Neuromuscular Blockade and PostOperative Respiratory Complications
Intro by Dr. Jim Ibinson
Journal Club presenters: Drs. Ricky Harika, Sharanya
Nama, Tom Talamo, Julie DeVore, and Andrew Gentilin
EBM Statistics
Jim Ibinson
Asst Prof
Dept of Anesthesiology
Journal Club
12/6/12
JC Goals and Objectives
Instruct and Practice Presentation Skills
Teach Critical Literature Reading Skills
Examine “Interesting” Topics and Articles
Highlight the statistics that are typically
addressed in “EBM” studies.
The 5 Steps of EBM
1)
2)
3)
4)
Well constructed clinical question
Search for the best evidence
Appraise the evidence
Integrate the evidence with expertise and
patient preference
5) Evaluate the effectiveness of the
intervention
“The use of mathematical estimates of
Trisha Greenhalgh
the risk of benefit and harm”
Stats You Have Heard of Before
•
•
•
•
•
•
•
Sensitivity
•
Specificity
•
Positive Predictive value •
Negative Predictive value
•
Pretest probability
Post-test probability
•
Likelihood ratio
Relative risk reduction
Absolute risk reduction
Number needed to
treat
Number needed to
harm
95 percent confidence
interval
Learn this Slide and You’re Set
Example using 2030
Patient Study
http://en.wikipedia.org/wiki/Sensitivity_and_specificity
OK, maybe this slide too…
• Relative risk reduction
– The percentage difference in risk or outcomes between treatment and control
groups. Example: if mortality is 30 percent in controls and 20 percent with
treatment, RRR is (30-20)/30 = 33 percent.
• Absolute risk reduction
– The arithmetic difference in risk or outcomes between treatment and control
groups. Example: if mortality is 30 percent in controls and 20 percent with
treatment, ARR is 30-20=10 percent.
• Number needed to treat / harm
– The number of patients that need to be treated in order to have an impact on
one person. If the probabilities pA and pB of this endpoint under treatments
A and B, respectively, are known, then the NNT is computed as 1/(pB-pA);
Example above would show that NNT = 1/0.10 = 10
http://www.thennt.com/the-nnt-explained/
http://www.aafp.org/online/en/home/publications/journals/afp/afpebmglossary.html
Forming the Question
 P – Patient or Population
Describe a group of patients with balance of
precision and brevity?
 I – Intervention; Prognostic Factor; Cause
What is the main intervention?
 C – Comparison
What is the main alternative?
 O – Outcome
What can this intervention actually affect?
http://www.cebm.net/index.a
spx?o=1036 10/3/12
This Month’s Paper is Looking at
P–
This Month’s Paper is Looking at
P – In patients requiring surgical anesthesia,
I–
This Month’s Paper is Looking at
P – In patients requiring surgical anesthesia,
I – does the use of intermediate acting nondepolarizing neuromuscular blocking agents
C-
This Month’s Paper is Looking at
P – In patients requiring surgical anesthesia,
I – does the use of intermediate acting nondepolarizing neuromuscular blocking agents
C - when compared to patients without them
O–
This Month’s Paper is Looking at
P – In patients requiring surgical anesthesia,
I – does the use of intermediate acting nondepolarizing neuromuscular blocking agents
C - when compared to patients without them
O – result in a greater incidence of desaturation
after extubation or reintubation and ICU
admission?
Reverse or Not to Reverse?
Sharanya Nama, Ricky Harika, Thomas Talamo, Andrew
Gentilin & Julie DeVore
University of Pittsburgh School of Medicine
Department of Anesthesiology
Journal Club
12/6/12
Background
• 1942
Wikipedia.com
– Griffith, H. Curare in Anesthesia. JAMA 1945;
127(11):642-644
• 1954
– Beecher, H. & Todd, D. A study of deaths associated
with anesthesia and surgery. Ann Surg 1954;140:2
• 1959
– Gray, T. & Wilson, F. The development and use of
muscle relaxants in the United Kingdom.
Anesthesiology 1959; 20:519-529.
Neuromuscular Blockade
• Residual neuromuscular blockade and other potential
causes leading to post-operative pulmonary
complications
• Monitoring of neuromuscular transmission
– Qualitative
– Quantitative
Classic Paper Revisited
Study Design
• Prospective, randomized, blinded study.
• 691 Patients randomized to three arms
– Pancuronium
– Atracurium
– Vecuronium
Methods
• Data collection
– Train-of-four (TOF) assessed immediately post-op
– Patients examined for pulmonary issues for 6 days
after procedure.
• Criteria for residual neuromuscular blockade
– TOF ratio: <0.7 indicating residual blockade
– Clinical criteria
• Five second head lift
• Arm lift across body
• Tongue protrusion/Eye opening
Results
• Incidence of residual
block (i.e. TOF <0.7)
was significantly
higher in the long
acting NMB group
(26%) compared to
the intermediate
NMB groups (5.3%)
Results
• In the long acting NMB group – of those
with residual blockade – there was
increased incidence of POPC compared to
patients with residual blockade in the
intermediate acting NMB group.
Results
• Risk factors for the development of POPC
Discussion
• Strengths
– Well designed, prospective randomized trial
– Well balanced arms
• Weaknesses
– Could not demonstrate a difference in POPC incidence
based upon NMB agent alone.
– Residual blockade was not associated with POPC for
intermediate NMB group; but this may be due to Type
II error
– Funded by Glaxo Wellcome – maker of atracurium
British Medical Journal 2012 Oct 15;345:e6329.
Hypothesis
• “…intermediate acting non-depolarizing
neuromuscular blocking agents would be
associated with an increased risk of
postoperative hypoxic events and reintubation
requiring unplanned admission to the ICU and
mechanical ventilation.”
DESIGN & METHODS
Study Design
•
•
•
•
Prospective cohort study
Included over 40,000 surgical procedures
Roughly 50% inpatient surgery
March 2006 to Sept 2010
Inclusion Criteria
• Tracheal intubation
• Extubation at end of surgery
• Multiple surgeries on same patient included
as separate events
Data collection
• Patient data
– Sex, age, BMI, ASA Physical Status, Charleson
comorbidity index.
• Operative management
– Surgical specialty, surgery duration, emergency
status, neuromuscular monitoring, use of volatile
anesthetics, NO, opioids, and neostigmine.
Charlson Comorbidity Index
• System used to predict the 10 year mortality
of a patient.
• Calculated by assigning point value to 22
different comorbid conditions, in addition to
age.
• Summation of scores used to calculate
predicted mortality.
Use of Neuromuscular Blocking Agents
• All anesthetics in which intermediate acting
non-depolarizing muscle relaxants were
included.
• Also all anesthetics in which patient
additionally or exclusively received
succinylcholine.
• Use of pancuronium or mivacurium excluded
an anesthetics.
Outcomes
• Primary outcomes
– Desaturation
• Below 90% or below 80% in first 20 minutes post-op
– Reintubation
• Within 7 days excluding reintubation for additional
procedures
• Secondary outcomes
–
–
–
–
Monitoring of neuromuscular transmission
Reversal of neuromuscular blockade
Length of stay
In-hospital mortality
Statistical Analysis
• JMP and SAS
• 2 tailed p value less than 0.05 considered
significant
Propensity Scoring
• Covariates selected to approximate the clinical
decision making process of anesthesiologists
in administering neuromuscular blockade.
Matching
• Greedy matching algorithm
• One reference procedure for each patient
exposed to non-depolarizing neuromuscular
blockade.
• Total of 18579 matched pairs.
Outcomes Models
• Logistic regression analysis applied to test
association of primary outcomes and
neuromuscular blockade as well as the
influence secondary outcomes.
• Results presented as Odds ratios with 95%
confidence intervals.
RESULTS
Results
• Between 2006-2010 57,068 surgical procedures in
46,899 patients met inclusionary criteria
• Propensity scores were calculated
• 18,579 patients who received at least one nondepolarizing agent were matched to 18,579 reference
patients who did not receive any such agent
Study population characteristics
Study population characteristics
(cont.)
Propensity score matched cohort
Propensity score matched cohort
(cont.)
Outcomes in propensity score matched cohort
• Greater amount of complications in group receiving neuromuscular
blocking agents
• Desaturation <90%, <80%, and reintubation found to be associated
with use of neuromuscular blocking agents
• Confidence intervals greater than 1, but not by much
Strategies to prevent residual
neuromuscular blockade and outcomes
So now what?
DISCUSSION
Discussion Questions:
• Will this study change your anesthetic strategy
with regard to the use of intermediate acting
non-depolarizing muscle relaxants and reversal
with neostigmine? If so, how?
– A – Yes
– B – No
– C – Maybe
Discussion
• Strengths
– Large, prospective study
– Successful propensity score matching, minimizing
confounders in an observational study.
• Weaknesses
– Not a blinded, randomized, controlled trial
– Not a multi-institutional study
– Unclear sub-group analysis
The Neostigmine Analysis
Received
neostigmine
18, 579 received
neuromuscular
blocking agent
37,158 patients in
matched cohorts
18,579 did not
receive agent
Did not receive
neostigmine
Received
neostigmine?
Did not receive
neostigmine
16,041
21,117
Neostigmine administration
Table 1: 20,351 Patients
?
Table 4: 16,041 Patients
Table 2: 11,737 Patients
Observational studies do not allow for
randomization. Does this add a significant
degree of confounding to this study? If so, to
what extent does this decrease the validity of the
results?
– A – No.
– B – Yes, but not to a degree that
I would discount its results.
– C – Yes, and its results are
therefore not valid.
0%
0%
0%
Among patients who receive nondepolarizing muscle blockade, in what
percentage do you use reversal?
– A – 100%
– B – 75 – 99%
– C – 50 – 74%
– D – <50%
0%
0%
0%
0%
How does train-of-four and clinical exam
influence your decision to give reversal?
– A – Everybody gets reversal regardless of
number of twitches.
– B – I wait until at least 1 twitch is present to
reverse.
– C – I wait until at least 2-3 twitches are
present to reverse.
– D – I wait until all 4 twitches are present to
reverse.
– E – Reversal can be skipped if patient
demonstrates adequate tidal volume, head
lift, etc.
0%
0%
0%
0%
0%
What form of neuromuscular
transmission monitoring do you
use and how often?
–A – Qualitative
–B – Quantitative
–C - Neither
0%
0%
0%
Do the respiratory complications associated with
intermediate acting non-depolarizing muscle
relaxants outweigh the benefits of these drugs?
– A – The benefits outweigh the risks.
– B – The risks/benefits are roughly
equal.
– C – The risks outweigh the benefits.
– D – It doesn’t matter. Surgeons
demand muscle relaxation.
– E – Depends on the patient
0%
0%
0%
0%
0%
Would you consider
succinylcholine infusion as an
alternative to intermediate acting
non-depolarizing muscle relaxants
and neostigmine (like these guys)?
"Use of Succinylcholine Infusion for a
Laparoscopic Sigmoid Colectomy Due
to a Shortage of Neostigmine"
– A – Yes
– B – No, those guys are crazy.
– C – Maybe, but only at the VA.
0%
0%
0%
Neuromuscular Block, Monitoring and
Reversal
December 2012
Susan Woelfel MD
Barbara Brandom MD
Residual Paralysis is Common : TOF < 0.9
• Long-acting NMBA 21-54%
• Intermediate-acting NMBA 19-42%
• Single intubating dose 44-57%
Single Intubating Dose of NMBA
Debaene et al 2003
N
TOF<0.7 TOF<0.9
On arrival 526
In PAR
16%
45%
2 hr later 239
10%
37%
Time at RISK
TOF ratio > 0.4 fade can NOT be
detected by palpation
TOF > 0.7 is associated with normal
minute ventilation
TOF > 0.9 is associated with normal
upper airway function
Significant Signs and Symptoms TOF ratio
of 0.70-0.75
•
•
•
•
•
•
Double vision, fatigue
Decreased hand-grip strength
“Tongue depressor test” negative
Inability to sit up without assistance
Severe facial weakness
Speaking a major effort
»Anesthesiology: April 1997
Patients With
Post-operative Residual Block :
• Increased risk of hypoxemia
• Decreased chemoreceptor sensitivity to
hypoxemia
• Decreased esophageal sphincter tone
• Increase in pulmonary complications
Rate of Pulmonary Complications
N=691
TOF<0.7*
Atracurium
Vecuronium
Pancuronium
5.3%
26%
Pulmonary
4.2% vs
complications 5.4%
16% vs
4.8%*
Berg, et al. Acta Anaesth Scand 1997; 41: 1095
Time at RISK
TOF < 0.9
Eriksson, et al. Anesthesiology 1997; 87: 1035
Clinical Tests of NM Recovery Unreliable
•
•
•
•
•
•
Sustained eye opening
Protrusion of the tongue
Arm lift to opposite shoulder
Tidal volume 5 ml/kg
Vital capacity 20 ml/kg
Max inspiratory force <40-50 cm H2O
1
10
25
Meistelman, et al. Anesthesiology 1988; 69: 97
Monitor your Patient !