Jacques J. Driessen

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.

Decreased plasma albumin concentration results in increased volume of distribution and decreased elimination of midazolam in intensive care patients

The pharmacokinetic parameters of 16 patients in the intensive care unit, sedated with midazolam, were evaluated. A large variation was observed in the plasma concentration of midazolam and between the plasma concentration of midazolam and its metabolite 1‐hydroxymethylmidazolam glucuronide. The plasma albumin concentration governs the volume of distribution of midazolam. Decreased plasma albumin concentration (25 gm/L) results in an increased volume of distribution and a decreased elimination rate of midazolam. The observed plasma concentration ratio between the parent drug and its metabolite 1‐hydroxymethylmidazolam glucuronide is governed by the variables of protein binding, the metabolic rate of midazolam, and the renal clearance of the glucuronide metabolite itself (which can be considered as a measure of the kidney function of the patient).

Multicentre, parallel-group, comparative trial evaluating the efficacy and safety of sugammadex in patients with end-stage renal failure or normal renal function

BACKGROUND Sugammadex, a modified gamma-cyclodextrin, is the first selective relaxant binding agent that specifically encapsulates the steroidal neuromuscular blocking agent, rocuronium. The action of rocuronium is prolonged in patients with renal failure. As sugammadex is primarily cleared renally, this phase III trial investigated the efficacy and safety of sugammadex for reversal of rocuronium-induced neuromuscular block (NMB) in patients with end-stage renal failure. METHODS Thirty adult patients were studied: 15 renally impaired [creatinine clearance (CL(CR)) <30 ml min(-1)] and 15 controls (CL(CR)>80 ml min(-1)). Anaesthesia was induced and maintained using i.v. opiates and propofol. Neuromuscular monitoring was performed by acceleromyography and train-of-four (TOF) nerve stimulation. Rocuronium (0.6 mg kg(-1)) was given, followed by a single i.v. dose of sugammadex (2.0 mg kg(-1)) at reappearance of the second twitch of the TOF. The primary efficacy variable was time from administration of sugammadex to recovery of the TOF ratio to 0.9. Safety variables included clinical evidence of reoccurrence of NMB. RESULTS After sugammadex administration, the mean (sd) time to recovery of the TOF ratio to 0.9 was 2.0 (0.72) min in renal patients and 1.65 (0.63) min in controls (NS). Recurrence of NMB was not observed in any patient. No sugammadex-related serious adverse events were reported. CONCLUSIONS Sugammadex administered at reappearance of T(2) rapidly and effectively reverses NMB induced by rocuronium in renal failure and healthy patients. Sugammadex was well tolerated by all patients. Further safety studies on sugammadex in patients with severe renal impairment are warranted.

Anesthesia-related morbidity and mortality after surgery for muscle biopsy in children with mitochondrial defects.

Background:  Children with mitochondrial defects (MD) may have an increased risk for cardiorespiratory and neurological complications from anesthesia. The aim of this study was to determine the incidence of perioperative complications and adverse events in children with MD.

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.

Time-course of action of rocuronium 0.3 mg.kg-1 in children with and without endstage renal failure.

Background: The time‐course of the neuromuscular effects of rocuronium 0.3 mg·kg−1 during nitrous oxide‐halothane anaesthesia in children with and without renal failure is unknown. This study compared the neuromuscular blocking effects in these groups.

Pharmacodynamics of rocuronium 0.3 mg kg(-1) in adult patients with and without renal failure.

Background and aim: The neuromuscular effects of a bolus dose of rocuronium 0.6 mg kg−1 under propofol anaesthesia in renal failure patients are prolonged compared to healthy patients. The present study aims to describe the neuromuscular effects of 0.3 mg kg−1 rocuronium under propofol anaesthesia in patients with renal failure and to compare these effects with healthy control patients. Methods: With institutional approval and informed consent, 18 healthy patients and 18 patients with renal failure took part in this prospective open label study. The renal failure patients were undergoing either renal transplantation or insertion of a shunt. Rocuronium 0.3 mg kg−1 was given intravenously after induction of anaesthesia with propofol 1‐2 mg kg−1 and fentanyl 2 μg kg−1. Propofol 6‐12 mg kg−1 h−1 was used for maintenance of anaesthesia. Four acceleromyographic responses of the thumb after supramaximal stimulation of the ulnar nerve using surface electrodes at 2 Hz every 15 s were measured and recorded. The onset time, the time to recovery of the first twitch to 25% recovery and the time to a train‐of‐four ratio of 0.7 were all recorded. Wilcoxon rank sum testing was used to compare the pharmacodynamics and to see if medication, gender or electrolytes influenced the duration of the block. P < 0.05 was significant. Results: No statistical differences were seen in the neuromuscular blocking effects of rocuronium between the two groups but there was a significant difference (P < 0.00001) in the variability of the total duration of the block. Conclusions: Rocuronium 0.3 mg kg−1 is suitable for use in patients with renal failure when endotracheal intubation and neuromuscular block for a short period of time are needed. Tracheal intubation is facilitated within 4 min and the block can be antagonized within 20 min.

Continuous infusion of midazolam during anaesthesia and postoperative sedation after maxillofacial surgery

The clinical effects and pharmacokinetics of 24 h infusion of midazolam (MDZ) during major maxillofacial surgery and postoperative observation in an Intensive Care Unit (ICU) were studied in 20 patients. During anaesthesia, infusion of MDZ at 5 mg/h combined with 67% nitrous oxide, 1.8 (s.d. = 0.8) mg of fentanyl, and 26.5 (s.d. = 11.4) mg of vecuronium, adequately suppressed clinical responses to surgical nociceptive stimuli. Postoperatively, infusion of MDZ was continued in the ICU at 5 mg/h until 9 a.m. of the first postoperative day for sedation of the intubated but spontaneously breathing patients. The depth of sedation in the ICU was scored from 1–5 (1 = “awake and tense”, 5 = “unable to communicate”). During infusion the sedation score decreased from 3.8 after ICU arrival to 2.2 at 8 a.m. of the first postoperative day. Neither ventilatory nor circulatory depression were observed. After cessation of MDZ, recovery from sedation was fast. The degree of amnesia was low. During constant rate infusion no increase in plasma concentration of either MDZ or metabolites occurred. of MDZ after cessation was 125 min (range 90–320) and its total body clearance was 10.5 ml/kg/min (s.d. = 3.1). The volume of distribution, clearance and T1/2β were significantly longer in women than in men. It was concluded that 24 h of MDZ infusion at 5 mg/h caused satisfactory ICU sedation with fast recovery, but that individual tailoring of the infusion rate may still improve the quality of sedation.

In vivo animal studies with sugammadex

A review is presented of animal studies of the selective steroidal neuromuscular blocking drug binding agent sugammadex. These studies demonstrate that sugammadex is faster in onset than the currently used acetylcholinesterase inhibitors, has no muscarinic effects, and is characterised by lack of adverse effects on other organs. These results offer support for the further development of sugammadex for clinical use in humans.

Stuve Wiedemann syndrome and related syndromes: case report and possible anesthetic complications

Stuve Wiedemann syndrome (SWS) is an autosomal recessively inherited syndrome which is characterized by bowing of the long bones, camptodactyly, facial dysmorphism, hypotonia, feeding and swallowing difficulties, and respiratory distress. In most cases episodes of unexplained hyperthermia are present. Patients with SWS can develop hyperthermia in conjunction with anesthesia and surgery, and a relationship has been suggested between the syndrome and malignant hyperthermia. We describe a 3‐year‐old child diagnosed with SWS to whom we administered general anesthesia during the removal of a corneal ulcer and dilatation of the lacrimal duct. Our patient had received, uncomplicated, inhalational anesthesia five times previously for different operations. There were no anesthesia‐related complications in the present or previous perioperative periods. On one occasion the patient developed mild postoperative hyperthermia. We believe that this hyperthermia is different from the specific disorder of malignant hyperthermia and that sevoflurane can be safely used in patients with SWS. We also describe symptomatically related syndromes and their theoretical risks for anesthesia.