock reaction and death of the bitch depending on the amount of endotoxin released and on the physical condition of the dog (antibiotics have no effect on concentrations of endotoxins). Clinical signs of endotoxemia include disorientation, hypothermia and shock.

Renal lesions are frequent in bitches with pyometra (especially in older bitches), being due to either the disease itself (because of pre-renal azotemia due to dehydration or glomerular/tubular disease due to the bacterial infection or endotoxemia) or because they were already present when pyometra developed. Bone marrow, liver and spleen disease can also be either already present or caused by the disease itself in bitches with pyometra.

Clinical signs: Clinical signs of pyometra may include depression, anorexia, abdominal distension, vomiting and diarrhea, and increased thirst and urination. A putrid vaginal discharge may or may not be present, depending on whether the cervix is open or closed. This is a diestrus disease, so estrus was probably within the last month. With open cervix pyometra you see a vaginal discharge, lethargy, depression, anorexia/inappetance, polyuria/polydypsia, and vomiting. The dogs are generally relatively healthy though. WBC count is high or normal. With closed cervix pyometra you see depression, lethargy, weakness, inappetance, polyuria/polydypsia, and vomiting. The WBC is usually high with a left shift.

Diagnosis: Diagnosing pyometra in the bitch may be very easy, especially if uterine enlargement and leukocytosis can be appreciated (Shukla & Kumar, 2005) along with the other classical signs of polyuria/polydipsia, anorexia, depression, vulvar discharge (in case of open cervix pyometra). Bitches with a closed cervix pyometra with only a slight to moderate increase in uterine size are the most challenging cases, especially if leukocytosis is absent or if there is neutropenia (which may be due to endotoxemia). The range of WBC count reported for bitches with pyometra is 2500-196,800 cells/mm3, with a left shift in 70-90% of cases. Average number of bands (toxic PMNs) is about 500 cells/mm3, with degree of toxic change correlated with the severity of disease. Other abnormalities (anemia, azotemia, hypergammaglobulinemia, hypoalbuminemia, metabolic acidosis, decreased urine specific gravity, proteinuria, bilirubinuria) may or may not be present and when present may or may not be related to the uterine disease. Although not always relevant to the diagnostic process, liver, kidney and bone marrow function tests should be carried out to allow for a proper clinical management of the disease, thus avoiding canine pyometra patients to die i.e., for a renal complication once the uterine problem has been cured. Pregnancy should always be ruled out, as it may coexist with pyometra. Less common differential diagnosis includes diabetes mellitus, hyperadrenocorticism, renal disease, and diabetes insipidus.

Treatment of pyometra:
(A) Medicinal
(i) Open-cervix pyometra
When the cervix is open the uterus can be easily emptied stimulating the contractility of the myometrium. PGF2a is the most indicated for the clinical treatment of pyometra for inducing contractibility of uterus. Oxytocin and ergot derivatives induce very strong, short-lasting contraction of the uterine wall which may be dangerous if the uterus is fully dilated with pus and/or the uterine wall is thin and atrophied or the cervix is only partially dilated.  This may cause either the pus to be forced backward into the uterine tubes and then into the abdomen or the uterine wall to rupture. Uterine rupture is a very rare event, but may be caused by any drug stimulating uterine contractility. Prostaglandin-based drugs which have been tested in the canine and for which safe dosages have been developed include natural PGF2a, cloprostenol and alfaprostol @ 0.05-0.1 mg/kg, 0.001-0.005 mg/kg & 0.02mg/kg b. wt., respectively. In order for a pus-filled uterus to be emptied prostaglandin administration should be continued as long as a vulvar discharge is present. Length of prostaglandin treatment should be based on careful evaluation of uterine dimensions before, during and after therapy in order to confirm that uterine diameter has gone back to normal.Based on studies done in diestrous bitches by Wheaton and Barbee (1993), PGF2a doses of 50 and 250 mcg/kg cause a maximum uterine pressure without any significant difference, and duration of the uterine contraction significantly lower at 23±3 minutes for the lower dosage vs 30±3 minutes for the higher dosage, respectively. Efficacy of low doses of natural PGF2a has been reported for bitches with pyometra (Lange et al., 1997). Such a treatment protocol is effective provided that prostaglandins are administered 2-3 times daily for as long as a vulvar discharge is present. Large amounts of pus in the uterus may require treatments of 2-3 weeks duration. The decision on when to stop the treatment should be based on disappearance of the uterine lumen detectable on ultrasound (in normal conditions the uterine lumen is not detectable, but it becomes distinguishable when liquid accumulates within the uterus). The risk of uterine rupture can be subjectively assessed looking at the thickness of the uterine wall with ultrasound using 7.5-10.0 MHz probes.
Antibiotic treatment should be specific (start with ampicillin at 22 mg/kg 3 times/daily and change antibiotics after culture results) and should last at least for one week but it should continue for as long as a purulent vulvar discharge is present (which may persist for a few days after the uterine diameter has become normal again). At the following proestrus a cranial vaginal culture should be taken and the bitch treated with a specific antibiotic until ovulation, and then bred to a proven fertile male at the proper time in order to ensure conception. When reproduction is not deemed necessary any longer the bitch should be spayed, as the recurrence rate of pyometra in older dogs may be higher than 50%.

When dealing with an open cervix pyometra in the bitch, prostaglandins are useful also for their luteolytic properties. Serum progesterone assay at the start of treatment will allow to monitor effectiveness of luteolysis which is important to avoid recurrence of pyometra during that same cycle. When presenting with a pyometra in early diestrus, a bitch might recover quickly following a specific antibiotic treatment, but if luteolysis is not achieved the clinical manifestations of the disease will recur as soon as the antibiotic concentration decreases in the general circulation. The use of antiprogestins such as aglepristone (the antiprogestin currently available for veterinary use in small animals in a few european countries) has an effect similar to the luteolysis produced by prostaglandin, in that progesterone receptors in all districts of the organism are blocked. For the treatment of open-cervix pyometra antiprogestins offer the advantage of causing virtually no side effects, while prostaglandins are characterized by a well known cascade of side effects. Side effects of prostaglandins should not be overemphasized as they are not observed in all bitches, tend to subdue during the course of the treatment and are significantly less common when using dosages of natural PGF2a <50 mcg/kg. However, side effects tend to be more evident in bitches with pyometra, perhaps because of the deteriorated physical conditions which characterize the uterine disease.

(ii) Closed-cervix pyometra
The availability of antiprogestin-based drugs has completely changed the clinical approach to a problem whose only solution for the last decades has been ovariohysterectomy. The administration of aglepristone during diestrus in the bitch will cause opening of the cervical os with consequent emptying of the uterine content. Following treatment with a dose of 10 mg/kg aglepristone administered on days 1, 2 and 8 in 15 bitches with closed pyometra, opening of the cervix was reported to occur after 26±13 hours in all treated animals. Although the success rate in closed cervix pyometra following 3 administrations of aglepristone alone is reported to be around 20%, a follow-up treatment of the same dosage of the antiprogestin at day 14 and 28 associated to a prostaglandin treatment once the purulent vulvar discharge becomes evident has risen the success rate to 90%. Antiprogestins can be used to avoid recurrence of pyometra at subsequent cycles should the owner decide not to breed the bitch immediately. Bitches with a closed cervix pyometra and with liver or kidney insufficiency are not considered good candidates for a medical treatment with aglepristone.

(B) Surgical treatment (Ovariohysterectomy):
The term “ovariohysterectomy” (OVH) means surgical removal of ovary and uterus. OVH is mainly indicated for sterilization of bitch, however, it can also be done in other pathological condition of female reproductive tract. The knowledge of anatomy of female reproductive tract is important for the OVH.

Patient preparation: In the case of normal appetite, 12-24 hour fasting and 6-12 hour water withholding is the prerequisite to reduce the anesthetic complications and reduction in the abdominal size. On the day of operation, physical examination is also done for evaluation of the patient whether it sustain the anesthesia and surgical stress or not. Once it is fit for OVH, surgical site is prepared aseptically.

Anesthetic protocol: The OVH is done under the general anesthesia, which includes a combination of both ketamine (5-10 mg/kg i.v.) and xylazine (0.5-1.0 mg/kg i.m.) or ketamine and diazepam (1-2 mg/kg i.m.). Anticholinergic drug atropine sulphate @ 0.045 mg/kg s.c. or i.m. is given to check the salivation and A V block produced by xylazine.

Surgical site: There are numerous sites for the OVH are documented in the literature, amongst them; oblique left flank incision (for large breed) and middle mid ventral incision (for small breed) are currently used.

Surgical procedure: The length of the midline abdominal incision is based on the size of the animal. The distance between the umbilicus and the pubis is divided into thirds. In the dog, the incision is made in the cranial third because the ovaries are more difficult to exteriorize than the uterine body. If the uterus is distended or enlarged, the incision is lengthened. The flank incision is generally not preferred for the pyometra, because entire uterine body is difficult to remove by this approach.   The right uterine horn is located by means of an ovario-hysterectomy hook or the index finger. The spleen is avoided. A    clamp   is   placed on the proper ligament of the ovary and is used to retract the ovary while the suspensory ligament is stretched e more difficult to exteriorize than the uterine body. If the uterus is distended or enlarged, the incision is lengthened. The flank incision is generally not preferred for the pyometra, because entire uterine body is difficult to remove by this approach.   The right uterine horn is located by means of an ovario-hysterectomy hook or the index finger. The spleen is avoided. A    clamp   is   placed on the proper ligament of the ovary and is used to retract the ovary while the suspensory ligament is stretched e more difficult to exteriorize than the uterine body. If the uterus is distended or enlarged, the incision is lengthened. The flank incision is generally not preferred for the pyometra, because entire uterine body is difficult to remove by this approach.   The right uterine horn isascular, it is ligated with one or two sutures before it is cut.

Three clamps are placed on the uterine body just cranial to the cervix. The uterine body is severed between the proximal and middle clamps. In the case of pyometra, the severed end of uterine body is needed to be inverted towards cervical end, either by lambert or cushing suturing pattern, to prevent the peritonitis. The uterine arteries are individually ligated caudal to the most caudal clamp. The caudal clamp is removed, and the uterus is ligated in the groove that remains. The uterine pedicle is grasped with a small hemostat above the clamp, the clamp is removed, and the pedicle is inspected for bleeding. The pedicle is gently replaced into the abdominal, and the hemostat is removed. Antibiotic and fluid therapy is given for 5-7 days post-operatively.

Complications:
1.   Hemorrhage: can occur during surgery or post-operative (bleed into abdomen or vagina) period. More potential problems if performed during estrus.
2.   Recurrent estrus: due to incomplete ovary removal and can be diagnose by identifying cornified vaginal epithelial cells and/or increased serum progesterone (>2 ng/ml).
3.   Uterine stump infection: if progesterone is present from ovary or exogenous source.
4.   Uterine or ovarian stump granuloma with or without fistulous tracts: secondary to braided non absorbable suture (Vetafil, silk).
5.   Ligation of ureter: It will develop unilateral hydronephrosis.  The ureters are usually damaged so they must be transected and reimplanted into the bladder.
6.   Urinary incontinence: Estrogen responsive incontinence may occur and can be treated with diethlystilbesterol or phenylpropanolamine.
7.   Eunuchoid syndrome: Decreased aggression and stamina
8.   Weight gain: Not a problem if diet and exercise are regulated.
9.   Infantile vulva: occur in animals who have surgery at 7 weeks of age, but generally have no clinical significance.
References:

Dow C (1957). The cystic hyperplasia-pyometra complex in the bitch. Vet Rec 69:1409.

Dow C (1958). The cystic hyperplasia-pyometra complex in the bitch. Vet Rec 70: 1102.

Dow C (1959). The cystic hyperpl;asia-pyometra complex in the bitch. J comp pathol 69: 237.

Hadley J C (1975). Unconjugated estrogens and progesterone concentrations in the blood of bitches with false pregnancy and pyometra. Vet Rec 96: 545-547.

Hardy RM, Osborne CA (1974). Canine Pyometra: pathophysiology, diagnosis and treatment of uterine and extra-uterine lesions. J Am An Hosp Assoc 10:245.

Lange K, Gunzel-Appel A-R, Hoppen H-O, Mischke R, Nolte I (1997). Effects of low dose prostaglandin F2a during the early luteal phase before and after implantation in beagle bitches. J Reprod Fert Suppl 51: 251-257.

Shukla, S.N; Kumar, Pankaj (2005) “Canine Pyometra: current concepts in diagnosis and treatment” Pashudhan.

Romagnoli SE, Cela M, Camillo F (1991). Use of prostaglandin F2alpha for early pregnancy termination in the mismated bitch. Vet Clin North Am, Small Animal Pract 21:487.

Stone EA, Littman MP, Robertson JL, Bovee KC (1988). Renal dysfunction in dogs with pyometra. J Am Vet Med Ass 193:457.

Slatter, D H (2002). Text book of Small Animal Surgery. 3rd edn. W A Saunders, Philadelphia. p 1496.

Wessels BC, Wells MT (1989). Antiendotoxins immunotherapy for canine pyometra endotoxemia. J Am An Hosp Ass 25: 455.

Wheaton and Barbee (1993). Theriogenology 40:111.

1.   Ph.D Scholar, Division of Surgery
2.   Principal Scientist, Animal Reproduction Division
3.   Ph.D Scholar, Division of Medicine
4.   M.V.Sc. Scholar, Division of VPH

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