In-hospital medical management of feline urethral obstruction: A review of recent clinical research

Abstract

Evidence-based medical practice requires that clinical research be conducted to help guide veterinary recommendations. Unfortunately, clinical research on the treatment of feline urethral obstruction (UO) is limited. Over the past decade, a body of clinically relevant scientific literature related to the in-hospital management of feline UO has been published. This review of the literature from December 2007 to February 2019 encompasses management options, stabilization, anesthetic considerations, unblocking procedures, urinary bladder lavage, intravesical treatments, post-obstructive diuresis, urinary catheter management, catheter-associated bacterial complications, and oral medications. Studies are briefly summarized with respect to their main findings and limitations. Common recurring limitations observed include small sample sizes leading to insufficient power and potential type II errors, lack of standardized treatment protocols, and assessment of multiple inter-related confounding variables. The authors’ intent is for this article to inform practitioners and inspire future clinical research initiatives which address these limitations, possibly with large-scale multicenter studies, standardized treatment protocols, and multivariate regression modeling.

Introduction

Feline urethral obstruction (UO) remains a commonly encountered emergency for small animal practitioners. Underlying causes and approximate historical incidence rates include idiopathic obstructions (54%), urethral plugs (20%), urolithiasis (20%), and other mechanical obstructions such as strictures and neoplasia (collectively, < 5% of cases) (1,2). Survival to discharge rates are high (91% to 94%) (3–5). Reported UO recurrence rates range from 11% to 58% at various time points after initial presentation (4–8). However, the long-term survival rate varies depending upon multiple factors such as client considerations, recurrence, and complications. Gerber et al (4) reported a 91% survival to discharge rate but 51% had recurrent signs, 36% experienced re-obstruction, and 21% were eventually euthanized, which suggested a guarded long-term prognosis.

Over the past decade, numerous interesting clinical research projects have been conducted on the in-hospital treatment of feline UO classified as idiopathic or secondary to urethral plugs. A review of the literature between December 2007 and February 2019 using Pub Med, Google Scholar, Web of Science and Scopus as search engines with the term “feline urethral obstruction” was conducted. This article is neither a tutorial of feline UO management nor an exhaustive systematic review. The authors’ objective is to outline the main findings and limitations of clinical research over the past decade, relating specifically to medical management decisions performed or initiated in-hospital.

Management options

In hospital versus outpatient management

Seitz et al (9) explored whether an outpatient intervention involving one-time catheterization and no IV fluid therapy was a viable alternative to the standard protocol employing an indwelling urinary catheter, IV fluids, and other supportive treatments. In this nonrandomized, non-blinded, prospective-cohort study, conducted at a private emergency service, client-owned male cats with naturally occurring urethral obstruction (NAUO cats) (n = 107; 91 finished the study) were enrolled in the inpatient group (n = 46) if clients accepted standard treatment or the outpatient group (n = 45) only when traditional care was declined. Groups were matched by signalment, metabolic compromise, urinalysis, and supportive treatments. Nineteen cats experienced a recurrent urethral obstruction (rUO): 11% (5/46) in the inpatient group and 31% (14/45) for outpatients. The risk of rUO within 30 d was significantly greater [odd’s ratio (OR), 3.7; 95% confidence interval (CI), 1.2 to 11.4] in the outpatient group than for inpatients. The results of this clinically relevant research endeavor support traditional inpatient therapy over outpatient management with respect to decreasing the risk of rUO within 30 d.

The main limitation is that the study is observational with owner-determined treatment groups rather than random assignment to the intervention. The clinician-client relationship can be influenced by a multitude of factors, leading to 1 group designation over another. This introduces possible selection bias as a result of the decision-making process. Although random assignment represents appropriate study design, it would not be considered ethical to intentionally treat a group of patients in a novel manner (1-time catheterization protocol) without offering standard-of-care therapy (traditional management) to every client. The sample size of this study was considered appropriate to test the primary hypothesis (1-time catheterization relative to traditional management), but speculated to be too small and underpowered with respect to evaluating the potential relationship of secondary factors to rUO.

Nontraditional management without passing a urinary catheter

Cooper et al (10) described a controversial nontraditional protocol offered to clients declining standard-of-care treatment at an academic emergency service. This protocol treats UO from a functional perspective and may facilitate passage of the obstructive material by utilizing a combination of sedatives and analgesia, intermittent decompressive cystocentesis, a low stress quiet room, and subcutaneous fluids as needed. A traditional unblocking procedure is not performed. Exclusion criteria were abnormal clinical findings (i.e., bradycardia, hypothermia, or unresponsive mentation), severe metabolic acidosis and hyperkalemia, and radiographic evidence of cystic or urethral calculi.

In this nonrandomized, non-blinded prospective observational study of NAUO cats (n = 15), spontaneous urination within 72 h, resulting in hospital discharge, was observed in 11 of the 15 cats without the need for urethral catheterization. The 4 cats that failed the intervention developed complications including uroabdomen (3 cats) or hemoabdomen (1 cat). Overall, cystocentesis was performed 3 times (range: 1 to 10 times) in each cat, but 7 times (range: 4 to 11 times) in those cats failing treatment. Repeated cystocentesis over a short period of time may have predisposed patients to uroabdomen. In addition to the small sample size limiting generalizations to a larger population of NAUO cats, this observational study lacks direct comparison of the patient cohort treated with nontraditional management to a group treated with standard-of-care therapy.

Based on these 2 studies investigating controversial alternative management options, clinicians should continue to initially offer standard-of-care treatment for all cases. If traditional management is declined, clinicians should consider a novel protocol as an alternative to euthanasia if appropriate.

Stabilization

Fluid management

Choice of fluid

Fluid therapy is routinely used in the treatment of feline UO for volume support, and addressing potassium and acid-base derangements (11,12). Traditionally, potassium-deficient 0.9% physiologic saline solution was believed to be the best option for treating hyperkalemia compared with potassium-containing replacement fluids (e.g., LRS, Normosol-R), as the latter were presumed to be contraindicated. However, due to the acidifying properties of physiological saline solution (PSS), concerns arose regarding its ability to resolve and potentially exacerbate metabolic acidosis (11).

Two studies compared alkalinizing balanced electrolyte solutions (BES) (LRS and Normosol R) to PSS (13,14). In a randomized, non-blinded study of 10 cats with experimentally induced UO at an academic institution, the PSS treated group (n = 5) had significantly lower blood pH, bicarbonate, and base excess values at multiple time points over the 48-hour post-unblocking period compared to the LRS treated group (n = 5) (13). Groups were matched by body weight, rectal temperature, heart rate, respiratory rate, and hematologic, biochemical, and venous blood gas-electrolyte parameters. A randomized, nonblinded prospective clinical trial in 68 NAUO cats, presenting to an academic emergency service, compared Normosol-R (n = 39) to PSS (n = 29) (14). The acid-base disturbance resolved more rapidly with the use of Normosol-R compared to saline at multiple time points over a 12-hour post-unblocking period. Groups were matched by breed, age, body weight, hydration status, and venous blood gas-electrolyte and biochemical parameters, but not blood glucose concentration. Fluid type did not influence normalization of serum potassium or the rate at which it occurred in either of these 2 studies. Compared with physiologic saline solution, balanced electrolyte solutions more rapidly resolved metabolic acidosis. Neither exacerbated hyperkalemia nor affected its resolution.

Although the experimental model used by Cunha et al (13) induced anticipated blood-gas and cardiovascular complications to allow for consistent sampling times, the naturally occurring disease state was not studied. A small sample size of normal cats in an experimental model at an academic institution limits generalizability to the larger NAUO cat population. In contrast, Drobatz and Cole (14) studied NAUO cats, but the clinical setting does not allow for strict standardization of therapy and introduces multiple confounding factors. To exemplify this limitation, 1 of the measured outcomes was serum potassium, but some of the cats received fluid therapy alone while others also received insulin and dextrose, all of which impact this electrolyte. Fortunately, repeat analysis, excluding patients receiving insulin and dextrose, did not change the results of this study.

Practitioners will have to make decisions regarding fluid therapy on a case by case basis. Both balanced electrolyte solutions and physiologic saline solution are appropriate for hyperkalemia management and initial stabilization.

Fluid overload

Fluid therapy is a prescription requiring ongoing reassessment due to the risk of volume or fluid overload (FO) (15). In a nonrandomized, non-blinded, retrospective case-control study of NAUO cats presented to an academic emergency service, a FO-group (n = 11) and a control-group (n = 51) selected from the same time period were evaluated for risk factors. FO was defined as the development of respiratory distress from either pulmonary edema or pleural effusion while receiving intravenous crystalloid fluids during UO treatment (16). Groups were matched by age, body weight, previous lower urinary tract disease (LUTD) episodes, and biochemical parameters, but not heart rate and serum sodium concentration.

Significant risk factors for FO were identified, including the administration of a fluid bolus at presentation (OR: 5.1; 95% CI: 1.3 to 20), and the development of a heart murmur (OR: 4.5; 95% CI: 1.1 to 18) or gallop sound (OR: 75; 95% CI: 8.1 to 694) during treatment. The development of fluid overload in this study was associated with increased cost (2.9×) and longer duration of hospitalization (4.1 versus 1.8 d) but had no effect on mortality rate. Lack of standardized diagnostic and treatment protocols, small sample size, and case misclassification, due to challenges retrospectively identifying FO cases, limit the generalizability of this study to the larger feline UO population. Thoracic radiographs and cardiac ultrasound ideally would have been performed before and after FO treatment to distinguish between FO of iatrogenic and cardiac origin.

This study emphasizes the importance of monitoring and reassessment of fluid therapy, especially in the presence of a gallop rhythm or heart murmur, and after administering a crystalloid bolus.

Decompressive cystocentesis

Decompressive cystocentesis is indicated in some situations, particularly difficult or delayed unblocking procedures. Routinely performing decompressive cystocentesis before the unblocking procedure is considered part of standard of care in some practice settings, though there is not currently supportive evidence. The main potential benefits include immediate emptying of the urinary bladder to relieve pain and to facilitate retrohydropulsion of the obstructive material, and passage of a urinary catheter by decreasing intraluminal pressure. An uncontaminated sample can also be collected by cystocentesis for urinalysis and culture. Major concerns revolve around the potential for iatrogenic trauma to further compromise the urinary bladder wall resulting in rupture and uroabdomen (11,17).

A nonrandomized, non-blinded, retrospective observational study evaluated the effect of routine decompressive cystocentesis in NAUO cats (n = 47) presenting to an academic emergency service (17). Evidence of abdominal effusion was present on survey abdominal radiographs in 19/34 (56%, 95% CI: 39% to 72%) cats undergoing radiography. However, none of the cats were definitively diagnosed with a urinary bladder rupture after decompressive cystocentesis. It is speculated that a transient, clinically insignificant abdominal effusion may have been present in some cats. The authors compared survival to discharge, duration of catheterization, and length of hospitalization to previously reported studies and detected no differences. The main limitation of this study is the lack of a true control group, in which decompressive cystocentesis was not performed prior to the unblocking procedure.

To address this issue, an important ongoing randomized, non-blinded multicenter prospective clinical trial known as the DECYST TRIAL is attempting to evaluate the effect of a decompressive cystocentesis before urinary catheterization (decompressive cystocentesis group) versus no intervention before urinary catheterization (UC group) (18). Interim analysis was published as an abstract in 2017. NAUO cats (n = 69), presenting to 2 academic emergency services, were randomly assigned to the decompressive cystocentesis group (n = 35) and UC group (n = 34). No complications related to decompressive cystocentesis, including uro- or hemo-abdomen, were observed. There were no significant between-group differences with respect to ease of catheterization scores, time to place urinary catheter, duration of catheterization and hospitalization, incidence of rUO, and concentrations of serum potassium, BUN, and creatinine. Although these interim results negate an interventional effect, it is still possible with further case recruitment that the finalized study will have the power to detect between-group differences.

Until the results of this study are published, clinicians will continue to use their judgment on the role of decompressive cystocentesis in UO management.

Anesthetic considerations

Protocols

Numerous anesthetic protocols have been used or suggested in feline UO (19,20). In the authors’ opinion, there is a striking paucity of clinical research comparing 2 anesthetic protocols for feline UO in a head-to-head manner. A single randomized, non-blinded study was identified in which ketamine [10 mg/kg body weight (BW)] with diazepam (0.5 mg/kg BW) was prospectively compared to propofol (5 mg/kg BW) using a model of experimentally induced UO in normal cats (n = 10) at an academic institution (21). Groups were matched by most venous blood gas-electrolyte and biochemical parameters, except total plasma protein and albumin. During recovery, time to standing was significantly shorter in the propofol group (16 min; range: 10 to 20 min) versus the ketamine-diazepam group (75 min; range: 45 to 90 min), but the quality of recovery appeared to be similar. Laboratory changes such as acid-base disturbances, azotemia, and electrolyte abnormalities stabilized in a similar manner between groups. Generalizability is limited because of the small sample size, and the use of an experimental UO model versus studying the naturally acquired disease state.

Coccygeal epidural

A 12-month nonrandomized, non-blinded, observational study of NAUO cats (n > 15) treated with coccygeal epidurals at a private emergency service has been reported as a brief clinical communication (22). A coccygeal epidural provides local analgesia to the perineum, tail, penis, urethra, colon, and anus. This report focused on describing the technical aspects of performing a coccygeal epidural including observations with respect to the possible efficacy of the block. Potential benefits proposed included minimal additional anesthetic and analgesic requirements in most cases, during both the unblocking procedure itself and the post-unblocking period. Performing the coccygeal epidural was also reported to be relatively simple requiring only 1 attempt in most cases. The biggest limitations of this observational study are the lack of both objective study outcomes (i.e., no data) and a placebo-group. In future research, possible objective study outcomes might include time to pass a urinary catheter during unblocking, ease of catheterization scores, and post-procedure pain scoring.

Further investigation is warranted with respect to anesthetic protocols and coccygeal epidurals for the clinical management of feline UO.

Unblocking procedure and urinary bladder lavage

Intraurethral atracurium besylate

The male feline urethra is narrow and consists of striated muscle distal to the prostate, which is the location of most obstructions (23). Nicotinic acetylcholine receptors on the postsynaptic motor endplate of the neuromuscular junction are competitively inhibited by atracurium besylate, resulting in relaxation of the striated urethral musculature (24).

A novel nonrandomized, non-blinded, placebo-controlled, prospective clinical trial investigated the potential for intraurethral atracurium besylate to facilitate the unblocking procedure in NAUO cats (n = 45) presenting to an academic emergency service (24). Both atracurium besylate (n = 25) and physiologic saline solution (n = 20) groups were matched for age and weight. The time required for the removal of the UO was significantly shorter in the atracurium besylate group (21.1 +/− 16.2 s) versus the physiologic saline solution group (235.2 +/− 132.4 s). The proportion of studied cats in which the urethral plug was removed at the first attempt was significantly higher in the atracurium besylate group (64%, 16/25) than in the physiologic saline solution group (15%, 3/20). No side effects were reported. Cats were segregated into either group in an alternating fashion as they were enrolled, but not truly randomized. The lack of clinician blinding with regard to the intervention may affect an individual’s perception of and approach to the unblocking procedure, impacting the study endpoint (time required to pass the urinary catheter).

To the authors’ knowledge, intraurethral atracurium besylate is not commonly used in small animal practice as a treatment option for feline UO. Further investigation is needed to understand the efficacy and safety of this novel approach.

Urinary bladder lavage

Traditionally, urinary bladder lavage has been recommended following relief of the obstruction and catheter placement (20). Despite the widespread practice of urinary bladder lavage, it was only recently evaluated in a randomized, non-blinded, placebo-controlled, prospective clinical study of NAUO cats (n = 137) presenting to an academic emergency service (25). After the unblocking procedure and catheter placement, urinary bladder lavage was performed using physiologic saline solution until the retrieved fluid was clear with volumes ranging from 50 to 500 mL. Both Flush- and No Flush-groups were matched by the following relevant factors: age, body weight, neuter status, previous blocking history, and presence of crystalluria. It was found that the practice of urinary bladder lavage had no impact on in-hospital UO recurrence rates [Flush, 13% (9/69) versus No Flush, 19% (13/68)], duration of urinary catheterization (Flush, 37 h; range: 3 to 172 h versus No Flush, 36 h; range: 1 to 117 h), or duration of hospitalization (Flush, 3 d; range: 0.5 to 12 d versus No Flush, 3 d; range: 1 to 9 d). Study limitations potentially affecting these outcomes include the lack of standardization for other aspects of medical treatment, the decision not to assess azotemia as an independent risk factor, and the non-blinded study design. Finally, a lower than expected recurrence rate may also suggest that the study was underpowered to detect between-group differences.

Small animal practitioners will need to continue to use their judgment on a case-by-case basis, as further research is needed to determine if there is truly no benefit to urinary bladder lavage during the management of feline UO.

Intravesical treatments

Glycosaminoglycans

Healthy urothelium is covered with a layer of glycosaminoglycans and glycoproteins (26). Significantly decreased urine glycosaminoglycan:creatinine ratios have been observed in cats with idiopathic cystitis compared with normal cats, suggesting a defect in the glycosaminoglycan layer of the uroepithelium (26,27). A number of clinical research studies have failed to demonstrate a beneficial effect of glycosaminoglycan supplementation in cats with non-obstructive idiopathic cystitis as summarized in a recent review article (26).

With respect to idiopathic feline UO, 2 randomized, blinded, placebo-controlled, prospective clinical trials assessing the effect of intravesical glycosaminoglycan treatment were identified (Table 1). A pilot study of NAUO cats (n = 16) receiving intravesical glycosaminoglycan solution did not demonstrate statistically significant differences between treatment (n = 9) and placebo-groups (n = 7) for pain scores and re-obstruction rates during the 7-day observation period (28). The authors of the study speculate that a Type II error may have occurred based upon the fact that re-obstruction rates between groups approached statistical significance in the face of a small sample size. Another study of NAUO cats (n = 35) did not document a beneficial effect of intravesical pentosan polysulfate sodium treatment (n = 18) over placebo (n = 17) for any of the study endpoints, including rUO rates and clinical scores based on demeanor, appetite, and abdominal pain (29). The main limitations of this study include a small sample size and missing data points, as samples were not collected at all time points, leading to the suspicion of insufficient statistical power and a Type II error.

Table 1.

Intravesical treatments.

Reference	Study type	Population, groups (Gs), and matched factors (MFs)	Treatment protocol	Main findings
(28)	Prospective placebo-controlled PILOT clinical trial — Randomized — Blinded	Population: 16 NAUO cats, academic ER. Gs: GAG (2.5 ml GAG + 1 mL PSS), n = 9 and PSS (3.5 mL), n = 7. MFs: pain scores, [creatinine] and [K+], but NOT USG, and urine protein. Previous UO episodes approached significance.	Intravesical GAG or PSS administered by UC at 0, 12, and 24 h with a 1 h retention time. Follow-up period 7 d.	7-day rUO rates in the GAG group 0/9 (0%) and control group 3/7 (42.9%) approached statistical significance.
(29)	Prospective placebo-controlled clinical trial — Randomized — Double-blinded	Population: 35 NAUO cats, academic ER. Gs: PPS (30 mg in 10 mL PSS), n = 18 and PSS (10 mL), n = 17. MFs: signalment, PE findings, and laboratory parameters i.e., [BUN], [creatinine], and [K+].	Intravesical PPS or PSS administered by UC at 0, 24, and 48 h with a 30-min retention time. Follow-up period 5 d.	5-day rUO rates in the PPS group 3/18 (16.7%) and the control 3/17 (17.6%) were similar. No SD between groups in clinical scores or urinalysis results.
(8)	Prospective clinical trial — Randomized — Non-blinded	Population: 26 NAUO cats, academic ER. Gs: AL, n = 12 (2 mg/kg BW lidocaine + NaHCO3, n = 4; and 4 mg/kg BW lidocaine + NaHCO3, n = 8); Control, n = 14 (Isovolumetric PSS + NaHCO3, n = 8; and no intravesical control if temperament not permitting, n = 6). MFs: age, breed, [BUN], [creatinine], [K+], and previous LUTD episodes, but NOT body weight.	Intravesical AL or control administered by UC every 24 h for a maximum of 3 d with a 1 h retention time. Client follow-up at 2 wk, 1 mo, and 2 mo.	Overall rUO rates in the AL group 7/12 (58%) and the control group 8/14 (57%) were similar. Composite AS were similar at all time points. Significantly higher AS for straining at 2 wk in the AL group versus control.

NAUO cats — client-owned male cats with naturally acquired urethral obstruction; UO — urethral obstruction; ER — emergency room; GAG; glycosaminoglycans; PSS; 0.9% physiological saline; UC — urinary catheter; PPS — pentosan polysulfate sodium; rUO — urea nitrogen concentration; [creatinine] — serum creatinine concentration; [K⁺] — serum potassium concentration; LUTD — lower urinary tract disease; AL — alkalinized lidocaine; AS — amelioration scores (improvement in clinical signs provided as a score); SD — significant difference.

Alkalinized lidocaine

A preliminary clinical study of once daily intravesical alkalized lidocaine treatment over 5 d for interstitial cystitis in humans reported amelioration of clinical symptoms in the treatment group versus placebo (30). This novel treatment has been recommended in human guidelines for the treatment of bladder pain syndrome or interstitial cystitis. Lidocaine’s mechanism of action may be the control of neuropathic pain and inflammation. The alkalinization of sodium bicarbonate converts lidocaine, a weak base, from its water-soluble ionized form to a lipid-soluble nonionized form that can penetrate the urinary bladder wall (8,30).

In veterinary medicine, a randomized, non-blinded, placebo-controlled, prospective clinical trial was conducted to investigate the potential effect of intravesical alkalinized lidocaine treatment in NAUO cats (n = 26) (Table 1) (8). The primary study endpoint was the determination of overall re-obstruction rates, for which no between-group differences were observed [treatment group 58% (7/12) and control group 57% (8/14)]. The secondary study endpoint consisted of amelioration scores defined as improvements, relative to baseline, in client assessments of clinical sign severity at 2 wk, 1 mo, and 2 mo after discharge. No between-group differences were found for most individual clinical signs and composite scores with one exception. Straining to urinate was associated with an increased amelioration score (improvement in straining to urinate) at 2 wk in the treatment group compared to the control group. Overall, follow-up data from only 11 cats, including 5 in the treatment group and 6 in the control group, were available for analysis of the secondary study endpoint. Limitations of this study include: a small sample size, lack of blinding of clients to the intervention, use of different lidocaine dosages in the treatment group, failure of some cats in the control group to receive intravesical placebo due to temperament, recall bias, and low case numbers for which follow-up was available for the secondary study endpoint.

There has not been widespread adoption of intravesical glycosaminoglycans or alkalinized lidocaine in clinical practice as their role in the treatment of feline UO remains uncertain.

Post-obstructive diuresis

The use of an indwelling urinary catheter for the measurement of urine output allows for individualized patient fluid therapy. Post-obstructive diuresis is defined as urine production of greater than 2 mL/kg BW/h (31,32). A nonrandomized, non-blinded, retrospective study of NAUO cats (n = 32), presenting to an academic emergency service, reported an overall post-obstructive diuresis rate of 46% (13/28), which appeared to increase throughout the 84-hour measurement period (31). However, neither fluid rate nor total volume received by this study population was controlled. It was consequently impossible to discriminate between diuresis due to fluid therapy and true post-obstructive diuresis.

Another nonrandomized, non-blinded, retrospective study of NAUO cats (n = 57) presenting to an academic emergency service observed that the frequency of post-obstructive diuresis changed from 87.7% (50/57) to 36.8% (21/57) if fluid therapy was taken into consideration as a factor (32). In other words, fluid therapy may significantly affect the observed incidence of post-obstructive diuresis (32). The influence of fluid therapy on post-obstructive diuresis was determined by: i) correlating fluid rate at time “x” with urine output at time “x + 1,” and ii) defining post-obstructive diuresis in relation to fluid therapy (post-obstructive diuresis_FR) as urine output greater than the administered amount of IV fluids on at least 2 subsequent time points. There was a significant correlation between IVFT at time “x” and urine output at time “x + 1” at most time points. The authors of the article proposed that adjusting fluid therapy based upon urine output may exacerbate post-obstructive diuresis and go beyond actual requirements in some patients (32).

It was also observed in both studies that patients with acidemia were more likely to have post-obstructive diuresis. Francis et al (31) observed that acidemia (pH < 7.35) was associated with a 5-fold increase in post-obstructive diuresis over the entire study period, while Frohlich et al (32) observed that venous pH (< 7.27) and bicarbonate levels (< 15 mmol/L) were inversely correlated with urine output during the first 4 h, but not beyond that time point (32). The findings of Frohlich et al (32) call into question the role of these 2 blood gas parameters in the pathophysiology of post-obstructive diuresis, suggesting an association but not necessarily causation.

Given that true post-obstructive diuresis and iatrogenic (fluid driven) post-obstructive diuresis cannot be readily differentiated, small animal practitioners will need to utilize clinical judgement and close patient monitoring to guide decision-making on a case-by-case basis. In future clinical research endeavors, it would be prudent to develop a rigorous definition of post-obstructive diuresis that corrects for fluid therapy, which will further elucidate the role of fluid therapy relative to other factors.

Management of indwelling urinary catheter

Size of indwelling urinary catheter

Theoretically, a larger diameter indwelling urinary catheter has 2 potential benefits by preventing the following: obstruction of the lumen from kinking, debris, or clots; and urine leakage around the catheter (6,11). Alternatively, it is possible that the larger diameter catheter results in more irritation and inflammation. In 2013, two studies reported on the relationship between the size of an indwelling urinary catheter and rUO, the latter served as a primary outcome measure.

A nonrandomized, non-blinded, retrospective study (6) of NAUO cats (n = 192, 163 with complete data at 24 h), presenting to a private emergency service, identified a significantly lower rate of rUO at 24 h post-indwelling urinary catheter removal with the use of a 3.5-French (6.67%, 7/105) versus 5-French (18.97%, 11/58) catheter. Groups were matched by age, rectal temperature, body weight, and proportion of cats with azotemia or hyperkalemia at presentation. An association between catheter size and rUO was identified at 24 h but not 30 d post-indwelling urinary catheter removal. The major limitation of this study is the potential for confounding effects due to the assessment of multiple parameters over different time periods in a clinical setting without standardized treatment protocols (6,11,33).

A nonrandomized, non-blinded, prospective case series (7) of NAUO cats (n = 83, 68 with complete data) presenting to 3 private emergency services did not document an association between catheter size (3.5- versus 5.0-French) and rUO rate. Recurrent UO- (n = 10) and no recurrent UO- (n = 58) groups were matched by body weight, azotemia, venous blood gas-electrolyte parameters, urine pH, USG, crystalluria, radiographic findings, duration of hospitalization, IVFT, and critical illness category, but NOT age and breed. Mixed-breed and older cats [median, 8.2 y (range: 2.1 to 14)] were more likely to be associated with the rUO group, while purebred and younger cats [median, 4 y (range: 0.5 to 15)] were overrepresented in the no rUO-group. Case enrolment was prospective to facilitate short-term follow-up when determining the incidence of rUO, thereby minimizing recall bias. The main limitations of this observational study include the lack of random case assignment to controlled treatment groups, a small sample size with a low rate of rUO (15%), and a large number of study variables with potential confounding relationships to one another.

Decision to remove indwelling urinary catheter

Duration of indwelling urinary catheter placement

The pathophysiologic basis for recommending a longer duration of catheterization includes time for resolution of post-obstructive diuresis, detrusor atony, lower urinary tract inflammation (urethritis and cystitis), and urinary characteristics such as abnormal urine color, debris, clots, and crystals. It may also allow time for antispasmodic medications to take effect (7,9,11). When evaluating the duration of indwelling urinary catheterization (IUC) and its relationship to rUO rates, these indications for urinary catheter placement and maintenance likely also serve as confounders.

Duration of IUC and rUO rates have been evaluated as primary outcome measures in 2 retrospective studies and a secondary outcome in 1 prospective clinical trial. Hetrick et al (6) reported no association between rUO and duration of IUC. In contrast, Eisenberg et al (7) reported that longer duration of IUC was associated with a lower probability of short-term rUO. In this study (7), rUO was associated with a shorter duration of IUC (24.5 h, range: 1 to 54 h); and no rUO was associated with a longer duration of IUC (26.5 h, range: 12 to 92 h). A 2018 nonrandomized, non-blinded, prospective cohort study (9) of NAUO cats (n = 107, 91 with complete data), presenting to a private emergency service, found no relationship between duration of IUC and rUO rates.

Abnormal urine color

Seitz et al (9) identified an association between rUO and abnormal urine color at the time of catheter removal. Improvement in the color and clarity of the urine may serve as a better indicator to support indwelling urinary catheter removal, rather than focusing on a preset minimum urinary catheterization time such as 24 to 48 h (11). It should be noted that gross urine color characteristics were subjectively determined in this study with no standardized descriptive scale or pictorial reference, which should be considered in future research (9).

The biggest limitation of these studies investigating indwelling urinary catheter management is the inability to assess the effect of 1 factor in the dynamic, ever-changing clinical setting. There are numerous highly inter-related measured outcomes which vary over time, by a myriad of patient, clinician, hospital, and client factors. Multivariate regression analysis might be employed to elucidate the role of inter-related, confounding factors. However, given the observational nature of these studies, there was no attempt to standardize treatment protocols to minimize some of these variable influences. As a result, the data set generated by these observational studies can preclude multivariate regression model-building (7). Finally, the analysis of multiple parameters may result in statistical significance due to chance alone rather than underlying clinical significance.

Until more conclusive evidence exists to guide indwelling urinary catheter management, clinicians are encouraged to develop patient-specific treatment plans, while taking many factors into consideration.

Catheter-associated bacterial complications

Historically, the incidence of bacteriuria has been observed to increase after 3 d of both open and closed IUC, supporting a direct relationship between duration of catheterization and incidence of bacteriuria (34,35). Two prospective studies of NAUO cats presenting to academic emergency services addressed: the method of urine collection; the number of colony-forming units (CFUs) used as cut-off points; the timing of sample collection; and the use of strict urinary catheter management. These studies did not document positive urine cultures in any of the cases at presentation (0/18 and 0/34) (36,37). After IUC, positive urine cultures occurred within 24 h in 13% (4/31) of cases in 1 study and 16.7% (3/18) in the other. In the second study, 48-hour cultures were positive in 33% (6/18) of cases (36,37). Organisms identified included Escherichia coli, Staphylococcus, Streptococcus, and Pasteurella. A small sample size and strict urinary catheter management protocol may limit the ability to generalize these findings to the larger population of NAUO cats. However, these study findings emphasize the low incidence of primary bacterial cystitis in cases of feline UO and the risk of bacterial colonization or infection after urinary catheterization.

The recently published 2019 ISCAID guidelines for the diagnosis and management of bacterial urinary tract infections in dogs and cats are an invaluable clinical resource (38). Catheter-associated asymptomatic bacteriuria (CA-ASB) is thought to represent a transient colonization of the lower urinary tract versus a true catheter-associated urinary tract infection (CAUTI) (38). Bacterial colonization is not predictive of cystitis and is likely to be self-limiting once the urinary catheter is removed (38). Current recommendations do not support antimicrobial treatment of asymptomatic bacteriuria (38).

It is very challenging for clinicians to differentiate between clinical signs related to the primary LUTD and CAUTI. The presence of lower urinary tract signs along with fever, bacteremia of unknown focus, sudden changes in character of the urine (gross appearance and odor), concurrent illness, and patient risk factors must all be considered before initiating antimicrobial therapy (38). A urine culture collected by cystocentesis should be submitted to guide therapy if CAUTI is suspected (38). Cultures of the catheter tip are not recommended (38).

To the authors’ knowledge, widely adopted good practice guidelines for the placement and maintenance of urinary catheters specifically in cats undergoing UO treatment, unfortunately, do not exist. A survey of UK veterinarians highlights the need for the development of such guidelines to minimize catheter-associated bacterial complications (39). Responding veterinarians self-reported on the standards of care used during their most recent placement of a urinary catheter: 73% used antibiotic therapy while the urinary catheter was in situ; 66% used open urine drainage (not a closed collection system); 59% did not use aseptic skin preparation of the prepuce and perineum; and 40% did not use aseptic hand preparation and gloving (39).

Oral medications

Prazosin

Despite widespread acceptance of urethral spasm as a concept in veterinary medicine, this phenomenon has never been definitively proven to occur. The only study attempting to document urethral spasm involves 6 NAUO cats at an academic institution (40). Urethral pressures were high in only 1 cat, and normal to low in the remaining 5 animals. General anesthetic was used in this study, which may have decreased urethral tone.

It is challenging to advocate for a pathophysiological basis, known as grade IV evidence, upon which α1-adrenergic antagonists might work (11,33). Most obstructions occur within the distal not the proximal portion of the male feline urethra (11,33). However, the proximal 28% to 37% of the male feline urethra consists of smooth muscle under the influence of α1-adrenergic activity, while the distal portion consists of striated skeletal muscle that is not under the same neurogenic control (11,23,33). Obstruction in the proximal urethra may occur secondary to irritation, inflammation, and urethral spasm post-catheterization (11). Proximal urethral spasms might contribute to rUO that is separate from the initial inciting cause, which could justify the use of α1-adrenergic antagonists (33).

Even though α1-adrenergic antagonist use remains controversial, these medications are routinely used in small animal clinical practice (11,33). Prazosin, a selective α1-adrenergic antagonist, has supplanted phenoxybenzamine, a non-selective α1- and α2-adrenergic antagonist as the medication of choice for feline UO due to its presumably shorter time to onset of action, and targeted activity (6,11). Prazosin is believed both to inhibit α1-adrenergic receptors in smooth muscle, and to reduce the activity of central sympathetic neurons without the sedative effects associated with acepromazine (11,41).

Conflicting study results have been reported for prazosin use in the routine management of feline UO. A nonrandomized, non-blinded retrospective study of NAUO cats (n = 192, complete data for 186 cases at 24 h and 151 cases at 30 d), presenting to a private emergency service, identified significantly lower rates of rUO with prazosin compared to phenoxybenzamine at 24 h [7.1% (10/140) versus 21.7% (10/46)] and at 30 d [18.2% (20/110) versus 39.0% (16/41)] post-indwelling urinary catheter removal (6). Groups were matched by age, rectal temperature, body weight, and proportion of cats with azotemia or hyperkalemia at presentation. A subsequent randomized, double-blinded, placebo-controlled prospective clinical trial of NAUO cats (n = 47) presenting to an academic emergency service did not identify differences between prazosin- (n = 27) and placebo- (n = 20) groups with respect to the rUO rates prior to discharge [7% (2/26) versus 5% (1/19)], and at 1 mo [15% (4/26) versus 17% (3/18)] and 6 mo [37% (7/19) versus 31% (4/13)] post-discharge (42). Groups were matched by age, body weight, body condition score, vaccination status, environment, diet, number of litter trays, number of other cats in household, previous episodes of UO, and venous blood gas-electrolyte parameters, but not previous episodes of LUTD.

Proposed explanations for these contradictory results involve the prazosin dosage administered, and differences between the animals randomized to the prazosin- and placebo-groups. The dosing of prazosin ranged from 0.5 to 1 mg/cat by mouth every 12 h in the retrospective study (6). In comparison, the prospective study consistently used 0.25 mg/cat by mouth every 12 h for 30 d (42). Reineke et al (42) proposed that it is possible the higher dosages in the retrospective study account for the significant differences observed between the prazosin and phenoxybenzamine groups, but not the prazosin- and placebo-groups in their prospective study. A second possible explanation for the discordant findings of these 2 studies is that the potential beneficial treatment effect of prazosin was masked as the groups were not matched by episodes of previous LUTD [prazosin-group had higher rates 44% (12/27) versus placebo-group 10% (2/20)] (42). Consequently, Reineke et al (42) speculate that the cats in the prazosin-group were more likely to have episodes of LUTD and, therefore, increased risk of rUO, rendering detection of a treatment effect more difficult.

Reineke et al (42) reported on additional outcomes. Prazosin was associated with significantly shorter duration of IUC and hospitalization. Although prazosin treatment may result in shorter times from urinary catheter removal to voluntary urination and thereby decreased hospitalization times, a multitude of other patient factors could act as confounders. An explanation for how prazosin might shorten the duration of IUC remains elusive, possibly suggesting statistical but not clinical significance. The severity of LUTD was also reported by owners at 1, 2, 3, and 4 wk after hospital discharge. No significant between-group differences were identified. Adverse side effects reported include lethargy, anorexia, ptyalism, diarrhea, and malodorous stool.

The main limitations associated with these studies relate to the type of study. It is highly suspected that the retrospective study assessed many related variables over different time periods, thereby confounding measured outcomes and limiting potential interpretation (6,11,33). The prospective study had a small sample size and low incidence of rUO, raising the suspicion of a type II error (42). For example, Reineke et al (42) reported that rUO rates of 15% (4/26) in the prazosin-group and 17% (3/18) in the placebo-group were associated with a power of only 0.04 to detect between-group differences. Post study power analysis revealed that in order to attain a power of 0.8 and alpha < 0.05, 1149 cats and 766 cats were required for enrolment in the prazosin- and placebo-groups, respectively. If α1-adrenergic antagonists have a modest treatment effect, it will require larger sample sizes to demonstrate the effect.

The controversy over the use of α1-adrenergic antagonists in the scientific literature will likely continue to be a topic of debate and research. Until resolved, prazosin remains part of standard therapy for most practitioners.

NSAIDs

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in the treatment of feline LUTD. A retrospective study by Hetrick et al (6) did not report a beneficial effect of meloxicam in the treatment of feline UO. Substantial challenges exist with the assessment of pain in retrospective studies, necessitating the need for prospective, placebo-controlled clinical trials.

The use of oral meloxicam was recently evaluated in a 2016 randomized, double-blinded, placebo-controlled, prospective clinical trial of NAUO cats (n = 37) presenting to an academic emergency service (43). Meloxicam- (n = 18) and placebo-(n = 19) groups were matched by age, body weight, and parameters associated with hematology, biochemistry, venous blood gas-electrolyte analysis, and urinalysis. Groups were not matched at presentation by episodes of previous LUTD, macroscopic hematuria and ionized calcium.

A 0.1 mg/kg BW dose of an oral meloxicam suspension was administered 24 h following presentation, after circulatory volume and hydration deficits were corrected. Oral meloxicam was continued for another 4 d at 0.05 mg/kg BW every 24 h. Pain assessments were performed daily throughout hospitalization, and at a 10- to 14-day recheck following discharge. During the first 5 d post-discharge, clients evaluated clinical parameters including demeanor, food intake and painful behavior using a questionnaire with a visual analogue scale. The rUO rates were 22% (4/18) in the meloxicam group and 26% (5/19) with placebo. No significant between-group differences were observed for any of the outcomes assessed. The main limitations of this study are the small sample size, and increased number of cats with previous LUTD episodes and macroscopic hematuria in the meloxicam group at presentation, making the detection of between-group differences more challenging and potentially leading to a type II error.

Until further evaluation of NSAIDs is conducted, feline clinicians must be mindful of Canadian meloxicam label restrictions in cats to short-term use (5 d), and warnings of acute kidney injury and death with repeated higher dosing schedules. Patients should have volume and hydration deficits corrected prior to administration of an NSAID, if prescribed.

Conclusion

There were important limitations with many of these studies. Enrolment was often based on the clinical presentation of a UO. A definitive etiology was not always established as retrograde cystourethrograms were not performed in most cases to rule out strictures or urolithiasis. Most of the populations evaluated were at academic institutions and a few at private emergency practices, which could restrict the generalization of any findings to a larger population of NAUO cats. Randomization and blinding were not performed in many of these studies. Overall, groups were matched by relevant factors in many of these studies with some notable exceptions such as the higher number of previous LUTD episodes in the prazosin-group (42), and the meloxicam-group (43) over controls. Recurrent urethral obstruction rates, a measured outcome, were lower than expected in some studies, which may have decreased statistical power and made the detection of between-group differences challenging. Various forms of bias may have arisen from incomplete medical records, retrospective group assignment (misclassification bias), inadequate follow-up (follow-up bias), and clinician-client decision making (case-selection bias).

Finally, the most commonly encountered limitations include insufficient statistical power and potential type II errors due to small sample sizes, lack of standardized treatment protocols, and multiple inter-related confounding variables. There is the potential for significant limitations to be encountered with clinical research as a result of the many dynamic influences involved in the management of feline UO. In a clinical setting, controlling for many of these variables is often not possible. Observational studies, retrospective or prospective, do not attempt to standardize treatment protocols, and may not generate a data set that allows for multivariate analysis to assess for confounders with multiple inter-related variables. Multi-center research collaborations that attempt, as much as possible, to standardize treatment protocols might maximize both sample size and statistical power, while increasing the generalizability of the results to the wider population of NAUO cats. CVJ