Halothane and children: the first quarter century

For the past 25 years, halothane has been the primary anesthetic agent at Children's Hospital, Columbus, Ohio. To confirm our impression that adverse reactions to halothane are rarely a problem in children, we examined the records of 200,311 cases conducted with halothane from June 1, 1958, through May 31, 1983. Life-threatening complications due to side effects were identified in fifteen patients, and could be grouped into three areas: hepatitis (one), malignant hyperthermia (ten), and cardiac arrhythmias (four). No child died or sustained permanent sequelae. In eleven instances, other drugs (succinylcholine, atropine, cocaine, and epinephrine) possibly contributed to the adverse reactions.     

Neonatal subgaleal haematoma: Associated risk factors, complications and outcome

Objective : To describe the obstetric and perinatal factors, in particular the method of delivery, associated with development of a subgaleal haematoma (SGH) and to determine the outcome of survivors with this type of birth trauma. Methodology : Perinatal and obstetric data were retrospectively reviewed for 37 infants admitted to the neonatal unit of the sole tertiary paediatric referral hospital in Western Australia with an SGH, over a 24 year period from 1970 to 1993. These data were compared to data for all Western Australian births. The long-term outcome was obtained through medical and private paediatric records for 26 of these infants. Results : All except one of the neonates had instrumental deliveries; 89% had a vacuum extractor applied to the head at some stage of delivery compared to 10% of the general population of births in Western Australia. There was also a significantly increased risk of failure of attempted vacuum extraction. Of the cases where a vacuum extraction was attempted, 45% also had forceps applied to the head. Coagulopathy was associated with the severity of the SGH. There was also a high frequency of occurrence (40%) of associated head trauma such as intracranial haemorrhage, skull fracture and cerebral oedema, as well as neonatal encephalopathy (73%). The occurrence of these associated features did not correlate significantly with the severity of SGH. Minor complications of SGH included jaundice and facial bruising. There was an excess mortality associated with SGH; however, the long-term outcome for neonatal survivors with this disorder was good. None of the cases studied subsequently developed cerebral palsy or intellectual disability, and minor neurological sequelae only were documented in four infants. Conclusions : SGH is an uncommon type of birth trauma, and is associated with delivery or attempted delivery by vacuum extraction. The most commonly associated clinical problems were hypovolaemia and coagulopathy. The long-term outcome for neonates with this condition is good.     

Colorectal complications of renal allograft transplantation.

The occurrence of perforated sigmoid diverticulitis in a renal transplant recipient stimulated a review of colorectal complications in renal allograft recipients. One hundred twenty-five renal transplantations were performed in 113 patients between January 1968 and December 1975. Six patients (5%) were identified as having colorectal complications and five of these patients died as a direct result. Chart analysis of these 113 transplant recipients identified 55 patients as having undergone colonic evaluation (contrast enema, postmortem examination), with seven of these 55 (13%) found to have diverticulosis and major colonic complications eventually developing in four of these seven. Since the mortality from the complications of colorectal diseases in immunosuppressed patients is so prohibitive, in patients with diverticulosis and a previous history suggestive of diverticulitis, consideration should be given to exclusion from transplantation or elective segmental colectomy prior to transplantation.     

Peptic ulcer disease following transplantation: the role of cimetidine

Of 253 consecutive renal transplants performed in 209 patients between January 1971 and December 1980, symptomatic gastroduodenal ulcerations developed in 22 (8.7 percent). Time of presentation ranged from 5 days to 9 years (mean 225 days) following transplantation with 16 of these patients presenting within the first 3 months. Nine (Group I) patients were diagnosed before the administration of H2 antagonist cimetidine. Mode of presentation in this group was upper gastrointestinal bleeding in each instance. Thirteen patients (Group II) were diagnosed after the clinical use of cimetidine was established. The mode of presentation in this group was bleeding in 11 patients and abdominal pain in 2 patients. In Group I, one patient died from liver failure and an ulcer was not contributory. The remaining eight patients were treated with antacids and blood transfusions (mean 12.7 units). Five patients in this group demonstrated ulcer healing, whereas three patients (37.5 percent) required emergency operations with two postoperative deaths. In Group II, one patient died from hemorrhagic shock before therapy could be instituted. In the other 12 patients treatment consisted of antacids, cimetidine, and blood transfusions (mean 6.8 units). Ten patients had relief of symptoms, whereas two patients (16.7 percent) required emergency operations with no deaths. During cimetidine therapy, two patients had rejection episodes that were reversible, and the remaining patients had no significant alterations in renal function. To conclude, cimetidine is a safe and effective adjunct in the treatment of peptic ulceration in renal transplant recipients.     

Recent advances in the regulation of nitric oxide in the kidney

Nitric oxide (NO) plays important roles in the regulation of renal function and the long-term control of blood pressure. New roles of NO have been proposed recently in diabetes, nephrotoxicity, and pregnancy. NO derived from all 3 NOS isoforms contributes to the overall regulation of kidney function, and recent advances in our understanding of their regulation have been made lately. In this regard, substrate and cofactor availability play important roles in regulating nitric oxide synthase (NOS) activity not only by limiting enzyme activity but also by influencing the coupling of NOS with its cofactors, tetrahydrobiopterin and NADPH. Protein-protein interactions are now recognized to be important negative and positive regulators of NOS. Phosphorylation is another component of the mechanism whereby NOS is activated or deactivated. Increased NOS expression can also influence enzyme activity; however, the degree of expression does not always correlate with enzyme activity because increased NO levels can result in inhibition of NOS. Finally, other potential regulators of NOS such as endogenous L-arginine analogs may also be important. In this article, we summarize recent advances in the regulation of activity and expression of the NOS isoforms within the kidney.     

Acute and chronic regulation of thick ascending limb endothelial nitric oxide synthase by statins

Statins, 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, acutely increase endothelial nitric oxide synthase (eNOS) activity and chronically increase eNOS expression in endothelial cells. NO decreases transport in thick ascending limbs (TAL). We hypothesized that statins inhibit TAL transport by acutely activating eNOS, thereby increasing NO production and chronically enhancing eNOS expression. Oxygen consumption (QO(2)) by TAL suspensions from Sprague-Dawley rats was used as a measure of active NaCl reabsorption. Na/K ATPase activity was assessed by measuring ATP hydrolysis in the presence and absence of ouabain. eNOS expression was measured by Western blot. A total of 50 micro M pravastatin decreased QO(2) by 18.6 +/- 3.4% (P < 0.01). In the presence of 500 micro M furosemide and 200 micro M amiloride, transport blockers, QO(2) remained the same after pravastatin was added. Na/K ATPase activity was not different from controls and TAL treated with 50 micro M pravastatin (0.33 +/- 0.07 versus 0.29 +/- 0.04 nmol P(i)/ micro g protein/min, where P(i) is inorganic phosphate). Nystatin stimulated QO(2) to 178 +/- 13.7 in pravastatin-treated TAL and 195 +/- 11.5 in furosemide-treated TAL. The inhibitory effect of pravastatin on QO(2) was blocked by L-nitroarginine methyl ester, an NOS inhibitor. In addition, pravastatin increased NO production as measured by the fluorescent dye DAF-2A. Pravastatin at a dose of 10 mg/kg per d had no effect on eNOS protein at 1 d (24.1 +/- 2.7 versus 25.5 +/- 1.1 arbitrary units [AU]) or 7 d (24.1 +/- 2.7 versus 20.9 +/- 1.3 AU). Similarly, at 1 d, 50 mg/kg per d had no effect on expression (24.1 +/- 2.7 versus 21.2 +/- 3.6 AU). At 7 d, this dose decreased eNOS protein from 24.1 +/- 2.7 to 11.8 +/- 4.4 AU. It is concluded that pravastatin acutely decreases NaCl entry into the TAL by releasing NO. Pravastatin does not chronically increase eNOS expression in TAL.     

Increased intracellular Ca++ in the macula densa regulates tubuloglomerular feedback

BACKGROUND: Tubuloglomerular feedback is initiated by an increase in NaCl at the macula densa lumen, which in turn increases intracellular Ca++. In the present study, we examined the role of increased intracellular Ca++ in tubuloglomerular feedback and the source of the increased Ca++. We hypothesized that an increase in intracellular Ca++ at the macula densa via the basolateral Na+/Ca++ exchanger, caused by an increase in luminal NaCl, initiates Ca++-mediated Ca++ release from intracellular stores, which is essential for tubuloglomerular feedback. METHODS: Rabbit afferent arterioles and attached macula densas were simultaneously microperfused in vitro. Tubuloglomerular feedback was induced by increasing macula densa Na+/Cl- from 11/10 mmol/L (low) to 81/80 mmol/L (high) and was measured before and after treatment. RESULTS: To investigate whether elevations in intracellular Ca++ are required for tubuloglomerular feedback, the calcium ionophore A23187 or the Ca++ chelator BAPTA-AM was added to the macula densa lumen. During the control period, tubuloglomerular feedback decreased afferent arteriole diameter from 18.1 +/- 1.1 microm to 15.3 +/- 0.8 microm. Adding 2 x 10-6 mol/L A23187 to the low NaCl macula densa perfusate induced tubuloglomerular feedback; diameter decreased from 18.0 +/- 1.0 microm to 15.4 +/- 0.9 microm (N = 6; P < 0.01). After adding BAPTA-AM (25 micromol/L) to the macula densa lumen, tubuloglomerular feedback response was completely eliminated. We next studied the source of increased macula densa Ca++ in response to increased NaCl concentration. During the control period, tubuloglomerular feedback decreased afferent arteriole diameter from 18.5 +/- 1.6 microm to 15.3 +/- 1.2 microm (N = 6; P < 0.01). After adding the Na+/Ca++ exchanger inhibitor 2'4'-dichlorobenzamil (10 micromol/L) or KB-R7943 (30 micromol/L) to the bath, the tubuloglomerular feedback response was blocked; however, the afferent arteriole response to angiotensin II or adenosine was not altered. Next, we tested the Ca++-adenosine triphosphatase (ATPase) inhibitor thapsigargin (0.1 micromol/L), which has been reported to inhibit sarcoplasmic reticulum Ca++-ATPase activity and prevent restoration of intracellular Ca++ stores. When thapsigargin was added to the macula densa lumen, it reduced the first tubuloglomerular feedback response by 33% and completely eliminated the second and third tubuloglomerular feedback responses. In the absence of thapsigargin, there was no significant decrease in the tubuloglomerular feedback responses (N = 6). Neither the L-type Ca++ channel blocker nifedipine (25 micromol/L), nor the T-type Ca++ channel blocker pimozide (10 micromol/L), inhibited tubuloglomerular feedback when added to the macula densa lumen. CONCLUSION: We concluded that (1). increased intracellular Ca++ at the macula densa is required for the tubuloglomerular feedback response; (2). Na+/Ca++ exchange appears to initiate Ca++-mediated Ca++ release from intracellular stores; and (3). luminal L-type or T-type Ca++ channels are not involved in tubuloglomerular feedback.