Adverse drug reactions causing admission to a paediatric hospital: a pilot study.

WHAT IS KNOWN AND OBJECTIVE: It is known that adverse drug reactions (ADRs) cause admission to hospital in adults and children. A recent adult study showed that ADRs are an important and frequent cause of hospital admission. The objective of this study is to develop methodology to ascertain the current burden of ADRs through a prospective analysis of all unplanned admissions to a paediatric hospital. METHODS: Prospective observational study over a 2-week period. RESULTS AND DISCUSSION: There were 19 admissions to the main hospital wards related to an ADR, giving an estimated incidence of 4%, with the ADR directly leading to the admission in 71% of cases. There were no deaths attributable to ADR. 33% of the reactions were possibly avoidable. The drugs most commonly implicated in causing admissions were anti-neoplastic agents. The most common reactions were neutropenia, vomiting and diarrhoea. The health burden of ADRs in the paediatric population is likely to be significant. This pilot study will be used to inform a much larger prospective study providing more detailed evidence of the burden of ill-health from ADRs in children. This larger study will add to a body of research aiming to identify drug-related problems within children to aid paediatric pharmacovigilance. WHAT IS NEW AND CONCLUSION: This study provides knowledge regarding the methodology to be used for a larger study investigating ADRs in children. The study will allow authors who wish to replicate the study in their own populations (internationally) to avoid some of the pitfalls in planning a large epidemiological study of paediatric ADRs. The study also provides an estimate of the incidence and problem of admissions caused by ADRs in a UK paediatric population.

Effects of dietary fat and L-carnitine on plasma and whole blood taurine concentrations and cardiac function in healthy dogs fed protein-restricted diets.

OBJECTIVE: To evaluate plasma taurine concentrations (PTC), whole blood taurine concentrations (WBTC), and echocardiographic findings in dogs fed 1 of 3 protein-restricted diets that varied in fat and L-carnitine content. ANIMALS: 17 healthy Beagles. DESIGN: Baseline PTC and WBTC were determined, and echocardiography was performed in all dogs consuming a maintenance diet. Dogs were then fed 1 of 3 protein-restricted diets for 48 months: a low-fat (LF) diet, a high-fat and L-carnitine supplemented (HF + C) diet, or a high-fat (HF) diet. All diets contained methionine and cystine concentrations at or above recommended Association of American Feed Control Officials (AAFCO) minimum requirements. Echocardiographic findings, PTC, and WBTC were evaluated every 6 months. RESULTS: The PTC and WBTC were not significantly different among the 3 groups after 12 months. All groups had significant decreases in WBTC from baseline concentrations, and the HF group also had a significant decrease in PTC. One dog with PT and WBT deficiency developed dilated cardiomyopathy (DCM). Taurine supplementation resulted in significant improvement in cardiac function. Another dog with decreased WBTC developed changes compatible with early DCM. CONCLUSIONS AND CLINICAL RELEVANCE: Results revealed that dogs fed protein-restricted diets can develop decreased taurine concentrations; therefore, protein-restricted diets should be supplemented with taurine. Dietary methionine and cystine concentrations at or above AAFCO recommended minimum requirements did not prevent decreased taurine concentrations. The possibility exists that AAFCO recommended minimum requirements are not adequate for dogs consuming protein-restricted diets. Our results also revealed that, similar to cats, dogs can develop DCM secondary to taurine deficiency, and taurine supplementation can result in substantial improvement in cardiac function.

Evaluation of urinary carnitine and taurine excretion in 5 cystinuric dogs with carnitine and taurine deficiency.

Five client owned dogs with cystinuria were diagnosed with carnitine and taurine deficiency while participating in a clinical trial that used dietary management of their urolithiasis. Stored 24-hour urine samples collected from the cystinuric dogs before enrollment in the clinical diet trial were quantitatively evaluated for carnitine and taurine. These results were compared to those obtained from 18 healthy Beagles. Both groups of dogs were fed the same maintenance diet for a minimum of 2 weeks before 24-hour urine collection. The protocol used for 24-hour urine collections was the same for cystinuric dogs and healthy Beagles except that cystinuric dogs were catheterized at baseline, 8 hours, 12 hours, and at the end of the collection, whereas Beagles were catheterized at baseline, 8 hours, and at the end of the collection. Three of 5 dogs with cystinuria had increased renal excretion of carnitine. None of the cystinuric dogs had increased renal excretion of taurine, but cystinuric dogs excreted significantly less (P < .05) taurine in their urine than the healthy Beagles. Carnitinuria has not been recognized previously in either humans or dogs with cystinuria, and it may be 1 risk factor for developing carnitine deficiency. Cystinuric dogs in this study were not taurinuric; however, cystine is a precursor amino acid for taurine synthesis. Therefore, cystinuria may be 1 risk factor for developing taurine deficiency in dogs. We suggest that dogs with cystinuria be monitored for carnitine and taurine deficiency or supplemented with carnitine and taurine.

Effects of dietary fat and carnitine on urine carnitine excretion in healthy dogs.

Turnover of carnitine in the body is primarily the result of renal excretion, and high-fat (HF) diets have been shown to increase urine carnitine excretion in healthy people. Recently, increased renal excretion of carnitine was observed in dogs diagnosed with cystinuria and carnitine deficiency. Carnitine deficiency has been linked to dilated cardiomyopathy and lipid storage myopathies in dogs and humans, and low-fat (LF) diets have been beneficial in some human patients with carnitine deficiency. In addition, HF, protein-restricted diets are often recommended for management of cystinuria in dogs. However, whether HF diets increase renal carnitine excretion in dogs or whether dogs with carnitine deficiency would benefit from LF diets remains unknown. Therefore, the purpose of this study was to determine the influence of dietary fat and carnitine on renal carnitine excretion in healthy dogs. Results from this study revealed that an HF diet increased urine carnitine excretion in dogs; however, carnitine excretion with the HF diet was not significantly different from that in dogs consuming an LF diet. Nonetheless, these results raise the possibility that increased renal carnitine excretion associated with HF diets could be one risk factor for development of carnitine deficiency in dogs with an underlying disorder in carnitine metabolism, and some dogs with carnitine deficiency may benefit from an LF diet. Another important observation in this study was that renal excretion of carnitine exceeded dietary intake in all diet groups, confirming previous reports that concluded that canine renal tubular cells reabsorb carnitine poorly when compared with those of humans.

Analysis of 77,000 canine uroliths. Perspectives from the Minnesota Urolith Center.

Of the hundreds of minerals that are found in the earth, most canine uroliths are comprised of only six types: (1) magnesium ammonium phosphate, (2) calcium oxalate, (3) calcium phosphates, (4) ammonium urate and other salts or uric acid, (5) cystine, or (6) silica. Each type has characteristics that allow its identification. During the past two decades, the prevalence of calcium oxalate canine uroliths has dramatically increased, while struvite has decreased. The most effective treatment and prevention protocols are based on knowledge of the primary mineral type comprising the urolith.

Medical dissolution and prevention of canine struvite urolithiasis. Twenty years of experience.

Two types of canine struvite uroliths have been recognized: infection-induced struvite is the most common type; sterile struvite is uncommonly recognized. Infection-induced struvite is most commonly associated with urease-producing staphylococcal UTI. For dogs that qualify, medical dissolution is an effective method of treatment. Medical dissolution protocols encompass: (1) eradication or control of UTI; (2) use of calculolytic diets; and (3) administration of urease inhibitors to patients with persistent UTI caused by urease-producing microbes.

Epidemiology of canine calcium oxalate uroliths. Identifying risk factors.

Calcium oxalate uroliths are most commonly encountered in Miniature Schnauzers, Lhaso Apsos, Yorkshire Terriers, Bichons Frises, Shih Tzus, and Miniature Poodles. They are more common in males than females, and more common in older than young dogs. Dogs that form abnormal nephrocalcin are also predisposed to calcium oxalate uroliths. Dietary risk factors for calcium oxalate uroliths include excessive calcium supplementation or excessive calcium restriction, excessive oxalic acid, high protein, high sodium, restricted phosphorus, restricted potassium, and restricted moisture (dry formulations). Dogs with hyperadrenocorticism or hypercalcemia are predisposed to calcium oxalate urolith formation.

Canine cystine urolithiasis. Cause, detection, treatment, and prevention.

Cystine uroliths are a sequela to cystinuria, an inherited renal tubular defect in reabsorption of cystine and some other amino acids. At the Minnesota Urolith Center, 67 breeds of dogs were identified, including English Bulldogs, Dachshunds, Mastiffs, and Newfoundlands. In some dogs, the severity of cystinuria may decline with advancing age. Current recommendations for dissolution of cystine uroliths include various combinations of diet modification, diuresis administration of 2-MPG, and alkalinization of urine.

Canine silica urolithiasis. Risk factors, detection, treatment, and prevention.

Uroliths containing 70% or greater silica comprise approximately 1% of the canine uroliths submitted to the Minnesota Urolith Center. Male dogs are far more commonly affected than females. In our series, 84 different breeds were affected. Currently available data suggest dietary factors play a role in their formation. Diagnosis is facilitated by the characteristic jackstone configuration of silica uroliths, but must be confirmed by quantitative analysis. Voiding urohydropropulsion or surgery are currently the most practical methods of removal of silica uroliths.

Canine and feline nephrolithiasis. Epidemiology, detection, and management.

Calcium oxalate (39%) and struvite (33%) were the predominant mineral types in canine nephroliths submitted to the Minnesota Urolith Center. Urate salts (12%) and calcium phosphate (2%) occurred less frequently. Provided they are not causing obstruction, struvite nephroliths may be dissolved with medical protocols. Although there are no dissolution protocols for nephroliths containing calcium, risk-benefit ratios should be considered before proceeding with surgery.

Drug-induced urolithiasis.

Diagnostic and therapeutic drugs may enhance urolithiasis in one or a combination of ways, including: (1) alteration of urine pH in such fashion as to create an environment that increases the solubility of some lithogenic substances, (2) alteration of glomerular filtration rate, tubular reabsorption, and tubular secretion of drugs of endogenous substances so as to enhance promoters or impair inhibitors of urolithiasis, and (3) precipitation (e.g., drugs or their metabolites) to form a portion or all of a urolith.

Voiding urohydropropulsion. Lessons from 5 years of experience.

Voiding urohydropropulsion is a nonsurgical method of removing uroliths from the urinary bladder. Any urocystolith of sufficient size to pass through the distended urethral lumen can be safely and effectively removed by this technique. Compared to cystotomy, voiding urohydropropulsion offers several advantages: urolith removal can be performed in minutes, anesthetic period is shorter, postprocedural dysuria and hematuria are less severe, and it provides greater success for complete removal of small urocystoliths. This technique is not suitable for removal of large urocystoliths or uroliths that become lodged in the urethral lumen.

Bioavailability and pharmacokinetics of intravenously and orally administered allopurinol in healthy beagles.

OBJECTIVES: To determine bioavailability and pharmacokinetic parameters for allopurinol and its active metabolite, oxypurinol. ANIMALS: 6 healthy, reproductively intact female Beagles, 4.9 to 5.2 years old, and weighing 9.5 to 11.5 kg. PROCEDURE: In the first part of the study, allopurinol was administered IV at a dosage of 10 mg/kg of body weight to 3 dogs and 5 mg/kg to 3 dogs; the sequence was then reversed. In the second part of the study, allopurinol was administered orally at a dosage of 15 mg/kg to 3 dogs and 7.5 mg/kg to 3 dogs; the sequence was then reversed. In the third part of the study, allopurinol was administered IV (10 mg/kg), orally (15 mg/kg) with food, and orally (15 mg/kg) without food. Plasma samples were obtained at timed intervals, and concentrations of allopurinol and oxypurinol were determined. RESULTS: Maximal plasma allopurinol concentration and area under plasma allopurinol and oxypurinol concentration-time curves were 2 times greater when dogs were given 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and when dogs were given 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg. Allopurinol elimination half-life, time to reach maximal plasma oxypurinol concentration, and oxypurinol elimination half-life were significantly greater when dogs received 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and when dogs received 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg. CONCLUSIONS: Elimination of allopurinol is dependent on nonlinear enzyme kinetics. The bioavailability of allopurinol, and pharmacokinetic parameters of allopurinol and oxypurinol after oral administration of allopurinol, are not affected by administration with food. CLINICAL RELEVANCE: A dose threshold exists beyond which additional allopurinol would not substantially further inhibit xanthine oxidase activity. Oral administration of > 15 mg of allopurinol/kg to dogs would not be expected to result in greater reduction of plasma and urine uric acid concentrations. Also, allopurinol may be administered to dogs for dissolution or prevention of urate uroliths without regard to time of feeding.

Influence of two diets on pharmacokinetic parameters of allopurinol and oxypurinol in healthy beagles.

OBJECTIVES: To determine whether diet influences the metabolism of IV administered allopurinol in healthy dogs. ANIMALS: 6 healthy female Beagles, 4.9 to 5.2 years old and weighing 9.6 to 11.5 kg. PROCEDURES: Allopurinol was administered IV (10 mg/kg) while dogs consumed a 10.4% protein (dry weight), casein-based diet or a 31.4% (dry weight), meat-based diet. After each dose, plasma samples were obtained at timed intervals, and concentrations of allopurinol and its active metabolite, oxypurinol, were determined by high-performance liquid chromatography. An iterative, nonlinear regression analytical program was used to determine the weighted least-squares, best-fit curves for plasma allopurinol and oxypurinol concentration-time data. From these data, pharmacokinetic parameters were calculated. RESULTS: Pharmacokinetic parameters for allopurinol and oxypurinol were not different when comparing the effect of diet. CONCLUSION: There is no influence of diet on pharmacokinetic parameters of allopurinol or oxypurinol. CLINICAL RELEVANCE: In contrast to observations in human beings, allopurinol metabolism is not influenced by diet. Therefore, formation of xanthine-containing calculi in dogs consuming a high-protein diet and receiving allopurinol is probably not attributable to alteration of allopurinol metabolism.

Diagnosis, medical treatment, and prognosis of feline urolithiasis.

Radiographic or ultrasonographic evaluation of the urinary tract is required to consistently detect feline uroliths. Evaluation of clinical, laboratory, and radiographic findings facilitate "guesstimation" of the mineral composition of uroliths. Therapy should not be initiated before appropriate samples have been collected for diagnosis. The objectives of medical management of uroliths are to arrest further growth and to promote urolith dissolution by correcting or controlling underlying abnormalities. For therapy to be effective, it must induce undersaturation of urine with calculogenic crystalloids by (1) increasing the solubility of crystalloids in urine, (2) increasing the volume of urine in which crystalloids are dissolved or suspended, and (3) reducing the quantity of calculogenic crystalloids in urine.

Influence of four diets on uric acid metabolism and endogenous acid production in healthy beagles.

OBJECTIVE: To evaluate the influence of 3 diets used to dissolve or prevent ammonium urate uroliths in dogs, and a diet formulated for growth, on 24-hour excretions of uric acid, ammonia, net acid, titratable acid, bicarbonate, and creatinine; 24-hour urine volumes; pH values of 24-hour urine samples; plasma uric acid concentration; serum creatinine concentration; and endogenous creatinine clearance values. DESIGN: Randomized block. ANIMALS: Six reproductively intact female Beagles, 3.9 to 4.2 years old, weighing 8.5 to 11.1 kg. PROCEDURES: Four diets were evaluated for their ability to dissolve magnesium ammonium phosphate hexahydrate (struvite) uroliths (diet S); to minimize uric acid excretion (diet U); to minimize clinical signs associated with renal failure (diet K); and to promote growth in pups (diet P). Each diet was fed for 14 days; then 24-hour urine samples were collected. An adult maintenance diet was fed during a 7-day washout period. RESULTS: Consumption of diet U was associated with lowest plasma uric acid concentration, lowest 24-hour urinary uric acid, ammonia, titratable acid, and net acid excretions, lowest endogenous creatinine clearance values, highest 24-hour urinary bicarbonate excretion and urine pH values, and highest 24-hour urine volumes. Consumption of diet P was associated with opposite results; results of consumption of diets S and K were intermediate between those for diets U and P. CONCLUSION: Consumption of diet U by healthy Beagles is associated with reduced magnitude of urinary excretion of uric acid and ammonia, with alkaluria, and with polyuria, which may be beneficial in the management of ammonium urate uroliths in dogs. CLINICAL RELEVANCE: Results support use of diet U for management of ammonium urate urolithiasis in dogs.

Feline urolithiasis. Etiology and pathophysiology.

A variety of different types of uroliths occur in cats, of which calcium oxalate and magnesium ammonium phosphate are the most common. Treatment and prevention are most likely to be successful if associated risk factors are identified and eliminated or controlled.

Feline urethral plugs. Etiology and pathophysiology.

Feline urethral plugs commonly are composed of large quantities of matrix mixed with minerals (especially struvite). However, some urethral plugs are composed primarily of matrix, some consist of sloughed tissue, blood, and/or inflammatory reactants, and a few are composed primarily of aggregates of crystalline minerals. The formation of matrix-crystalline urethral plugs may be analogous to the preparation of fruit jello.

Feline crystalluria. Detection and interpretation.

Crystalluria results from oversaturation of urine with crystallogenic substances. However, oversaturation may occur as a result of in vivo and in vitro events. Therefore, care must be used not to overinterpret the significance of crystalluria. Evaluation of urine crystals may aid in (1) detection of disorders predisposing cats to urolith or matrix-crystalline urethral plug formation; (2) estimation of the mineral composition of uroliths or urethral plugs; and (3) evaluation of the effectiveness of medical protocols initiated to dissolve or prevent urolithiasis.

Urolith analysis. Submission, methods, and interpretation.

The detection, treatment, and prevention of the causes underlying urolithiasis depend on knowledge of the composition and structure of the entire stone. Therefore, proper and complete analysis of uroliths is an important part of proper patient care. This article discusses methods of urolith retrieval, proper sample submission, methods of urolith analysis, and interpretation of results.