Effect of Deep BLock on Intraoperative Surgical Conditions (BLISS)

Effect of Deep BLock on Intraoperative Surgical Conditions, Perioperative Hemodynamic Status and Respiratory Parameters Following Reversal With Sugammadex in Patients Undergoing Laparoscopic Renal and Prostate Surgery.

Rationale: A deep neuromuscular block is often associated with improved surgical conditions especially in laparoscopic surgery. However, a deep block comes at the expense of a variety of items that may conflict with the use of a deep surgical muscle blockade including a long recovery phase, the need for muscle reversal, postoperative ventilation, impaired postoperative breathing. With the introduction of Sugammadex there is now the possibility to reverse an even deep surgical block. This may overcome most if not all of the issues mentioned.

Objective: To assess whether a deep neuromuscular block provides better surgical conditions than a moderately deep block as derived from a surgical rating score.

Study design: Single center, double-blind randomized controlled trial. Study population: 24 ASA I-III patients scheduled for laparoscopic renal (n=12, GROUP 1) or prostatic surgery (n=12, GROUP 2).

Intervention: In both GROUP 1 and GROUP 2, 6 six patients will receive neuromuscular blockade according to current practice (atracurium (bolus) plus mivacurium (cont. infusion)) aimed at a moderately deep neuromuscular block (1-2 twitches in the Train of Four (TOF) monitor). The other six will receive a bolus plus continuous infusion with rocuronium aimed at a deep neuromuscular block (1-2 twitches post tetanic count (PTC)). All surgical procedures will be performed by one surgeon.

Main study parameters/endpoints: To study the surgical conditions in patients undergoing laparoscopic renal or prostate surgery during deep versus less deep neuromuscular block as assessed by the surgical rating score.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Compared to current practice there will be no additional risk.

Study Overview

• Status: Completed
• Conditions: Renal Disease; Prostate Hypertrophy
• Intervention / Treatment: Drug: Surgical block (rocuronium; atracurium/mivacurium); Drug: Surgical block (rocuronium; atracurium/mivacurium)

Detailed Description

Surgical conditions in laparoscopic surgery are largely determined by the degree of neuromuscular relaxation during surgery. Especially in procedures which are confined to a narrow working field such as renal and prostatic laparoscopic surgery, deep neuromuscular relaxation may be beneficial. Until recently however, deep neuromuscular block (1-2 twitches post tetanic count) came at the expense of a variety of items that conflicted with its use. Occurrence of postoperative residual neuromuscular blockade after deep neuromuscular block was a common adverse event. Residual neuromuscular block is a risk factor for developing airway obstruction and pulmonary complications such pneumonia and atelectasis. The use of acetylcholinesterase inhibitors, like neostigmine, as a traditional neuromuscular blocking reversal agent, have a slow onset of action. Side effects due to muscarine receptor stimulation are bradycardia, hypersalivation, nausea and vomiting. Coadministration of a muscarine agonist like atropine is often necessary to address the heart rate-related side effects of neostigmine. Atropine, however, in itself may induce other side effects.

Rapid, safe and complete reversal of neuromuscular blockade was not possible until the discovery of Sugammadex. Sugammadex is a modified y-cyclodextrin. It was developed to selectively bind free plasma rocuronium, a non-depolarizing steroidal neuromuscular blocking agent. By binding free rocuronium, less rocuronium becomes available at the neuromuscular junction to bind to the muscarine receptor. Non-depolarizing neuromuscular blocking agents (NMBA's) block the muscarine receptor at the neuromuscular junction, making them unavailable to acetylcholine based signal transmission. Sugammadex has proven to rapidly and safely reverse rocuronium and vecuronium. Even high dose rocuronium (1.2 mg/kg and continuous rocuronium infusion used to achieve deep neuromuscular blockade can safely be reversed by Sugammadex.

Theoretically, the availability of Sugammadex makes it possible to use deep neuromuscular block (DNB) during surgery to improve surgical conditions without the occurrence of the above-mentioned adverse events. The use of DNB to improve surgical conditions, however, has not yet been evaluated. The investigators therefore aim to investigate the use of rocuronium induced-DNB in renal and prostatic laparoscopic surgery. Current anesthesiologic practice during these procedures in the LUMC consists of an intravenous (propofol) or volatile (sevoflurane) anesthetic combined with mivacurium and atracurium to achieve a moderately deep neuromuscular block (0-2 twitches TOF). Reversal of NMB is by the neostigmine atropine combination. In the current study the investigators will assess the effect of a DNB (1-2 twitches post tetanic count) using a continuous rocuronium infusion on surgical conditions. After surgery Sugammadex 4 mg/kg will be used to safely and rapidly reverse the neuromuscular blockade within 5-min.

The main end-point of the study is the effect of the deep block on the surgical conditions. The investigators will study these conditions using two methods. (1) Assessment of the surgical condition by the operating surgeon (all surgeries will be performed by one surgeon), using a 5-point rating surgical rating scale from 1 (= extremely poor surgical condition) to 5 = optimal surgical condition. (2) Video images, used by the surgeon to perform the surgery, will be rated by a team of surgical and non-surgical experts. Apart from the additional scoring data, this approach allows for the validation of the surgical rating scale.

Minor end-points of the study are (1) measurement of hemodynamics during surgery using a non-invasive cardiac output and blood pressure device. Assuming that intra-abdominal pressure will affect the venous return and hence cardiac output during surgery, a deep neuromuscular block might affect the hemodynamic parameters positively; (2) measurement of respiration, pain, and alertness in the recovery room to assess whether reversal with Sugammadex influences these parameters positively compared to neostigmine/atropine reversal.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • ZH
    • Leiden, ZH, Netherlands, 2333 ZA
      • Leiden University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients diagnosed with renal or prostatic disease who are will undergo an elective laparoscopic renal surgical procedure or laparoscopic prostatectomy;
• ASA class I-III
• > 18 years of age;
• Ability to give oral and written informed consent

Exclusion Criteria:

• Known or suspected neuromuscular disorders impairing neuromuscular function;
• Allergies to muscle relaxants, anesthetics or narcotics;
• A (family) history of malignant hyperthermia;
• Patients who have a contraindication for neostigmine administration;
• Women who are or may be pregnant or are currently breast feeding;
• Renal insufficiency, as defined by serum creatinine x 2 of normal, or urine output < 0.5 ml/kg/h for at least 6 h. When available, other indices will be taken into account as well such as glomerular filtration rate < 60 ml/h and proteinuria (a ratio of 30 mg albumin to 1 g of creatinine).
• Previous retroperitoneal surgery at the site of the current surgery.
• Body mass index > 35 kg/m2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Deep surgical block; Continuous rocuronium infusion will be used to induce a deep surgical block with post tetanic twitch count of max 2. Rocuronium loading dose = 1.0 mg/kg, followed by 0.6-1.0 mg/kg per hour.	Drug: Surgical block (rocuronium; atracurium/mivacurium); The surgical block will be varied by either induction of a deep block (via rocuronium infusion) or a moderate/normal block (using atracurium/mivacurium infusion); Other Names: deep muscle blockade; Drug: Surgical block (rocuronium; atracurium/mivacurium); A surgical block will be induced by infusion of either rocuronium (deep block) or atracurium/mivacurium (normal/moderate block); Other Names: moderate muscle blockade
Active Comparator: Moderate/normal surgical block; A normal block will be induced by an atracurium bolus dose followed by a mivacurium infusion to induce a train of four count of 1-2.	Drug: Surgical block (rocuronium; atracurium/mivacurium); The surgical block will be varied by either induction of a deep block (via rocuronium infusion) or a moderate/normal block (using atracurium/mivacurium infusion); Other Names: deep muscle blockade; Drug: Surgical block (rocuronium; atracurium/mivacurium); A surgical block will be induced by infusion of either rocuronium (deep block) or atracurium/mivacurium (normal/moderate block); Other Names: moderate muscle blockade

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Surgical Rating Scale	During the procedure, the surgical condition will be scored by the surgeon using a 5-point surgical rating scale. In order to reduce variability in the surgical rating all surgeries will be performed by one single surgeon. The rating scale will be a 5-point ordinal scale ranging from 1 = poor condition to 5 = optimal surgical conditions. The surgeon will score the condition at 15 minute intervals. In case of a sudden change in surgical conditions additional scores will be added to the case record form. If conditions are poor (score 1 or 2), muscle relaxation will be increased, a score of 1 will be used. In each subject the scores over time were averaged and a comparison between treatments was performed using a t-test	Measurements will be made during the stay in the operating room for an average period of 3 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breathing	In the recovery room the respiratory rate will be measured continuously using the Respir8 respiratory rate monitor. The data will be recorded on the CRF at 15 min intervals. Breathing rate units are "number of breaths" as measured in 1 min. Comparison by t-test: NS between treatments	Measurements will be made during the stay in the recovery room for an average period of 3 hours
Post-operative Pain	Using a 10 cm visual analogue score pain relief score will be measured. 0 = no pain 10 = most severe pain No statistical analysis was performed!	measurements are made in the recovery room following surgery for an average prior of 1 hour
Postoperative Sedation Score	Using a 5-point sedation scale, sedation levels will be obtained throughout the postoperative period. 0 = wide awake 5= severely sedated, The sedation data were averaged over time.	Measurements will be made during the stay in the operating room for an average period of 3 hours
Nausea and Vomiting	Using a yes - no questionnaire, the patients will be asked whether they are nauseated or not or whether they vomited. In fact yes indicates the nr of participants. No statistical analysis was performed.	Measurements will be made during the stay in the operating room for an average period of 3 hours

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Investigators: Principal Investigator: Albert Dahan, MD {hD, LUMC

Publications and helpful links

General Publications

• Boon M, Martini CH, Aarts LP, Bevers RF, Dahan A. Effect of variations in depth of neuromuscular blockade on rating of surgical conditions by surgeon and anesthesiologist in patients undergoing laparoscopic renal or prostatic surgery (BLISS trial): study protocol for a randomized controlled trial. Trials. 2013 Mar 1;14:63. doi: 10.1186/1745-6215-14-63.

Helpful Links

• Website of the hospital in which the study will be performed

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: June 19, 2012
• First Submitted That Met QC Criteria: June 27, 2012
• First Posted (Estimate): June 28, 2012

Study Record Updates

• Last Update Posted (Estimate): October 17, 2016
• Last Update Submitted That Met QC Criteria: August 23, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: anesthesia; laparoscopy; muscle relaxation; rocuronium; urology
• Additional Relevant MeSH Terms: Prostatic Diseases; Pathological Conditions, Anatomical; Prostatic Hyperplasia; Hypertrophy; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Neuromuscular Agents; Nicotinic Antagonists; Neuromuscular Nondepolarizing Agents; Neuromuscular Blocking Agents; Rocuronium; Atracurium; Mivacurium
• Other Study ID Numbers: bliss s

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided