CURES: The Effect of Deep Curarisation and Reversal With Sugammadex on Surgical Conditions and Perioperative Morbidity

Obesity Clinical Trial

— CURES  

Official title:

Effect of Deep Curarisation and Reversal With Sugammadex on Surgical Conditions and Perioperative Morbidity in Patients Undergoing Laparoscopic Gastric Bypass Surgery

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01748643
• Other study ID #: PVRA-01
• Secondary ID: 2012-005533-3786
• Status: Completed
• Phase: Phase 4
• First received: December 6, 2012
• Last updated: January 24, 2015
• Start date: April 2013
• Est. completion date: January 2015

Study information

• Verified date: January 2015
• Source: Ziekenhuis Oost-Limburg
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Ethics CommitteeBelgium: Federal Agency for Medicinal Products and Health Products
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to investigate if a deep neuromuscular block with a continuous infusion of rocuronium titrated to a post-tetanic count (PTC) of 1-2 responses combined with reversal of neuromuscular blockade with sugammadex results in improved surgical conditions for the surgeon and/or improved post-operative respiratory function for the patients as compared to a standard technique with an intubation dose of rocuronium and top-ups as needed to maintain a neuromuscular blockade with a TOF count of 1-2 and reversal of neuromuscular blockade with neostigmine/glycopyrrolate.

Furthermore, we want to investigate the effect of pneumoperitoneum, and NMB with rocuronium and reversal with sugammadex or neostigmine/glycopyrolate on cerebral tissue oxygenation.

Description:

Laparoscopic bariatric surgery poses special demands on the anaesthesiologist as well as the surgeon. The surgeon requires good visualisation of the operative field while the anaesthesiologist is concerned with adequate postoperative respiratory function in these morbidly obese patients. With the advent of advanced laparoscopic techniques the time span between adequate neuromuscular blockade (NMB) and adequate postoperative recovery of respiratory muscle function is growing ever shorter with an increasing risk of postoperative residual NMB.

Even minimal postoperative residual NMB with a train of four ratio (TOF) of 0.8 is associated with impaired respiratory function as witnessed in reductions of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) in healthy volunteers. Moreover, a TOF < 0.7 correlates with increased postoperative respiratory complications due to the inability to swallow normally leading to aspiration, atelectasis and pneumonia. However, neuromuscular blocking agents not only impair respiratory function due to skeletal muscle relaxation. Also the body's response to hypoxia is impeded due to carotid body chemoreceptor suppression. Worryingly, reversal of NMB with neostigmine can lead to respiratory complications such as bronchospasm and even induce neuromuscular transmission failure in patients who already recovered from NMB.

Obese patients are at even greater risk for postoperative respiratory complications. In a recent study after bariatric surgery, 100% of patients had at least one hypoxic event (oxygen saturation <90% more then 30seconds). Restrictive ventilatory defects are clearly associated with body mass index (BMI) and obesity hypoventilation syndrome. Since respiratory failure is responsible for 11.8% of mortalities after bariatric surgery, optimal respiratory care for these patients is primordial. Optimal reversal of NMB plays an important role herein. With the advent of Sugammadex, a cyclodextrin molecule that encapsulates and inactivates rocuronium and vecuronium, rapid and dose-dependent reversal of profound NMB by high dose rocuronium is possible without the risk of impaired upper airway dilator muscle activity when given after recovery from NMB.

Furthermore, little is known about the cerebral tissue oxygen saturation (SctO2) in these morbidly obese patients during laparoscopic gastric bypass surgery. Since the unexpected finding that NMB influences hypoxic ventilatory response, more research is needed into the effect of neuromuscular blockers and their reversing agents on cerebral oxygenation. Using near infrared spectroscopy (Fore-sight®) technology absolute brain tissue oxygenation can be quantified to study these effects.

In this study we wish to investigate if a deep neuromuscular block with a continuous infusion of rocuronium titrated to a post-tetanic count (PTC) of 1-2 responses combined with reversal of NMB with sugammadex results in:

i. Improved surgical conditions for the surgeon ii. Improved post-operative respiratory function for the patients

as compared to a standard technique with an intubation dose of rocuronium and top-ups as needed to maintain a NMB with a TOF count of 1-2 and reversal of NMB with neostigmine/glycopyrrolate.

Furthermore, we wish to investigate the effect of pneumoperitoneum, and NMB with rocuronium and reversal with Sugammadex or neostigmine/glycopyrrolate on cerebral tissue oxygenation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: January 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Able to give written informed consent

2. American Society of Anaesthesiologists class I, II or III

3. Obese or morbid obese as defined by BMI > 30 and >40 kg/m2 respectively

Exclusion Criteria:

1. Neuromuscular disorders

2. Allergies to, or contraindication for muscle relaxants, neuromuscular reversing agents, anaesthetics, narcotics

3. Malignant hyperthermia

4. Pregnancy or lactation

5. Renal insufficiency defined as serum creatinine of 2x the upper normal limit, glomerular filtration rate < 60ml/min, urine output of < 0.5ml/kg/h for at least 6h

6. Chronic obstructive pulmonary disease GOLD classification 2 or higher.

7. Clinical, radiographic or laboratory findings suggesting upper or lower airway infection

8. Congestive heart failure.

9. Pickwick syndrome

10. Psychiatric illness inhibiting cooperation with study protocol or possibly obscuring results

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Supportive Care

Related Conditions & MeSH terms

• Cerebral Tissue Oxygenation
• Disease
• Laparoscopic Gastric Bypass Surgery
• Obesity
• Respiratory Function
• Surgical Conditions

Intervention

Drug:
• deep neuromuscular blockade with rocuronium, reversal with sugammadex
after induction of anesthesia, a rocuronium infusion (0.6mg/kg (lean body mass)/h,) is started and titrated to a post tetanic count of 1-2 twitches. At the end of surgery neuromuscular blockade will be reversed with sugammadex 4mg/kg. Patients are extubated when TOF ratio > 0.9.
• normal neuromuscular blockade reversal with rocuronium, reversal with neostigmine
After induction of anesthesia, top-ups of rocuronium (10mg) are given as needed to maintain a train of four count of 1-2. At the end of surgery neuromuscular blockade will be reversed with neostigmine 50µg/kg and glycopyrrolate 10µg/kg (lean body mass). Patients are extubated when the train of four ratio is > 0.9.

Locations

Country	Name	City	State
Belgium	Ziekenhuis Oost-Limburg	Genk	Limburg

Sponsors (2)

Lead Sponsor	Collaborator
Ziekenhuis Oost-Limburg	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

Belgium, 

References & Publications (15)

Ali HH, Wilson RS, Savarese JJ, Kitz RJ. The effect of tubocurarine on indirectly elicited train-of-four muscle response and respiratory measurements in humans. Br J Anaesth. 1975 May;47(5):570-4. — View Citation

Berg H, Roed J, Viby-Mogensen J, Mortensen CR, Engbaek J, Skovgaard LT, Krintel JJ. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand. 1997 Oct;41(9):1095-1103. — View Citation

Cohen LB, Delegge MH, Aisenberg J, Brill JV, Inadomi JM, Kochman ML, Piorkowski JD Jr; AGA Institute. AGA Institute review of endoscopic sedation. Gastroenterology. 2007 Aug;133(2):675-701. Review. — View Citation

Eikermann M, Groeben H, Hüsing J, Peters J. Accelerometry of adductor pollicis muscle predicts recovery of respiratory function from neuromuscular blockade. Anesthesiology. 2003 Jun;98(6):1333-7. — View Citation

Eikermann M, Zaremba S, Malhotra A, Jordan AS, Rosow C, Chamberlin NL. Neostigmine but not sugammadex impairs upper airway dilator muscle activity and breathing. Br J Anaesth. 2008 Sep;101(3):344-9. doi: 10.1093/bja/aen176. Epub 2008 Jun 16. — View Citation

Eriksson LI. Reduced hypoxic chemosensitivity in partially paralysed man. A new property of muscle relaxants? Acta Anaesthesiol Scand. 1996 May;40(5):520-3. — View Citation

Gallagher SF, Haines KL, Osterlund LG, Mullen M, Downs JB. Postoperative hypoxemia: common, undetected, and unsuspected after bariatric surgery. J Surg Res. 2010 Apr;159(2):622-6. doi: 10.1016/j.jss.2009.09.003. Epub 2009 Sep 25. — View Citation

Miller MR, Dickinson SA, Hitchings DJ. The accuracy of portable peak flow meters. Thorax. 1992 Nov;47(11):904-9. — View Citation

Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS. Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg. 2008 Jul;107(1):130-7. doi: 10.1213/ane.0b013e31816d1268. — View Citation

Payne JP, Hughes R, Al Azawi S. Neuromuscular blockade by neostigmine in anaesthetized man. Br J Anaesth. 1980 Jan;52(1):69-76. — View Citation

Pratt CI. Bronchospasm after neostigmine. Anaesthesia. 1988 Mar;43(3):248. — View Citation

Pühringer FK, Rex C, Sielenkämper AW, Claudius C, Larsen PB, Prins ME, Eikermann M, Khuenl-Brady KS. Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial. Anesthesiology. 2008 Aug;109(2):188-97. doi: 10.1097/ALN.0b013e31817f5bc7. — View Citation

Saliman JA, Benditt JO, Flum DR, Oelschlager BK, Dellinger EP, Goss CH. Pulmonary function in the morbidly obese. Surg Obes Relat Dis. 2008 Sep-Oct;4(5):632-9; discussion 639. doi: 10.1016/j.soard.2008.06.010. Epub 2008 Jul 17. — View Citation

Sundman E, Witt H, Olsson R, Ekberg O, Kuylenstierna R, Eriksson LI. The incidence and mechanisms of pharyngeal and upper esophageal dysfunction in partially paralyzed humans: pharyngeal videoradiography and simultaneous manometry after atracurium. Anesthesiology. 2000 Apr;92(4):977-84. — View Citation

Wyon N, Joensen H, Yamamoto Y, Lindahl SG, Eriksson LI. Carotid body chemoreceptor function is impaired by vecuronium during hypoxia. Anesthesiology. 1998 Dec;89(6):1471-9. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Subjective evaluation of the view on the operating field by the surgeon	At the end of surgery, the view on the operating field will be graded by the surgeon using a 5-point rating scale: Extremely poor; Poor; Acceptable; Good; Optimal	Participants will be followed for the duration of the laparoscopic gastric bypass surgery, an expected average of 1.5h	No
Primary	Number of intra-abdominal pressure rises > 15cmH2O	The number of intra-abdominal pressure rises > 15cmH2O detected by the intra-abdominal CO2 insufflator.	Participants will be followed for the duration of the laparoscopic gastric bypass surgery, an expected average of 1.5h	No
Secondary	Respiratory function	Respiratory function will be assessed by measuring peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1) with the Vitalograph® electronic portable peak flow meter. A mean of 3 measurements in the upright posture in bed before and after surgery will be used.	Measured the day before surgery and 30min after completion of surgery (when the modified observer's assessment of alertness/sedation scale is 5 (Patient responds readily to name spoken in normal tone))	Yes
Secondary	Oxygen saturation	Oxygen saturation will be measured non-invasively with a pulse oxymeter	Measured the day before surgery and 30min after completion of surgery (when the modified observer's assessment of alertness/sedation scale is 5 (Patient responds readily to name spoken in normal tone))	Yes
Secondary	Effect of pneumoperitoneum on cerebral tissue oxygenation.	Using near infrared spectroscopy (Fore-sight®) technology, absolute brain tissue oxygenation can be quantified non-invasively by applying 2 skin electrodes to the forehead of the patient.	Participants will be followed for an expected average of 5min after the start of intra-abdominal CO2 insufflation by the surgeon	No
Secondary	Effect of neuromuscular blockade on cerebral tissue oxygenation	Using near infrared spectroscopy (Fore-sight®) technology, absolute brain tissue oxygenation can be quantified non-invasively by applying 2 skin electrodes to the forehead of the patient.	Participants will be followed for an expected average of 5min after the intravenous injection of rocuronium	No
Secondary	The effect of reversal of neuromuscular blockade (with sugammadex or neostigmine) on cerebral tissue oxygenation	Using near infrared spectroscopy (Fore-sight®) technology, absolute brain tissue oxygenation can be quantified non-invasively by applying 2 skin electrodes to the forehead of the patient.	Participants will be followed for an expected average of 5min after the intravenous injection of sugammadex or neostigmine	No