Hans D. de Boer

Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by sugammadex: a multicenter, dose-finding and safety study.

Background: Reversal of rocuronium-induced neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a modified &ggr;-cyclodextrin derivative. This study investigated the efficacy and safety of sugammadex in reversing rocuronium-induced profound neuromuscular blockade at 5 min in American Society of Anesthesiologists physical status I and II patients. Methods: Forty-five American Society of Anesthesiologists physical status I and II patients (aged 18–64 yr) scheduled to undergo surgical procedures (anticipated anesthesia duration ≥ 90 min) were randomly assigned to a phase II, multicenter, assessor-blinded, placebo-controlled, parallel, dose-finding study. Anesthesia was induced and maintained with propofol and an opioid. Profound neuromuscular blockade was induced with 1.2 mg/kg rocuronium bromide. Sugammadex (2.0, 4.0, 8.0, 12.0, or 16.0 mg/kg) or placebo (0.9% saline) was then administered 5 min after the administration of rocuronium. Neuromuscular function was monitored by acceleromyography, using train-of-four nerve stimulation. Recovery time was the time from the start of administration of sugammadex or placebo, to recovery of the train-of-four ratio to 0.9. Safety assessments were performed on the day of the operation and during the postoperative and follow-up period. Results: A total of 43 patients received either sugammadex or placebo. Increasing doses of sugammadex reduced the mean recovery time from 122 min (spontaneous recovery) to less than 2 min in a dose-dependent manner. Signs of recurrence of blockade were not observed. No serious adverse events related to sugammadex were reported. Two adverse events possibly related to sugammadex were reported in two patients (diarrhea and light anesthesia); however, both patients recovered without sequelae. Conclusions: Sugammadex rapidly and effectively reversed profound rocuronium-induced neuromuscular blockade in humans and was well tolerated.

Reversal of profound rocuronium neuromuscular blockade by sugammadex in anesthetized rhesus monkeys

Background: Reversal of neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a synthetic γ-cyclodextrin derivative. The current study determined the feasibility of reversal of rocuronium-induced profound neuromuscular blockade with sugammadex in the anesthetized rhesus monkey using train-of-four stimulation. Methods: Four female rhesus monkeys each underwent three experiments. In each experiment, first, a 100-&mgr;g/kg dose of rocuronium was injected and spontaneous recovery was monitored. After full recovery, a 500-&mgr;g/kg dose of rocuronium was injected. Up to this point, all three experiments in a single monkey were identical. One minute after this rocuronium injection, either one of the two tested dosages of sugammadex (1.0 or 2.5 mg/kg) was injected or saline was injected. Results: Injection of 100 &mgr;g/kg rocuronium resulted in a mean neuromuscular blockade of 93.0% (SD = 4%), and profound blockade was achieved by injection of 500 &mgr;g/kg. In all experiments, a 100% neuromuscular blockade was achieved at this dose. After injection of the high rocuronium dose, the 90% recovery of the train-of-four ratio took 28 min (SD = 7 min) after saline, 26 min (SD = 9.5 min) after 1 mg/kg sugammadex, and 8 min (SD = 3.6 min) after 2.5 mg/kg sugammadex. Signs of residual blockade or recurarization were not observed. Injection of sugammadex had no significant effects on blood pressure or heart rate. Conclusions: Chemical encapsulation of rocuronium by sugammadex is a new therapeutic mechanism allowing effective and rapid reversal of profound neuromuscular blockade induced by rocuronium in anesthetized rhesus monkeys.

GUIDELINES FOR OPTIMIZING GROWTH HORMONE REPLACEMENT THERAPY IN ADULTS

To minimize the rate of side-effects, a retrospective analysis of 28 studies of GH replacement therapy in adults indicates that the maintenance dose should usually not exceed 1.0 IU/m2/day

Reversal of rocuronium-induced profound neuromuscular block by sugammadex in Duchenne muscular dystrophy.

A case is reported in which a child with Duchenne muscular dystrophy received a dose of sugammadex to reverse a rocuronium‐induced profound neuromuscular block. Sugammadex is the first selective relaxant binding agent and reverses rocuronium‐ and vecuronium‐induced neuromuscular block. A fast and efficient recovery from profound neuromuscular block was achieved, and no adverse events or other safety concerns were observed.

Neuromuscular transmission: New concepts and agents

Sugammadex is the first selective relaxant binding agent which was originally designed to reverse the steroidal NMB drug rocuronium. The results of recent studies demonstrate that sugammadex is effective for reversal of rocuronium and vecuronium-induced neuromuscular block without apparent side-effects. This is in contrast to the currently available cholinesterase inhibitors used to reverse neuromuscular block and which are even ineffective against profound neuromuscular block and have a number of undesirable side-effects. Sugammadex-rocuronium complexes are highly hydrophilic and it has been demonstrated that sugammadex is excreted in a rapid and dose-dependent manner in urine, resulting in a complete elimination from the body. The ability of sugammadex to reverse rocuronium and vecuronium-induced neuromuscular block may have major implications for routine anesthetic practice. Once sugammadex becomes commercially available, anesthesiologists will be capable of maintaining the desired depth of neuromuscular block at any time, thereby assuring optimal surgical conditions. The mechanism by which sugammadex encapsulates rocuronium and vecuronium appears to be superior to currently used neuromuscular block reversal strategies in terms of speed, efficacy and side effects. In this article, clinical studies of sugammadex are discussed.

Hypophosphatemia on the intensive care unit: individualized phosphate replacement based on serum levels and distribution volume.

BACKGROUND Hypophosphatemia occurs in about 25% of patients admitted to the intensive care unit. To date, a safe and validated phosphate replacement protocol is not available. OBJECTIVE To evaluate an individualized phosphate replacement regimen. DESIGN Fifty consecutive intensive care unit patients with a serum phosphate level<0.6 mmol/L were treated with sodium-potassium-phosphate intravenously at a rate of 10 mmol/h. The dose was calculated according to the following equation: Phosphate dose in mmol=0.5×Body Weight×(1.25-[serum Phosphate]). Phosphate levels were measured immediately upon completion of the infusion, as well as the next morning at 8 am. RESULTS Post-infusion phosphate levels were >0.6 mmol/L in 98% of the patients. Hyperphosphatemia, hyperkalemia or a decrease in serum calcium were not observed. In about a third of patients serum phosphate decreased to <0.6 mmol/L within the next 24 hours after infusion. The phosphate distribution volume calculated from the results of infusion and corrected for renal phosphate loss during the infusion period was 0.51 L/kg (95% CI 0.42-0.61 L/kg). CONCLUSION This study shows that phosphate replacement with dose calculation based on serum phosphate levels and a Vd of 0.5 L/kg is effective and safe.

Intestinal Calcium Absorption and Bone Metabolism in Young Adult Men with Childhood-Onset Growth Hormone Deficiency

Suboptimal growth hormone (GH) replacement therapy during childhood is a major cause of osteopenia in young adults with childhood‐onset GH deficiency (CO‐GHD). This is primarily attributed to reduced bone formation in childhood. It is currently not known whether GHD also has adverse effects on bone metabolism in adult life. To examine the impact of GHD on calcium and bone metabolism in adults, we evaluated 50 men with CO pituitary failure at a mean age of 28.2 ± 4.5 years, i.e., 8.8 ± 4.1 years after the discontinuation of previous GH treatment for short stature. Thirty‐three patients had multiple pituitary hormone deficiencies (MPHD) for which they received conventional replacement therapy, seventeen patients had isolated GHD (IGHD), and forty‐nine age‐matched men served as controls. Intestinal calcium absorption, serum calcium concentration, serum phosphate levels, and renal calcium and phosphate excretion were normal in IGHD and MPHD patients. IGHD patients had marginally elevated serum levels of the carboxy‐terminal cross‐linked telopeptide of type I collagen (ICTP: 5.0 ± 1.2 vs. 4.2 ± 1.2 μg/l, p < 0.05), but other indices of bone turnover were normal. In contrast, MPHD patients had reduced levels of the carboxy‐terminal propeptide of type I procollagen (PICP: 137 ± 76 vs. 179 ± 72 μg/l, p < 0.01), elevated serum ICTP levels (6.0 ± 3.8 vs. 4.2 ± 1.2 μg/l, p < 0.001), and reduced serum 1,25‐dihydroxyvitamin D levels (55.1 ± 16.7 vs. 73.0 ± 23.0 pmol/l, p < 0.001). Multivariate regression analysis showed that the serum levels of bone resorption and bone formation markers in MPHD patients were correlated with the hydrocortisone, thyroxine, and testosterone replacement doses. There was no relationship with serum insulin‐like growth factor I concentration. Panhypopituitary adults receiving conventional hormone replacement therapy are at risk to develop osteopenia either caused by reduced bone formation or by increased bone resorption activity. Predominantly, these abnormalities result from nonoptimal thyroid, gonadal, or adrenal hormone replacement therapy. GHD is not an important factor. In adults, GHD does not adversely affect intestinal calcium absorption or bone formation activity. Bone resorption activity may be slightly higher than normal, but the abnormality is too small to expect substantial bone loss as a consequence of GHD.

Effects of human growth hormone on fuel utilization and mineral balance in critically ill patients on full intravenous nutritional support

PURPOSE The effects of recombinant human growth hormone (GH) on fuel utilization, mineral and fluid balance in critically ill patients were studied. METHODS Twenty patients requiring mechanical ventilation and receiving standard parenteral nutrition were studied. GH 0.1 mg/kg/day (n = 10) or placebo (n = 10) was administered as continuous intravenous infusion for 3 days. Plasma mineral levels, urinary nitrogen, and mineral excretion were measured. Indirect calorimetry was used to calculate energy production rate and fuel utilization. RESULTS Insulin-like growth factor I concentrations increased: day 4 GH, 18.9 +/- 7.0 ng/mL; controls 11.6 +/- 3.2 ng/mL (P < .05). During GH administration, the nitrogen balance became zero, whereas it remained negative in controls (P = .03). Fuel utilization did not differ between the groups. Neither did oxygen consumption, carbon dioxide production, or the respiratory quotient (RQ). Nonprotein RQ showed a tendency to decrease in the GH group, whereas an increase was present in controls. Mineral balance improved in both groups. Phosphate balance improved by 250% in the GH group (P = .054). CONCLUSIONS GH administration in critically ill patients reduces nitrogen loss and improves phosphate retention but does not have an important effect on fuel utilization.

Rocuronium and sugammadex in a 3 days old neonate for draining an ovarian cyst. Neuromuscular management and review of the literature

A case is reported in which a 3-days old neonate with a giant ovarian cyst was scheduled for surgery. The patient received a dose of sugammadex to reverse a rocuronium-induced neuromuscular block. A fast and efficient recovery from neuromuscular block was achieved within 90s. No adverse events or other safety concerns were observed. Furthermore, a review of the literature on the use of sugammadex in neonates was performed.

Composition of renal basement membranes isolated under various conditions

GBM isolated from a surgical biopsy directly or after a 22 hr incubation period--to imitate the usual interval between death and isolation--appeared to be nearly identical in amino acid composition. Sonication and detergent procedures for isolation of GBM and TBM lead to preparations of different chemical composition. Phosphorus analysis and electron micrographs indicate the presence of material of supposedly cellular origin in sonicated but not in detergent-treated bovine and human GBM. Detergent-treated bovine and human GBM preparations are more enriched in the collagen-typical amino acids than sonicated samples. SDS-PAGE analyses show a nearly identical polypeptide pattern. Sonicated and detergent-treated bovine TBM preparations are free of cellular material. They show in SDS-PAGE a similar heterogeneous polypeptide pattern, but with lower intensities of three components with molecular weights between 30 and 60 kdalton. Sulfated GAGs are present in higher concentration in sonicated than in detergent-treated GBM and TBM. Collagen is not extracted from glomeruli and tubules by detergent treatment.