Clinical trial NCT03138577
Conditions: Surgery of Right Upper Extremity
Sponsor: Weill Medical College of Cornell University
Start date: 2018-02-12; Completion date: 2019-07-30
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This clinical trial is for subjects undergoing right upper extremity surgery. The aim of the study is to investigate the dose-response relationship between local anesthetic volume and ipsilateral hemidiaphragmatic paresis (HDP) in patients getting ultrasound-guided supraclavicular brachial plexus blocks in a blinded, prospective trial.

Detailed description:
With traditional landmark-based or nerve-stimulator techniques, the incidence of HDP following supraclavicular blocks is approximately 50-67%. Ultrasound-guided techniques are thought to enhance precision while reducing the volume of anesthetic used, but even then HDP incidence is nearly 60%. To date, no trials have studied the dose-response relationship between local anesthetic volume and degree of HDP.

Patient Selection

30 eligible patients undergoing right upper extremity surgery and eligible for supraclavicular blocks will be recruited at NewYork-Presbyterian/Weill Cornell Medical Center.

Evaluation of HDP

Baseline M-mode recordings of diaphragm function will be made by an anesthesiologist. Patients will perform "voluntary sniff" (VS) tests, or forceful nasal inhales, immediately preceding the brachial plexus blockade, and again at 15 minutes and 30 minutes after the block.

Diaphragmatic excursion from baseline will be measured in centimeters; three measurements will be made and averaged. Hemidiaphragmatic paresis will be defined as greater than or equal to 60% reduction in diaphragmatic excursion, no movement, or paradoxical movement in the VS test.

Evaluation of Pulmonary Function

A bedside negative inspiratory force (NIF) meter will be used to measure negative inspiratory force prior to the block and 30 minutes after the block.

Evaluation of Supraclavicular Block

At the 15- and 30-minute marks, the investigators will assess sensory blockade and motor block in the axial, musculocutaneous, radial, median, and ulnar distributions. Both will be judged on 3-point scales. The investigators will also apply a 0-10 point verbal rating scale to assess dyspnea at 30 minutes. Oxygen saturation will be measured off of supplemental oxygen before the block and 30 minutes after the block.

Following the assessments, patients will have surgery using brachial plexus blockade as the primary anesthetic.

Arms: arm 1: 5 mL of 2:1 mixture of 1.5% mepivacaine and 0.5% bupivacaine Ultrasound Imaging Bedside Negative Inspiratory Force Meter arm 2: 10 mL of 2:1 mixture of 1.5% mepivacaine and 0.5% bupivacaine Ultrasound Imaging Bedside Negative Inspiratory Force Meter arm 3: 15 mL of 2:1 mixture of 1.5% mepivacaine and 0.5% bupivacaine Ultrasound Imaging Bedside Negative Inspiratory Force Meter arm 4: 20 mL of 2:1 mixture of 1.5% mepivacaine and 0.5% bupivacaine Ultrasound Imaging Bedside Negative Inspiratory Force Meter arm 5: Supraclavicular Block: 25 mL of 2:1 mixture of 1.5% mepivacaine and 0.5% bupivacaine Ultrasound Imaging Bedside Negative Inspiratory Force Meter arm 6: 30 mL of 2:1 mixture of 1.5% mepivacaine and 0.5% bupivacaine Ultrasound Imaging Bedside Negative Inspiratory Force Meter arm 7: 35 mL of 2:1 mixture of 1.5% mepivacaine and 0.5% bupivacaine Ultrasound Imaging Bedside Negative Inspiratory Force Meter
Interventions: intervention 1: Ultrasound Imaging intervention 2: Supraclavicular Block intervention 3: Bedside Negative Inspiratory Force Meter
Intervention descriptions: intervention 1: M-mode tracings of right diaphragm motion will be made and recorded by a skilled anesthesiologist. Patients will be examined in the supine position and scanned from a low intercostal or subcostal approach using the liver as an acoustic window. Patients will be asked to perform a "voluntary sniff" (VS) test, for which they will be asked to forcefully inhale through the nose in a sniffing position. The above measurement will be performed immediately preceding the brachial plexus blockade, and then at 15 minute and 30 minutes after block. intervention 2: The patient will be positioned supine with the head turned to the contralateral side. The ultrasound will be placed in the supraclavicular fossa, and the skin and subcutaneous tissues will be infiltrated lateral to the probe with 2% lidocaine. The anesthesiologist can redirect the needle and perform additional injections for complete coverage of the brachial plexus. The local anesthetic will be a 2:1 mix of 1.5% mepivacaine and 0.5% bupivacaine. intervention 3: A bedside negative inspiratory force (NIF) meter will be used to measure negative inspiratory force prior to the block and 30 minutes after the block.

Protocol documents:
Prot_SAP_000.pdf: 
Dose-Response Relationships for Hemidiaphragmatic Paresis 
Following Ultrasound-Guided Supraclavicular Brachial Plexus Blockade 
 
NCT #: 1609017547 
 
Document Versions: 
 
PROTOCOL NUMBER 
IRB APPROVAL DATE 
1 (Original) 
April 11, 2017 
2 
May 29, 2017 
3 
June 30, 2017 
4 (Current) 
December 5, 2017 
 


Dose-Response Relationships for Hemidiaphragmatic Paresis Following Ultrasound-
Guided Supraclavicular Brachial Plexus Blockade 
 
Weill Cornell Medical College 
Department of Anesthesiology 
525 East 68th Street, Box 124 
New York, NY 10065 
 
 
 
Principle Investigators:  
Tiffany Tedore, M.D. 
Email:   
 
 
 
 
Lead Author:  
 
 
 
Co-Investigators:  
 
 
 
 
 
 
 
 
 
 
Statistician: 
 
 
 
 
 


1.0 
STUDY PROTOCOL 
 
1.1 
Background and Significance 
 
1.1.1 Supraclavicular brachial plexus block 
 
The brachial plexus is formed by the lower four cervical nerve roots and first thoracic 
nerve root (C5-C8, T1). Local anesthetic can be deposited anywhere along the course of 
the brachial plexus, from the neck to the axilla, depending on the desired block 
distribution for surgical anesthesia. Performed at the level of the brachial plexus 
trunks/divisions, which are located just superior to the first rib and posterior to the 
subclavian artery, supraclavicular blocks can provide dense surgical anesthesia for 
procedures below the level of the shoulder and is often called the “spinal of the arm.”  
 
The phrenic nerve, which is comprised of the anterior branches of the C3-C5 nerve roots 
and innervates the diaphragm, typically lies on the anterior surface of the anterior 
scalene muscle underneath the sternocleidomastoid muscle and enters the thorax 
behind the subclavian vein. Due to its close proximity to the brachial plexus, the phrenic 
nerve is often inadvertently blocked during supraclavicular blocks, resulting in ipsilateral 
hemidiaphragmatic paresis (HDP). Although this is usually well tolerated in most 
individuals, complications (such as insufficient ventilation) may arise in those with pre-
existing pulmonary impairments.   
 
With traditional landmark-based or nerve-stimulator techniques, the incidence of HDP 
following supraclavicular blocks has been reported to be 50-67%.1 Ultrasound-guided 
techniques are thought to facilitate more precise deposition of local anesthetic and 
enable operators to use less volume to achieve a successful block. However, even with 
the utilization of ultrasound visualization, the incidence of HDP has been reported to be 
up to 60% after supraclavicular block.1,2  Furthermore, there is no established consensus 
regarding what volume of local should be used to achieve a successful supraclavicular 
block while also minimizing HDP. Kant et al. estimated an ED95 of 27 cc of 0.5% 
bupivacaine for achieving a successful supraclavicular block but did not determine the 
level of corresponding HDP.3 In practice, volumes of local anesthetic used for 
supraclavicular blocks range from 20-40cc. Proponents of using larger volumes often 
argue that it achieves faster onset with lower incidences of block failure. There have 
been no studies to date, however, determining the dose-response relationship between 
local anesthetic volume and the degree of HDP.  
 
All doses used in this study are ones routinely used in our clinical practice.  Lower 
volumes do lead to a higher likelihood of inadequate surgical anesthesia, however, 
which is why we have provided a mechanism with which to supplement the block if 
necessary. 
 
 


1.1.2  Phrenic Nerve Palsy (PNP) and HDP 
 
The left and right phrenic nerves are derived from cervical nerve roots C3-C5 to 
innervate the corresponding sides of the diaphragm. Phrenic nerve palsy results in 
hemidiaphragmatic paresis (partial loss of excursion) or paralysis.  In patients without 
pre-existing respiratory issues who experience PNP and HDP following a supraclavicular 
block, the contralateral hemidiaphragm and accessory muscles of respiration are able to 
compensate to generate adequate negative pleural pressure necessary for inspiration. 
Therefore, patients are usually asymptomatic at rest but may experience dyspnea with 
exertion. Patients with underlying lung diseases (i.e. pneumonia, chronic obstructive 
pulmonary disease) or respiratory dysfunction (i.e. patients with neuromuscular disease, 
PNP of the contralateral side) already rely heavily on the accessory respiratory muscles 
for ventilation and may be susceptible to insufficient ventilation following a 
supraclavicular block. These patients may have dyspnea at rest and show signs of 
ventilatory failure (i.e. hypercapnia, hypoxemia) with HDP.  
 
1.1.3   Diaphragmatic Motion Assessed by Ultrasonography 
 
Motion-mode (M-mode) ultrasonography has been shown to be a reliable modality for 
detecting anatomical or functional diaphragmatic abnormalities by measuring 
diaphragmatic excursions.4 Motion of the right hemidiaphragm is more reliably imaged 
than the left due to the smaller acoustic window of the spleen compared to the liver. 
 
1.1.4  Respiratory Volumes Assessed by Spirometry 
 
Vital capacity (VC) measured in the supine position has been shown to fall by as much as 
55% in patients with diaphragm paralysis.5  Measuring changes in VC can quantify the 
change in lung function resulting from unilateral diaphragmatic paresis or paralysis. 
 
1.2  Rationale and Hypothesis 
 
The rationale of this study is to investigate the dose-response relationship between local 
anesthetic volume and ipsilateral HDP in patients undergoing ultrasound-guided 
supraclavicular brachial plexus blocks for surgeries of the right upper extremity in an 
observer-blinded, prospective trial. In this study, we hypothesize that higher volumes of 
local anesthetic will be associated with an increased incidence of HDP. By identifying 
this dose response relationship, this study aims to help practitioners safely administer 
supraclavicular blocks, particularly in high-risk patients with underlying lung disease or 
respiratory dysfunction.  
 
1.3.1  Primary Objective 
 


To define the dose-response relationship between local anesthetic volume and 
ipsilateral HDP in patients undergoing ultrasound-guided supraclavicular brachial plexus 
blocks. 
 
1.4  
Patient Selection 
 
30 eligible patients undergoing right upper extremity surgery and eligible for 
supraclavicular blocks will be recruited from the inpatient units and surgery clinics of 
NewYork-Presbyterian/Weill Cornell Medical Center.   
 
1.4.1  Inclusion criteria 
 
Each subject must meet all of the following criteria: 
 
i. 
Undergoing right upper extremity surgery with supraclavicular block as the 
primary anesthetic 
ii. 
Age ≥ 18 years of age 
iii. 
American Society of Anesthesiologists (ASA) physical status 1 to 3 
iv. 
Able to give informed consent 
 
1.4.2  Exclusion Criteria 
 
Subjects will not be enrolled if any of the following criteria exist: 
 
i. 
Patient refusal for supraclavicular block 
ii. 
Inability to give informed consent 
iii. 
Allergy to local anesthetics 
iv. 
Hemidiaphragmatic dysfunction, suspected or known PNP 
v. 
Neuromuscular disease 
vi. 
Obstructive or restrictive pulmonary disease 
vii. 
Medical or anatomic contraindication to supraclavicular blockade as judged 
by clinician 
viii. 
Pregnancy 
 
1.5  
Study Design 
 
1.5.1 Preoperative Evaluation and Consent 
 
Patients admitted to the hospital on the day of surgery will be consented for this study 
in advance by phone or in-person during a pre-anesthesia clinic visit.  Those already 
admitted to the hospital as inpatients will be evaluated and consented during a 
preoperative workup prior to the patient being transported to the operating room.  
 
 


1.5.2 Supraclavicular Blockade 
 
All supraclavicular blocks will be performed in a dedicated regional block area or 
operating room suite. Prior to placement of the block, intravenous access will be 
established and standard ASA monitors placed. Baseline M-mode recordings of 
diaphragm function will be made by a skilled anesthesiologist. 
 
 
At the discretion of the attending anesthesiologist, up to 0.03 mg/kg of midazolam may 
be given for sedation prior to the block.  In cases of extreme patient anxiety 
unresponsive to 0.03 mg/kg of midazolam, additional midazolam may be administered 
up to a total dose of 0.05 mg/kg.  The patient will be positioned supine with the head 
turned to the contralateral side, and the injection site will be disinfected with a 2% 
chlorhexidine and alcohol solution. The ultrasound will be placed in the supraclavicular 
fossa to obtain a transverse cross-sectional view of the brachial plexus and subclavian 
artery. The skin and subcutaneous tissues will be infiltrated lateral to the probe with 2% 
lidocaine. Using an in-plane technique, a 22-gauge block needle will be inserted through 
the skin lateral to the probe and directed medially toward the “corner pocket” at the 
junction of the first rib and subclavian artery.6 Local anesthetic will be injected initially 
at this location. The anesthesiologist will be at liberty to redirect the needle and 
perform additional injections for complete coverage of the brachial plexus. The local 
anesthetic will be a 2:1 mix of 1.5% mepivacaine and 0.5% bupivacaine, and the volume 
administered will be determined per the continual reassessment method (CRM) 
protocol described below. Per clinical routine, all injections will be made in 5cc 
increments using frequent aspiration, to test for inadvertent intravascular needle 
placement as well as ascertaining the absence of high resistance indicative of a possible 
intraneural injection.  
 
1.5.3  Intercostobrachial Nerve Blockade 
 
Following performance of the supraclavicular block, an additional block of the ipsilateral 
intercostobrachial nerve will also be completed. Brachial plexus blocks do not 
anesthetize the intercostobrachial nerve, a branch of T2 that is responsible for sensation 
of the skin of the proximal medial arm.  
 
With the patient remaining supine and with the arm abducted and externally rotated, a 
1.5-inch, 25-gauge needle will be inserted at the deltoid prominence and a 
subcutaneous field block will be performed in a linear fashion inferiorly to the most 
inferior aspect of the medial arm using 10 cc of 0.5% bupivacaine. Given that this is a 
subcutaneous field block that does not contribute to PNP and HDP, all patients will 
receive the same amount of local to ensure adequate anesthesia.     
 
1.5.4 Evaluation of HDP 
 


M-mode tracings of right diaphragm motion will be made and recorded by a skilled 
anesthesiologist.  Patients will be examined in the supine position and scanned from a 
low intercostal or subcostal approach using the liver as an acoustic window. Patients will 
be asked to perform a “voluntary sniff” (VS) test, for which they will be asked to 
forcefully inhale through the nose in a sniffing position. The above measurement will be 
performed immediately preceding the brachial plexus blockade, and then at 15 minute 
and 30 minutes after block.   
 
The M-mode recordings will be reviewed by two  blinded anesthesiologists.  
Diaphragmatic excursion from baseline will be measured in centimeters. Three 
measurements will be made, and the average will be taken. Significant 
hemidiaphragmatic paresis will be defined as greater than 75% reduction in 
diaphragmatic excursion, no movement, or paradoxical movement in the VS test.  
Partial paresis will be defined as a 25-75% reduction in diaphragmatic excursion.  If the 
two reviewers come to different conclusions regarding the diagnosis of significant 
paresis, partial paresis, or no paresis, a third blinded anesthesiologist will review the 
images and serve as a “tie-breaker”.   
 
1.5.5   Evaluation of Pulmonary Function 
 
A bedside spirometer will be used to record Forced Vital Capacity (FVC), Forced 
Expiratory Volume in 1 second (FEV1), and Peak Expiratory Flow (PEF) prior to the block 
and 30 minutes after the block.   
 
1.5.6 Evaluation of Supraclavicular Block 
 
At 15 and 30 minutes, we will assess sensory blockade in the axillary (lateral upper arm), 
musculocutaneous (lateral forearm), radial (dorsal hand), median (thenar eminenece), 
and ulnar (hypothenar eminence) distributions with the use of ice and a 3 point scale (0 
= normal sensation of cold, 1 = perception of touch/pressure but not cold, 2 = no 
perception of touch/pressure, or cold).2  Motor function will be evaluated at 15 and 30 
minutes in the distribution of the axillary nerve (abduction at shoulder), 
musculocutaneous nerve (flexion at the elbow), radial nerve (extension at the elbow), 
median nerve (flexion at the wrist and opposition of the second finger and thumb), and 
ulnar nerve (opposition of the fifth finger and thumb). Motor block in each distribution 
will be graded on a 3 point scale (0 = normal strength, 1 = weakness, or 2 = no 
movement).7  Failure to achieve loss of cold sensation or motor weakness at any of these 
dermatomes after 30 minutes will constitute an ineffective block, and the patient will 
receive a supplementary anesthetic block after the final M-mode ultrasound lung exam. 
The supplemental local anesthetic volume administered will be at the discretion of the 
attending anesthesiologist. During placement of the nerve block, a "catheter over 
needle" system will be used to place a catheter.  This catheter will be dosed with 
additional local anesthetic if supplemental nerve blockade is needed to provide 


satisfactory anesthesia.  No additional procedure will be required. The patient will 
proceed to surgery following successful sensory blockade of the above dermatomes. 
 
We will apply a 0-10 point verbal rating scale to assess dyspnea at 30 minutes (0 = no 
difference from baseline, 10 = extreme difficulty breathing).  Oxygen saturation will also 
be measured off of supplemental oxygen 30 minutes after the block.  Following the final 
assessment, patients will undergo surgery using the brachial plexus blockade as the 
primary anesthetic, with optional light sedation at the discretion of the anesthesiologist. 
Any instance requiring unscheduled conversion to general anesthesia intraoperatively or 
the need for supplementary rescue block or local infiltration by the surgeon will be 
recorded. Also, if the patient is brought to the operating room at any time before the 
30-minute mark, the 30-minute assessments above will be performed just before the 
transfer. 
 
 
1.5.7 Continual Reassessment Method (CRM) 
 
The Continual Reassessment Method (CRM), developed by O’Quigley et al.8 is a study 
design for dose-finding/Phase I studies.  It is different from traditional dose-escalation 
studies in that it “learns” from information gained at earlier time points in order to limit 
patient exposure to non-efficacious and potentially toxic doses.   The general idea 
behind the CRM is that an a-priori dose-response curve (DRC) is assumed and a desired 
effect rate chosen.  The estimated DRC is updated after each subject’s outcome is 
observed, so that the next patient’s dose is based on the information about how the 
previous patient tolerated the intervention. As the number of subjects accumulates, the 
DRC becomes based on observed data instead of the a-priori assumptions. 9   
 
In this study we are attempting to define the dose-response curve for the degree of HDP 
caused by various doses of local anesthetic administered in a supraclavicular block. 
Based upon clinical experience and data found in the literature, we have developed the 
following a-priori probabilities for significant HDP after various doses of local anesthetic: 
 
Dose Level 
Volume of Local 
Anesthetic (mL) 
Probability of HDP 
1 
5 
0.05 
2 
10 
0.1 
3 
15 
0.15 
4 
20 
0.2 
5 
25 
0.3 
6 
30 
0.5 
7 
35 
0.6 
8 
40 
0.8 
 


CRM trials typically employ dose cohort sizes of 1,2 or 3 subjects per dose.  We will use 
3 subjects per cohort.  The trial will begin with 3 subjects treated at a dose of 35 mL, 
which is a volume routinely used in clinical practice.  The DRC will be re-estimated based 
on the HDP outcomes of the treated subjects.  If, any of the patients experience 
significant HDP, the subsequent cohort will receive the next lowest dose of 30 mL.  If 
none of the patients experience HDP, the subsequent cohort will instead receive the 
next highest dose of 40 mL.  This will continue until a minimum sample of 30  subjects 
are enrolled, provided that the DRC has changed less than 10% after the final cohort.  If 
the DRC changes by more than 10% after 30 subjects, additional subjects will be 
enrolled until the change is less than 10%. 
 
We anticipate that some of the lower volumes used may not provide surgical 
anesthesia.  We will overcome this by testing the subjects’ blocks after US scan for 
diaphragm function, and if insufficient for anesthesia, we will supplement the blocks to 
insure complete coverage for the surgical procedure. 
 
1.6 
Statistical Analysis  
 
Participant characteristics, such as age, sex, American Society of Anesthesiologists (ASA) 
score, and type of surgery will be characterized by means (standard deviations) or 
medians (interquartile ranges), as appropriate.  
 
The dose-response curve of the local anesthetic on HDP, as well as sequential dose 
allocation, will be calculated using Stata 13 IC’s CRM command (StataCorp, College 
Station, TX) and the BMA-CRM Simulator (MD Anderson Cancer Center, Houston, TX).  
 
 
2.0  
MANAGEMENT OF INTERCURRENT EVENTS 
 
2.1 
Potential Risks 
 
2.1.1 Potential Risks of Supraclavicular Blocks 
 
Ultrasound-guided supraclavicular blocks are widely used and safe. In addition to 
ipsilateral phrenic nerve palsy, potential procedure-related side effects include 
ipsilateral oculosympathetic palsy (Horner’s syndrome) (incidence 1%) and recurrent 
laryngeal nerve palsy (1%), both of which are self-limited.  Rare procedure-related 
complications include subclavian artery puncture (0.4%), and pneumothorax (<0.1%).9  
Nerve palsies are usually self-limited, and the risk of permanent neurological damage is 
rare (<0.01%).9 
 
Supraclavicular brachial plexus blockade is the anesthetic standard of care for isolated 
upper extremity surgeries at our institution. Therefore, eligible subjects will incur no 
additional risks from participating in this study.   


 
2.1.2 Other Potential Risks 
 
No psychological risks to subjects are expected. In order to prevent loss of 
confidentiality, investigators will keep subjects’ participation confidential to the extent 
permitted by law.   
 
2.2 
Procedure to Minimize Potential Risks 
 
Subjects will be admitted for post-operative care to NewYork-Presbyterian Hospital. A 
physician from the primary surgical service and trained nursing personnel will provide 
continuous care for the subject during the hospital admission.  
 
All clinicians performing supraclavicular blocks and measuring diaphragmatic excursion 
are board-certified anesthesiologists trained and experienced in administering regional 
anesthesia. The procedure will be performed using aseptic technique to minimize any 
potential for infection.  Ultrasound guidance will be used for block placement to 
minimize the risk of subclavian artery and lung puncture.  
 
Inclusion and exclusion criteria, fasting requirements, monitoring, and the clinical 
protocol are designed to ensure that risks are absolutely minimal. Subjects are informed 
that participation is voluntary and they may refuse to participate and may withdraw 
from the study at any time without penalty. Subjects will be told that in the event of a 
physical injury as the direct result of study procedures, they will be cared for by a 
member of the investigating team at no cost, within the limits of the NewYork-
Presbyterian Hospital compensation plan. 
 
 
 


REFERENCES 
 
1. Renes SH, Spoormans HH, Gielen MJ, rettig HC, van Geffen GJ. 
Hemidiaphragmatic paresis can be avoided in ultrasound-guided supraclavicular 
brachial plexus block.  Reg Anesth Pain Med 2009; 34: 595-99. 
 
2. Petrar SD, Seltenrich ME, Head SJ, Schwarz SKW.  Hemidiaphragmatic paralysis 
following ultrasound-guided supraclavicular versus infraclavicular brachial plexus 
blockade:  A randomized clinical trial.  Reg Anesth Pain Med 2015; 40:  133-38. 
 
3. Kant A, Gupta IK, Zohar S, Chevret S, Hopkins PM.  Application of the continual 
reassessment method to dose-finding studies in regional anesthesia:  An 
estimate of the ED95 dose for 0.5% bupivacaine for ultrasound-guided 
supraclavicular block.  Anesthesiology 2013; 119: 29-35. 
 
4. Boussuges A, Gole Y, Blanc P.  Diaphragmatic motion studied by M-mode 
ultrasonography.  Chest 2009; 135: 391-400. 
 
5. Mier-Jedrzejowicz A, Brophy C, Moxham J, Green M.  Assessment of diaphragm 
weakness.  Am Rev Respir Dis 1988; 137: 877-83. 
 
6. Soares LG, Brull R, Lai J, Chan VW.  Eight ball, corner pocket:  The optimal needle 
position for ultrasound-guided supraclavicular block.  Reg Anesth Pain Med 2007; 
32: 94-95. 
 
7. Tedore TR, YaDeau JT, Maalouf DB, Weiland AJ, Tong-Ngork S, Wukovits B, Paroli 
L, Urban MK, Zayas VM, Wu A, Gordon MA.  Comparison of the transarterial 
axillary block and the ultrasound-guided infraclavicular block for upper extremity 
surgery: a prospective randomized trial.  Reg Anesth Pain Med 2009; 34: 361-5. 
 
8. O’Quigley JO, Pepe M, Fisher L.  Continual Reassessment Method:  A practical 
design for phase I clinical trials in cancer.  Biometrics 1990; 46: 33-48. 
 
9. Garrett-Mayer E.  The continual reassessment method for dose finding studies:  
A tutorial.  Clin Trials 2006; 3: 57-71. 
 
10. Neal JM.  Ultrasound-Guided Regional Anesthesia and Patient Safety.  Reg 
Anesth Pain Med 2016; 41: 195-204.