Ibrahim M. Eltorai

Decreased Systemic Clearance of Lorazepam in Humans With Spinal Cord Injury

Serum concentration‐time course profiles, serum protein binding, and disposition parameters of lorazepam (LRZ), a benzodiazepine with sedative‐hypnotic, anxiolytic, and antiseizure properties, were studied as part of a systematic effort to define population‐specific pharmacokinetic behavior in humans with chronic spinal cord injury (SCI). Twenty‐four healthy subjects (nine tetraplegic, six paraplegic, nine able‐bodied) were given an IV bolus of 2.0 mg of LRZ. Noncompartmental estimation of pharmacokinetic parameters disclosed a 37% decrease in the total systemic clearance (CL) of LRZ in tetraplegic patients. Altered LRZ clearance was observed independently of significant changes in volume of distribution or serum protein binding. The early elimination of LRZ (0–10 hr) was characterized by wide fluctuations in serum concentration suggestive of impaired enterohepatic circulation and could be distinguished from LRZ elimination observed in able‐bodied subjects. We conclude that decreased systemic CL and the altered terminal elimination profile of LRZ are attributable to the pathophysiology of SCI.

Effects of Chronic Spinal Cord Injury and Pressure Ulcer on 25(OH)-Vitamin D Levels

We studied 92 spinal cord injured (SCI) men (50 paraplegics and 42 quadriplegics) with normal renal function, 38 of whom had single or multiple pressure ulcers. The results were compared with those of 28 able-bodied normal controls. Serum concentrations of calcium and magnesium were measured by atomic absorption spectrometry, and 25(OH)-vitamin D was quantitated by a specific competitive binding assay using a sensitive vitamin D binding protein and tritiated 25(OH)-vitamin D. The SCI group exhibited significant reductions in serum 25(OH)-vitamin D and total calcium concentrations as compared to the normal control group. Although the mean serum concentration of 25(OH)-vitamin D in the quadriplegic patients as a whole was lower than that found in the entire paraplegic group, the difference did not attain statistical significance. Similar observations were made when the ulcer-free subgroups of paraplegics and quadriplegics were compared. The SCI subgroup which was least physically active, i.e., those with pressure ulcers, showed the greatest depression of serum 25(OH)-vitamin D, calcium, and magnesium concentrations. The observed reduction in serum 25(OH)-vitamin D in SCI patients appears to be partly related to reduced cutaneous vitamin D biosynthesis from sunlight deprivation occasioned by physical disability and hospitalization. In addition, nutritional deficiency and altered intestinal transport may be involved. The reduction in serum calcium concentration may be related to abnormal vitamin D metabolism and hypoalbuminemia (reduced protein-bound calcium).

Amikacin Pharmacokinetics in Patients with Spinal Cord Injury

The influence of chronic (> 1 yr duration) spinal cord injury (SCI) on the disposition of amikacin was studied in seven healthy subjects with SCI (five paraplegic, two tetraplegic) and seven able‐bodied controls (intact neuraxes). The time course of amikacin serum concentration after a 30‐minute infusion (7.5 mg/kg) was followed for up to 8.5 hours using fluorescence polarization immunoassay. Pharmacokinetic values were estimated by a noncompartmental analysis (NC). Amikacin steady‐state volume of distribution (Vss) was increased to 0.20 ± 0.04 l/kg (mean ± SD) as compared to 0.17 ± 0.02 l/kg in able‐bodied controls (p 0.03), and its mean terminal elimination half‐life in patients with SCI was prolonged by 0.64 hours over the control value of 2.11 ± 0.27 hours (p 0.01). The NC estimated mean residence time (MRT) in patients with SCI (3.65 ± 0.75 hrs) was 0.89 hours longer than that observed in controls (p 0.03). Our data suggest that the Vss, half‐life, and MRT of amikacin are increased in persons with chronic SCI. As a result, amikacin dosing regimens developed in able‐bodied humans may demonstrate diminished efficacy when extrapolated uncritically to these patients.

ENDOCRINE PATHOLOGY IN SPINAL CORD INJURED PATIENTS ON MAINTENANCE DIALYSIS

We studied the histopathological changes of the thyroid, adrenal and parathyroid glands, testes and pancreata in 15 patients with end-stage renal disease associated with long-standing spinal cord injury. All patients were males aged 42.7 ± 9.4 years and were treated with maintenance haemodialysis for 20.4 ± 17.7 months. Thyroid amyloidosis was present in eight of 12 glands and was extensive in four and moderate in four. Thyromegaly was noted in five of the glands with amyloid involvement. Of the 30 available adrenal glands, 26 showed amyloid involvement which was extensive in ten and moderate in 16. Of 18 testes examined all exhibited marked atrophy, decreased or absent spermatogenesis and marked peritubular and interstitial fibrosis. Amyloid involvement was also noted in two subjects. Pancreata were examined in 15 subjects with amyloidosis and pancreatitis noted in eight and four glands, respectively. Of the 22 parathyroid glands examined in nine subjects, hyperplasia was noted in 13 glands (four patients) and moderate amyloidosis was noted in six glands (two patients). Our results demonstrate a high prevalence of endocrine organ pathology in dialysis patients with longstanding spinal cord injury. Functional significance of these pathological findings is unclear and requires further investigation.

Clinicopathological Characteristics of Dialysis Patients with Spinal Cord Injury

Forty-three spinal cord injured patients with endstage renal disease (ESRD) maintained on hemodialysis were studied. The most prevalent renal lesions consisted of chronic pyelonephritis and amyloidosis while the main renal functional features included nephrotic range proteinuria, high urine output and relatively low serum creatinine for the degree of renal insufficiency. Normocytic, normochromic anemia with low reticulocyte response, low serum iron and iron binding capacity and high transfusion requirement and serum ferritin were noted. Various cardiovascular, pulmonary and gastrointestinal abnormalities were found with considerable frequencies. The incidence of amyloidosis was much higher than that reported previously. This is thought to be due to continued progression of amyloidosis occasioned by longer survival in the present series.

Extrinsic and Common Coagulation Pathways in End-stage Renal Disease Associated with Spinal Cord Injury

Data on the effects of combined long-standing spinal cord injury (SCI) and end-stage renal disease (ESRD) on blood coagulation system are limited. We studied the extrinsic and common pathways of blood coagulation system in 9 men with SCI-ESRD treated with maintenance hemodialysis. Plasma procoagulant activities of factors (F)VII, X and II were measured in a clotting assay using appropriate deficient plasmas as substrate. In addition, the antigen concentration of FII was measured using monospecific antibodies against human FII raised in goat in a gradient plate immunodiffusion system. Also measured were plasma fibrinogen concentration and platelet count. The results were compared with those obtained in a group of 10 ambulatory ESRD patients and 8 normal control volunteers. Plasma coagulant activity of FVII was markedly elevated and plasma fibrinogen concentration was moderately increased in SCI-ESRD patients: In contrast, plasma FII was mildly depressed while platelet count was within normal limits in SCI-ESRD patients. The data indicate that the combination of SCI and ESRD can lead to the alteration of the extrinsic and common coagulation pathways. Further studies are needed to elucidate the precise mechanism and the clinical significance of the observed abnormalities.

Giant urinoma in spinal cord injury: report of two cases.

Abstract Background: A urinoma is a cyst formed by the extravasation of urine from any constituent of the urinary tract; that is, via the kidney, ureter, urinary bladder, or the urethra. It may vary in its site and size according to its etiology, the point of the extravasation, and its duration and time of diagnosis. It commonly is associated with obstruction of the lower urinary tract by an impacted urinary calculus. Method: Case reports. Findings: Two cases of fatal intra-abdominal urinomas in patients with spinal cord injury (SCI). Conclusion: Complications of SCI place these patients at risk for the development of urinoma. Risk is highest among individuals with recurrent urinary tract infection, stone disease, and obstructive uropathy. Providers need to be alert to this potentially curable condition that may be obscured by the paucity of intra-abdominal findings due to the nature of the spinal cord syndrome.

Fibronectin and factor XIII in spinal cord injured patients with end-stage renal disease

Fibronectin and factor XIII play a major role in blood coagulation cascade and contribute to wound healing and phagocytic function of macrophages. Spinal cord injured (SCI) patients with end-stage renal disease (ESRD) have been shown to exhibit a variety of coagulation abnormalities, a high incidence of infection and poor healing pressure ulcers. Earlier studies in SCI patients with no discernible renal disease revealed a marked rise in plasma fibronectin in patients with fast healing pressure ulcers. However, no significant rise is found in those with poor healing ulcers. We compared plasma concentrations of fibronectin and factor XIII in a group of 13 SCI-ESRD patients with those of a normal control group. Despite the presence of pressure ulcers, the SCI-ESRD patients as a group failed to show a significant rise in plasma fibronectin concentration. In addition, the mean plasma factor XIII value in the SCI-ESRD group was not significantly different from that of the normal control group. Accordingly, the combination of SCI, ESRD and associated conditions seems to impair the patients ability to mount a rise in plasma fibronectin concentration in response to the presence of pressure ulcers. Failure of SCI-ESRD patients to produce a rise in plasma fibronectin concentration may, in part, account for the poor healing property of pressure ulcers in this population.

Fibrinolytic and Protease Inhibitory Systems in Spinal Cord Injured Patients with End-Stage Renal Disease

Earlier studies have revealed a variety of coagulation abnormalities in patients with long-standing spinal cord injury (SCI) and end-stage renal disease (ESRD). The present study was undertaken to examine the fibrinolytic and protease inhibitory systems in this population. Twelve spinal cord injured men with ESRD were studied. All patients had chronic active urinary tract infections, pressure ulcers and were practically bed-bound. The results were compared with those obtained in a group of 32 normal volunteers. Plasma plasminogen and unstimulated tissue-type plasminogen activator (t-PA) concentrations in the SCI-ESRD group were comparable with those found in the control group. No significant difference was found in plasma plasminogen activator inhibitor (PAI) activity in the two groups. In contrast, plasma alpha 2-antiplasmin antigen concentration and antiplasmin activity were significantly reduced in the study population. In addition, plasma alpha 1-antitrypsin activity and antigen concentration were significantly increased while the alpha 2-macroglobulin activity-to-antigen concentration ratio was significantly reduced in the SCI-ESRD group. Although the mechanism of the observed reduction in alpha 2-antiplasmin and total antiplasmin activity is uncertain, its presence could enhance fibrinolysis in this otherwise thrombosis-prone population. Likewise, elevated alpha 1-antitrypsin could attenuate tissue damage by leukocyte-derived proteases in the face of persistent suppurative infections. The reduced alpha 2-macroglobulin activity-to-antigen concentration ratio was thought to reflect the presence of alpha 2-macroglobulin complexes with various proteases generated by the activation of leukocytes, coagulation, fibrinolytic and other proteolytic systems.