Deoxycorticosterone-Secreting Adrenocortical Carcinoma in a Dog
Nyssa J. Reine, Ann E. Hohenhaus, Mark E. Peterson, and Amyia K. Patnaik
A n 11-year-old, 33-kg, male, castrated, mixed-breed dog was examined because of a 3-day history of vomiting and hind limb weakness. On physical examination, the mu- cus membranes were injected, the dog was unable to stand, and it was hyperthermic (40℃).
Venous blood gas analysis, blood glucose concentration, CBC, and serum biochemistry were obtained. Abnormali- ties included mildly high serum alkaline phosphatase activ- ity (86 U/L; reference range, 1-70 U/L), marked hypoka- lemia (2.3 mEq/L; reference range, 4.0-5.6 mEq/L), mild metabolic alkalosis (pH 7.49; reference range, 7.35-7.45; HCO3 26 mEq/L; reference range, 16-24 mEq/L), and hy- poglycemia (59 mg/dL; reference range, 80-120 mg/dL). A 3 × 4-cm, echogenically complex, left adrenal mass was identified on abdominal ultrasonography. The right adrenal gland was not seen. The liver was large and contained mul- tiple hyperechoic nodules. Three-view thoracic radiographs were normal.
Differential diagnoses for the adrenal mass included ad- renocortical carcinoma and adenoma, pheochromocytoma, and nodular hyperplasia. Differential diagnoses for the ab- normal liver included primary and metastatic hepatic neo- plasia and nodular hyperplasia.
Initial treatment consisted of administration of lactated Ringer’s solution (30 mL/kg/day) with potassium and dex- trose supplementation (0.1 mEq potassium/kg/hour and 2.5% dextrose, respectively), withholding food and water, enrofloxacin (10 mg/kg IV q12h), and ranitidine (5 mg/kg IV q12h). On day 2 of hospitalization, the rate of potassium supplementation was increased to 0.15 mEq potassium/kg/ hour because of persistent hypokalemia. The dog was re- cumbent, vomiting, febrile, and hypoglycemic. Isosthenuria (specific gravity, 1.015) and an inactive sediment were identified on urinalysis. Urine culture yielded no microbial growth. Potassium supplementation was adjusted until nor- mal serum potassium concentration was achieved (Fig 1). Metabolic alkalosis persisted throughout hospitalization, but intermittent control was achieved (Fig 2). On day 3 of hospitalization, the dog was no longer febrile. Antibiotic therapy was continued, but no source of infection was iden- tified, and the role of antibiotics in fever resolution was unclear.
In attempt to identify paroxysmal hypertension associ-
ated with pheochromocytoma, indirect arterial blood pres- sure was monitored every 4 hours on days 2 and 3. Mild hypertension with systolic blood pressure ranging from 150 to 170 mm Hg was detected. A low-dose dexamethasone suppression test was normal, excluding cortisol-secreting adrenal neoplasia.
Exploratory laparotomy was performed on day 5 of hos- pitalization. A 4-cm, well-defined left adrenal gland adher- ent to the left renal vein and caudal vena cava was seen. The right adrenal gland was small. The liver was discolored but no nodules were observed. The left adrenal gland was excised and incisional biopsy specimens of the liver were taken. Although assessed grossly to be unremarkable, bi- opsy specimens of the stomach, jejunum, and duodenum were obtained, because vomiting was part of the clinical presentation and could not be fully explained by the sus- pected adrenal tumor. Postoperatively, the dog was main- tained on lactated Ringer’s solution (30 ml/kg/day) with potassium supplementation (0.2 mEq/kg/hour), and butor- phanol (0.25 mg/kg IV as required). An adrenocorticotropic hormone (ACTH) stimulation test was performed postop- eratively and prednisone (0.1 mg/kg/day IM) was admin- istered to supplement cortisol production after adrenalec- tomy. Enrofloxacin (5 mg/kg IV) was continued.
On day 7 of hospitalization, serum potassium concentra- tion was stable and IV supplementation was decreased. Within 24 hours, serum potassium concentration began to decrease and high-dose supplementation (0.2 mEq/kg/hour) was reinstituted. A 2nd attempt to reduce intravenous po- tassium supplementation was begun on hospital day 10, and oral potassium administration (16 mEq potassium/day with food) was initiated (Fig 1). The postoperative plasma base- line and ACTH-stimulated cortisol concentration both were normal (27 nmol/L; reference range, 15-110 nmol/L and 240 nmol/L; reference range, 220-550 nmol/L, respective- ly). Prednisone therapy was discontinued. At this time, the dog was able to walk with assistance, vomiting had re- solved, and arterial blood pressure was normal (mean sys- tolic pressure, 125 mm Hg). The dog was discharged 12 days after admission on oral potassium supplementation.
Grossly, the adrenal gland measured 4.2 × 3.0 × 3.0 cm, appeared encapsulated, and was tan, red, and soft. Mi- croscopic examination disclosed an intracortical tumor. It appeared nonencapsulated and replaced most of the adrenal cortex, including the zona glomerulosa. The neoplasm was characterized by sheets of plump cells separated by thin vascular stroma with scattered cystlike spaces. The nuclei of the oval to polyhedral neoplastic cells had scattered chro- matin and 1 or 2 small nucleoli. The ample granular cyto- plasm varied from intensely eosinophilic to vacuolated. Rare mitotic figures were seen. Tumor cells were seen in several periadrenal vessels, consistent with adrenocortical carcinoma. The tumor was immunohistochemically stained
From the Bobst Hospital of The Animal Medicial Center, Depart- ment of Medicine (Reine, Hohenhaus), The Caspary Research Institute (Peterson), and the Department of Pathology (Patnaik), The Animal Medical Center, New York, NY 10021.
Reprint requests: Nyssa J. Reine, DVM, The Animal Medical Center, 510 East 62nd Street, New York, NY 10021; e-mail: nyssa.reine@ amcny.org.
Copyright @ 1999 by the American College of Veterinary Internal Medicine
8
8
7
7
Serum potassium (mEq/L)
Potassium dosage (mEq/kg/day)
6
6
5
5
4
4
3
3
2
2
1
1
0
0
1
2
3
4
5
6
7
8
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10
11
12
13
Hospital Day
with synaptophysin C (Supersensitive Biotin Streptavidin Method, Synaptophysin, BioGenex Laboratory, San Ra- mon, CA), with the adjacent medulla serving as control. In contrast to the cells of the medulla, the neoplastic cells stained negatively for synaptophysin C (Fig 3). Results of liver biopsies were consistent with biliary cystadenoma and nodular hyperplasia. Results of the gastrointestinal biopsies were unremarkable.
Immunohistopathologic evaluation excluded a diagnosis of pheochromocytoma (ie, tumors of the adrenal medulla generally stain positive for synaptophysin).1,2 Frozen serum obtained preoperatively was submitted for measurement of aldosterone concentration by a radioimmunassay (RIA) pre- viously validated for use in dogs.3,4 Serum aldosterone con- centration was undetectable (reference range, 14-957 pmol/ L; Animal Health Diagnostic Laboratory, Lansing, MI). Plasma aldosterone concentration measured 1 month post- operatively also was undetectable and serum potassium concentration determined on this sample was normal (5.0 mEq/L). Results of an ACTH stimulation test revealed nor- mal baseline and ACTH-stimulated serum cortisol concen- trations. The blood pressure at this time was normal (mean systolic pressure, 130 mm Hg). Ultrasonongraphy disclosed a normal-sized right adrenal gland (0.8 × 3 cm) and a 1.5 × 3-cm smooth-margined, hyperechoic mass effect in the area of the excised left adrenal gland. This finding was assessed as representing probable tumor regrowth.
Three months after surgery, another ACTH stimulation test was performed to assess aldosterone secretion.3,4 The baseline plasma aldosterone concentration was normal (32 pmol/L; reference range, 14-957 pmol/L) but only in- creased to 52 pmol/L after ACTH administration (reference range, 197-2103 pmol/L; Animal Health Diagnostic Lab- oratory). Serum potassium concentration, acid-base status, and arterial blood pressure were normal at that time. Oral potassium supplementation was decreased to 8 mEq/day.
At 6 months after surgery, the baseline plasma aldoste- rone concentration again was undetectable. Arterial blood pressure was normal. Serum potassium concentration re- mained normal, and oral potassium supplementation was
7.50
7.45
Venous blood pH
7.40
7.35
7.30
1
2
3
4
5
6
7
8
9
10
11
12
13
Hospital Day
discontinued. At 7 months, plasma aldosterone concentra- tion and plasma renin activity were measured simultaneous- ly, and both were undetectable. Serum potassium concen- tration was normal, as were plasma concentrations of cor- tisol, progesterone, and testosterone.
Plasma deoxycorticosterone concentration was high (288 ng/dL) compared to plasma concentrations in 8 clinically normal dogs (range, 16-46 ng/dL; median, 17 ng/dL). 11- Deoxycorticosterone was measured by a procedure devel- oped at Endocrine Sciences, Calabasas Hills, CA. After ex- traction of serum, the extracts were evaporated and purified by high-pressure liquid chromatography and then assayed by use of RIA. Assays of serial dilutions of a serum sample from the dog of this report containing high concentrations of deoxycorticosterone resulted in inhibition curves with slopes parallel to those of the standard curve. The interas- say CV of the assay was 15%, and the sensitivity of the assay was 0.5 ng/ml. The 8 clinically normal dogs ranged in age from 1 to 12 years (median, 5.5 years) and in weight from 4 to 30 kg. Five breeds were represented. Four dogs were male and 4 were females. All were considered healthy on the basis of history and results of physical examination and routine laboratory tests.
On examination 13 months after surgery, the dog was healthy and had normal serum potassium concentration. However, systolic arterial blood pressure again was slightly high (mean systolic pressure, 180 mm Hg), and the serum potassium was 4.1 mEq/L. On abdominal ultrasonography, a normal-sized right adrenal gland and a 1 × 2-cm smooth margined, hypoechoic mass effect in the area of the excised left adrenal gland were observed, No metastasis was evi- dent. An ACTH stimulation test also was performed to as- sess cortisol, aldosterone, and deoxycorticosterone secre- tion. Plasma baseline and ACTH-stimulated cortisol con- centrations both were normal (93 nmol/L and 430 nmol/L, respectively). The baseline plasma aldosterone concentra- tion again was undetectable (reference range, 14-957 pmol/ L) but only increased to 28 pmol/L after ACTH adminis- tration (reference range, 197-2,103 pmol/L; Animal Health Diagnostic Laboratory). The baseline plasma deoxycorti- costerone concentration again was high (403 ng/dL) and
deoxycorticosterone concentration after ACTH administra- tion also was high (583 ng/dL) compared to concentrations after ACTH administration measured in 2 clinically normal dogs (95 and 109 ng/dL, as described above). Plasma renin activity, measured simultaneously on the baseline sample, again was undetectable (Endocrine Sciences, Calabasas Hills, CA). Spironolactone was instituted (2 mg/kg PO di- vided daily) because of its competitive inhibition of the mineralocorticoid receptor.5
At 14 months, the dog was doing well and had a normal serum potassium concentration (4.6 mEq/L) and blood pH (7.43). The systolic blood pressure still was slightly high (mean systolic pressure, 165 mm Hg). Administration of spironolactone was continued, but the daily dosage was in- creased to 4 mg/kg PO.
This case illustrates the clinical, pathologic, and endo- crine findings in a dog with a deoxycorticosterone-produc- ing adrenal tumor. In humans, deoxycorticosterone-produc- ing tumors are associated with clinical signs of mineralo- corticoid excess (ie, hypertension and hypokalemia) as was apparent in this dog.5-9 Preoperatively, the dog’s clinical signs could have been attributed to any of the 3 major types of secretory adrenal tumors (ie, cortisol- or mineralocorti- coid-secreting adrenocortical tumor, or pheochromocyto- ma), 10-12 but information obtained from endocrine testing and histopathologic examination confirmed the presence of a deoxycorticosterone-secreting adrenal tumor.
Metabolic alkalosis was a persistent feature of this dog during the initial presentation. In hyperaldosteronism, met-
abolic alkalosis results from direct effects of aldosterone on distal tubular H+-ATPase pumps of the cortical and med- ullary collecting tubules, as well as hypokalemia-associated transcellular shifting and hydrogen ion secretion.13 Tubular reabsorption of bicarbonate increases, which enables the metabolic alkalosis to persist. Deoxycorticosterone is a pre- cursor of aldosterone produced in the zona glomerulosa and zona fasciculata. Deoxycorticosterone has mineralocorti- coid activity and acts on the same receptors as does aldo- sterone (mineralocorticoid receptors).5,14 Hypersecretion of deoxycorticosterone is believed to have caused the meta- bolic alkalosis in this dog. Metabolic alkalosis resolved af- ter resection of the adrenal tumor.
Profound and persistent hypokalemia was another major clinical feature in this dog. Like other mineralocorticoids, an excess of deoxycorticosterone is expected to potentiate renal potassium excretion.15 When supplementing potassi- um, it is important to consider the mechanism of loss. A dog with chronic hypokalemia caused by excess potassium excretion from overproduction of deoxycorticosterone re- quires long-term potassium supplementation because the source of loss cannot be eliminated. In such cases, the se- verity of hypokalemia may not be a true reflection of total body potassium, because potassium readily shifts out of the cells to maintain serum potassium concentration at the ex- pense of intracellular potassium.15 Similarly, initial potas- sium supplementation may not readily increase serum po- tassium concentrations, because potassium is rapidly trans- ported intracellularly. Serum potassium will only rise once
cells are replete. When the potassium supplementation in this dog was acutely decreased, his serum potassium rapidly declined (Fig 1, day 7). We suspect that this was because the excessive loss had not been corrected or intracellular concentrations were not adequately repleted. The addition of oral potassium supplementation while tapering the intra- venous potassium administration was successful in ulti- mately maintaining the serum potassium concentration.
Another clinical abnormality in this dog was mild sys- temic hypertension. Experimental administration of large dosages of deoxycorticosteone is well known to induce hy- pertention in dogs.16 Hypertension is a defining clinical sign of hyperaldosteronism and mineralocorticoid excess in hu- mans. The presence of hypokalemia and hypertension, in absence of diuretic therapy, is often what signals the cli- nician that these disorders should be considered.5-9 The cause of systemic hypertension associated with mineralo- corticoid excess is initially secondary to an increase in vas- cular volume due to sodium retention. Chronic systemic hypertension associated with mineralocorticoid excess is caused by increased systemic vascular resistance.5
The clinical decision of whether or not to provide glu- cocorticoid supplementation in this dog postoperatively was difficult. A cortisol-secreting tumor seemed unlikely in this dog based on the normal results of the low-dose dexameth- asone suppression test performed preoperatively. Intraop- eratively, the right adrenal gland was assessed as being small. Clearly, clinicopathologic findings provide more sol- id evidence for absence of cortisol production than surgical visualization. However, the risks of not supplementing glu- cocorticoids, if indicated, are greater than providing sup- plement while pending ACTH stimulation test results post- operatively. In this case, postoperative supplementation was discontinued after the normal ACTH stimulation test was reported.
Histopathologic examination is useful to distinguish be- tween adrenocortical neoplasia and pheochromocytoma, but standard hematoxylin and eosin staining cannot reliably dif- ferentiate between cortisol- and mineralocorticoid-secreting tumors. Synaptophysin and chromogranin A stain the neu- roendocrine granules in the adrenal medulla and therefore can be used to confirm a diagnosis of pheochromocytoma, whereas tumors of the adrenal cortex show negative im- munostaining with these stains.1,2 Synaptophysin is a mem- brane component of synaptic vesicles in neurons and neu- roendocrine cells.
Simultaneous measurement of plasma renin activity and plasma aldosterone concentrations provides an accurate di- agnosis of mineralocorticoid excess in humans.5-9 The re- nin-angiotensin system plays an important regulatory role in mineralocorticoid homeostasis. An increase in plasma renin concentration causes an increase in plasma aldoste- rone concentration via direct action of angiotensin II.5,14 De- termination of the serum potassium concentration at the time of sampling also is important because potassium is a direct stimulus for aldosterone secretion. Plasma renin ac- tivity is suppressed in humans with hyperaldosteronism be- cause of negative feedback effects of the high circulating aldosterone concentations.5-9 Plasma renin activity also is
suppressed in dogs made hypertensive by administration of deoxycorticosterone.16 The dog of this report had signs of mineralcorticoid excess (ie, hypertension, hypokalemia, and weakness), but plasma renin and plasma aldosterone con- centrations both were suppressed. These clinicopathologic hormonal and electrolyte abnormalities have been described in humans with deoxycorticosterone-producing adrenal tu- mors.5-9,14 These adrenal tumors typically are malignant, as was the tumor in this dog, but benign tumors have been described that often are associated with production of other adrenal steroids.6
Based on the clinicopathologic findings, deoxycorticoste- rone-producing adrenocortical tumor was confirmed in this dog. Mineralocorticoid excess, whether in the form of ex- cess aldosterone or deoxycorticosterone production, is rare. However, mineralocorticoid excess should be included in the list of differential diagnoses in a dog with evidence of systemic hypertension, profound hypokalemia, and an ad- renal tumor. Confirmation of mineralocorticoid excess can be achieved via assessment of concurrent plasma renin ac- tivity and plasma mineralocorticoid (ie, aldosterone and de- oxycorticosterone) concentrations.
References
1. Miettinen M. Synaptophysin and neurofilament proteins as mark- ers for neuroendocrine tumors. Arch Pathol Lab Med 1987;111:813- 818.
2. Vyberg M, Horn T, Francis D, et al. Immunohistochemical iden- tification of neuron-specific enolase, synaptophysin, chromogranin and endocrine granule constituent in neuroendocrine tumours. Acta His- tochem Suppl 1990ic38:179-181.
3. Willard MD, Refsal K, Thacker E. Evaluation of plasma aldo- sterone concentrations before and after ACTH administration in clin- ically normal dogs and in dogs with various diseases. Am J Vet Res 1987;48:1713-1718.
4. Graves TK, Schall WD, Refsal K, et al. Basal and ACTH-stim- ulated plasma aldosterone concentrations are normal or increased in dogs with trichuriasis-associated pseudohypoadrenocorticism. J Vet In- tern Med 1994;8:287-289.
5. Biglieri EG, Kater CE, Mantero F. Adrenocortical forms of hu- man hypertension. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management, 2nd ed. New York, NY: Raven Press; 1995:2145-2161.
6. Irony I, Biglieri EG, Perloff D, et al. Pathophysiology of deoxy- corticosterone-secreting adrenal tumors. J Clin Endocrinol Metab 1987;65:836-840.
7. Ishikawa SE, Saito T, Kaneko K, et al. Hypermineralocorticism without elevation of plasma aldosterone: Deoxycorticosterone-produc- ing adrenal adenoma and hyperplasia. Clin Endocrinol (Oxf) 1988;29: 367-375.
8. Saha PK, Ura T, Suzu H, et al. A case of deoxycorticosterone- producing benign adrenocortical tumor. Urol Int 1990;45:367-369.
9. Wada N, Kubo M, Kijima H, et al. A case of deoxycorticoste- rone-producing adrenal adenoma. Endocr J 1995;42:637-642.
10. Ortega TM, Feldman EC, Nelson RW, et al. Systemic arterial blood pressure and urine protein/creatinine ratio in dogs with hyper- adrenocorticism. J Am Vet Med Assoc 1996;209:1724-1729.
11. Breitschwerdt EB, Meuten DJ, Greenfield CL, et al. Idiopathic hyperaldosteronism in a dog. J Am Vet Med Assoc 1985;187:841- 845.
12. Barthez PY, Marks SL, Woo J, et al. Pheochromocytoma in dogs: 61 cases (1984-1995). J Vet Intern Med 1997;11:272-278.
13. Rose BD. Metabolic alkalosis. In: Clinical Physiology of Acid- Base and Electrolyte Disorders. New York, NY: McGraw-Hill; 1994: 515-539.
14. Orth DN, Kovacs WJ. The adrenal cortex. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams Textbook of Endo- crinology. Philadelphia, PA: WB Saunders; 1998:517-664.
15. Rose BD. Hypokalemia. In: Clinical Physiology of Acid-Base and Electrolyte Disorders. New York, NY: McGraw-Hill; 1994:776- 822.
16. Ferrario CM, Mohara O, Ueno Y, et al. Hemodynamic and neu- rohormonal changes in the development of DOC hypertension in the dog. Am J Med Sci 1988;295:352-359.
Erratum
Lofstedt J, Dohoo IR, Duizer G. Model to predit septicemia in diarrheic calves. J Vet Intern Med 1999;13: 81-88.
Please note corrections to Table 2 as shown on page 391.
| Variable | Septicemic Calves | Nonsepticemic Calves | ORª (95% CI) | P | ||
|---|---|---|---|---|---|---|
| n (%) | Mean | n (%) | Mean | |||
| Continuous | ||||||
| Dehydration, % | 72 | 7.7 | 166 | 6.7 | 0.079 | |
| Respiratory rate, breaths/minute | 74 | 44 | 159 | 37 | 0.011 | |
| Rectal temperature, ºF (°C) | 76 | 99.7 (37.6) | 169 | 100.8 (38.2) | 0.009 | |
| Band neutrophils, ×103/pL (×109/L) | 54 | 2.4 (2.4) | 146 | 1.3 (1.3) | 0.005 | |
| Packed cell volume, % (L/L) | 72 | 40 (0.40) | 160 | 36 (0.36) | 0.001 | |
| Total plasma protein, g/dL (g/L) | 65 | 6.14 (61.4) | 147 | 6.72 (67.2) | 0.002 | |
| Serum albumin, g/dL (g/L) | 59 | 2.82 (28.2) | 133 | 2.94 (29.4) | 0.053 | |
| Ionized calcium, mg/dL (mmol/L) | 68 | 4.72 (1.18) | 152 | 4.92 (1.23) | 0.046 | |
| Serum globulin, g/dL (g/L) | 59 | 2.59 (25.9) | 133 | 3.05 (30.5) | 0.02 | |
| Serum glucose, mg/dL (mmol/L) | 54 | 60 (3.3) | 123 | 89.09 (4.9) | 0 | |
| Total serum protein, g/dL (g/L) | 59 | 5.40 (54.0) | 133 | 5.94 (59.4) | 0.012 | |
| Blood CO2, mmHg | 68 | 54.5 | 153 | 48.5 | 0.004 | |
| Categorical | ||||||
| Age | ||||||
| >5 days | 45 (57.7) | 134 (77.5) | 0.001 | |||
| ≤5 days | 33 (42.3) | 39 (22.5) | 2.5 | |||
| (1.42-4.46) | ||||||
| Creatinine | ||||||
| <1.98 mg/dL (≤175 mmol/L) | 29 (49.2) | 93 (68.9) | 0.001 | |||
| 1.99-5.66 mg/dL (176-500 mmol/L) | 22 (37.3) | 40 (29.6) | 1.8 | |||
| (0.91-3.42) | ||||||
| >5.66 mg/dL (>500 mmol/L) | 8 (13.6) | 2 (1.5) | 12.8 | |||
| (2.88-nd) | ||||||
| (2.57-63.83)b | ||||||
| Neutrophil toxic changes | ||||||
| No (≤1+) | 30 (56.6) | 125 (85.6) | 0.000 | |||
| Yes (≤2+) | 23 (43.4) | 21 (14.4) | 4.6 | |||
| (2.25-9.26) | ||||||
| Failure of passive transfere | ||||||
| No | 21 (30.9) | 95 (62.9) | 0.000 | |||
| Yes | 47 (69.1) | 56 (37.1) | 3.8 | |||
| (2.07-6.97) | ||||||
| Attitude | ||||||
| Bright, alert | 1 (1.3) | 27 (13) | 0.000 | |||
| Depressed | 53 (68.8) | 120 (71) | 11.9 | |||
| (1.99-nd) | ||||||
| (1.58-90.07)b | ||||||
| Unresponsive or comatose | 23 (29.9) | 57 (16) | 23.0 | |||
| (3.63-nd) | ||||||
| (2.90-182.6)b | ||||||
| Mucous membrane color | ||||||
| Pink | 21 (28) | 93 (68.9) | 0.002 | |||
| Pale | 33 (44) | 40 (29.6) | 3.7 | |||
| (1.89-7.04) | ||||||
| Hyperemic or cyanotic | 21 (28) | 2 (1.5) | 46.5 | |||
| (11.1-nd) | ||||||
| (10.1-218.8)b | ||||||
| Posture | ||||||
| Standing | 12 (15.4) | 81 (48.2) | 0.000 | |||
| Sternal or lateral recumbency | 66 (84.6) | 87 (51.8) | 5.1 | |||
| (2.6-10.1) | ||||||
| Scleral injection | ||||||
| No | 53 (74.6) | 135 (88.8) | 0.007 | |||
| Yes | 18 (25.4) | 17 (11.2) | 2.7 | |||
| (1.3-5.58) | ||||||
| Suckling reflex | ||||||
| Strong | 6 (8.2) | 64 (39.8) | 0.000 | |||
| Weak or absent | 67 (91.8) | 97 (60.2) | 7.4 | |||
| (3.08-17.55) | ||||||
a Odds ratios for categorical variables with >2 categories were computed by comparing each level to the baseline level. CI, confidence interval.
b Woolf’s approximation for CI was used when the upper limit of the Cornfield’s approximation was not defined (nd).
· Failure of passive transfer defined as IgG ≤ 800 mg/dL, serum globulin ≤ 2.0 g/dL, or serum total protein ≤ 5.0 g/dL.
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