ENIGMA trial Nitrous oxide, morbidity and mortality in major abdominal surgeries Cardiac morbidity due to Nitrous oxide

1. Kate Leslie, MBBS, MD, MEpi, FANZCA,* Paul S. Myles, MBBS, MD, MPH,
FANZCA, FCARSCI, FRCA,†
MatthewT.V. Chan, MBBS, FANZCA,‡ Andrew Forbes, MSc, PhD,§
Michael J. Paech, MBBS, DM, DRCOG, FRCA, FANZCA, FFPMANZCA,
FRANZCOG (Hon),_
Philip Peyton, MBBS, MD, FANZCA,¶ Brendan S. Silbert, MBBS, FANZCA,#
and Elizabeth Williamson, PhD**

2. BACKGROUND
 plausible pathophysiologic rationale for increased long-term CVS morbidity
& mortality in pts receiving significant exposure to N2O.
 However, not been established clinically.
 ENIGMA trial randomized 2050 patients having noncardiac surgery lasting >2
hrs to N2O–based/N2O–free anesthesia.
 conducted a follow-up study of ENIGMA pts to evaluate the risk of CVS
events in the longer term.
 N2O oxidizes cobalt atom on vitamin B12, inactivating methionine synthase,
causing dose-dependent increase in plasma homocysteine conc for days
after surgery.
 Acutely increased plasma homocysteine conc impair endothelial function,
induce oxidative stress, potentially destabilize coronary artery plaques.
 several studies reported increased incidences of myocardial ischemia within
48 hour & cardiovascular events within 30 days in patients receiving N2O.
 Tested hypothesis that pts exposed to N2O during noncardiac surgery would
be at greater risk of death, MI, and stroke in subsequent years than would pts
whose indexed anesthetic did not include N2O.

3. METHODS
 In ENIGMA trial, 2050 surgical pts aged 18 yrs +
were randomized to 70% N2O in 30% O2 / 80%
O2 in 20% N2.
 In all other respects, perioperative care was at
discretion of anesthesiologists.
 rimary end point was duration of hospital stay.
 Major complications were assessed in hospital
and at a 30-day medical record review and
telephone interview.
 patients consented to blood sampling for plasma
homocysteine and folate assays preoperatively
and on the first postoperative day.

4. Protocol
 ethics committee approval was obtained at each participating
site.
 Pt consent obtained for original study, pts could refuse
participation at time of follow-up
 trial case report forms and medical records of all study patients
were reviewed for the study endpoints.
 date and cause of death or the occurrence of MI or stroke were
recorded.
 followed by a structured telephone interview with all surviving
patients, with verbal consent (about occurrence of MI/stroke
since surgery).
 If pt had died, patient’s relatives/doctors were interviewed, after
verbal consent had been obtained, using the same questionnaire.
 At least 3 attempts were made to contact pts with contact
details.
 If these attempts failed, at least 3 attempts were made to contact
the patients’ relatives, doctors, or both.

5.  primary endpoint of the study was survival - recorded as time to last
confirmed contact with pt /time of death.
 Secondary endpoints were MI & stroke, defined by
(1) a verbal report by the patient or his or her relatives or doctors or
(2) a note in the patient’s medical record.
 MI was defined as a typical increase & decline in cardiac enzymes
(trop or CKMB) with at least one of following:
1. typical ischemic symptoms,
2. new Q-wave or ST-segment ECG changes,
3. coronary intervention,
4. pathologic findings of MI.
 Stroke was defined as new neurologic deficit persisting for 24 hours
or longer, confirmed by assessment by a neurologist or computed
tomography or magnetic resonance imaging.

6. Data Analysis
 following preop & intraop characteristics were
chosen prospectively as predictors in models:
 age, gender, weight, ASA physical status, history of
CAD, anemia, emergency sx, abd sx, propofol
maintenance, volatile anesthetic administration,
N2O use, BIS, duration of anesthesia.
 Median volatile anesthetic concentrations for case
recorded by anaesthesiologist on case report form -
converted to MAC equivalents before analysis.
 Survival rates computed for each category of each
predictor & expressed as deaths/1000 person yrs.
 Univariate Cox proportional hazard models were
used to define hazard ratios and 95% confidence
intervals (CIs).

7.  multivariable Cox proportional hazard models
were constructed as follows:
 preoperative variables (age, gender, wt, ASA,
h/o CAD, anemia, emergency/abd sx) adjusted
for each other.
 N2O, propofol maintenance, BIS monitoring
were adjusted for each other & preop variables.
 Volatile anesthetic administration 0.75 MAC
equivalents (median MAC value in pts receiving
volatile anesthetic maintenance) & duration of
anesthesia were adjusted for each other.
 This approach was taken to minimize bias.

8.  Assessment of proportionality of hazard functions was
performed.
 In many cases, date of MI/stroke imprecise/missing, so
logistic regression used to compute odds ratios & 95% CIs
for MI /stroke during follow-up period.
 preplanned assessment of the interaction of each variable
with N2O performed using interaction terms in the
regression models.
 Used 90th percentile of preop homocysteine conc of pts in
whom it was measured (single measurement/pt) to define
postop hyperhomocysteinemia.
 No further blood sampling undertaken as part of follow-up.
 Data were compared using paired t-tests as appropriate.
 Analyses were conducted using Stata 10.0 (Stata
Corporation, College Station, TX, USA).
 All P values are twosided, and P _ 0.05 was considered
statistically significant.

9. RESULTS
 Recruitment between April 2003 - November 2004
 2012 pts were included in intention-to-treat analysis.
 Long-term follow-up between January 2007 - November
2008, with median follow-up of 3.5 (range: 0 to 5.7) years.
 No attempt made to follow-up 227 pts who survived 30
days due to lack of resources at recruiting centers; 113 pts
who survived 30 days could not be contacted; 2 pts declined
further participation.
 follow-up time of all these pts was recorded as 30 days;
coded as alive, & occurrence of MI/stroke by 30 days was
used in analyses.
 Follow-up data were obtained for 1660 (83%) of study pts.
 380 pts (19%) had died since indexed surgery (12 before 30
days & 368 subsequently).

11.  causes of death were cancer (76%), MI (5%), stroke (1%), other
CVS death (2%), resp failure (1%), sepsis (6%), others (6%),
unknown (3%).
 Interviews therefore were completed in 1290 (65%) pts.
 91 patients (4.5%) were recorded as having MI, 44 patients (2.2%)
recorded as having stroke during entire follow-up period.
 N2O did not increase risk of death (hazard ratio _ 0.98; 95% CI:
0.80 to 1.20; P _ 0.82).
 Increasing age, male gender, abd surgery, propofol maintenance,
MAC equivalents >0.75, longer duration of anesthesia -
significant predictors of death.
 significant interaction between N2O administration & abd
surgery (overall P _ 0.028).
 hazard ratio for death after N2O in abd sx was 1.02 (95% CI: 0.55
to 1.90; P _ 0.95), & in nonabd sx was 0.64 (95% CI: 0.43 to 0.96; P
_ 0.03) (i.e., 36% reduction in risk of mortality among nonabd sx
pts having N2O–free anesthesia, but no effect in abd sx).

12.  adjusted odds ratio for MI in pts receiving N2O was 1.59
(95% CI: 1.01 to 2.51; P _ 0.04) .
 In addition, increasing age, higher ASA , CAD, anemia,
increasing duration of anesthesia were significant
predictors of MI & no significant interactions among
predictors.
 N2O did not increase risk of stroke (odds ratio _ 1.01 (95%
CI: 0.55 to 1.87; P _ 0.97).
 Increasing age was only significant predictor of stroke in
multivariable model that included same predictors used in
survival & MI analyses (results not shown).
 Postop plasma homocysteine & folate conc were
significantly increased in comparison with preop values in
pts who had MI.
 In addition, larger proportion of pts with MI recorded
postop hyperhomocysteinemia.
 no differences found between surviving & deceased pts
with respect to plasma homocysteine & folate conc.

16. DISCUSSION
 N2O was associated with marginal increase in long-term
risk of MI, but not of death/stroke in ENIGMA pts.
 ENIGMA trial recruited relatively unselected pts with low
30-day & long-term event rates, & therefore may have been
underpowered to confidently confirm a “true” increased
risk of MI in patients receiving N2O.
 They are conducting RCT of N2O–based v/s N2O–free
anesthesia in 7000 noncardiac sx pts who have /are at risk of
IHD (ENIGMA–II trial)
 Their long-term follow-up results are consistent with 30-
day incidences of MI (0.5%) & stroke (0.1%) in ENIGMA pts.
 These patients were not selected on basis of CVS risk
factors: only 11% of pts reported h/o CAD, only 4%
reported h/o stroke.

17.  Epidemiological, dietary, and genetic studies
support higher incidences of cardiac events in pts
with hyperhomocysteinemia.
 However, folate supplementation (which normalizes
plasma homocysteine conc)& omission of N2O not
currently convincingly proven to reduce risk of MI.
 N2O may adversely affect outcomes through
mechanisms other than hyperhomocysteinemia.
 This includes immunosuppression, impairment of
RBC production, promotion of pulmonary
atelectasis, need to use low FiO2.
 ENIGMA pts had increased risk of wound infection,
fever, & pul complications during 1st 30 postop days.
 However, follow-up study did not provide any
evidence to support concern that these
consequences of N2O use increase long-term
mortality in noncardiac surgery patients.

18.  administration of lower volatile anesthetic conc to pts who
subsequently died probably reflects presence of serious
comorbidities & intolerance of HD effects of volatile
anesthetics
 potential limitation of ENIGMA trial – FiO2 was not same in
2 gps (30% in N2O–based gp & 80% in N2O–free group).
 study was designed that way because these gaseous
combinations reflected routine practice.
 In addition, design allowed examination of data for an
independent effect of O2, which we did not find.
 Further limitation of follow-up study was that surveillance
for postop MI & stroke was at the discretion of pts’ doctors.
 For these reasons, reported incidences of MI & stroke
likely to be underestimated.
 Finally, they did not collect data on intraop HD treatment
/anesthetic depth, both of which have been implicated in
adverse postop outcomes.

19. CONCLUSIONS
 administration of N2O was associated with
increased long-term risk of myocardial
infarction, but not of death/stroke in pts
enrolled in ENIGMA trial.
 exact relationship between N2O
administration and serious long-term adverse
outcomes will require confirmation by an
appropriately designed large RCT.

20. Prem N Kakar, Jyotirmoy Das, Preeti Mittal Roy, Vijaya Pant
Department of Anesthesiology Pain Management and Perioperative
Care, Fortis Hospital, Shalimar Bagh, New Delhi, India

21.  Robotic device is a powered, computer controlled manipulator
with artificial sensing that can be reprogrammed to move &
position tools to carry out a wide range of tasks.
 Robots and Telemanipulators 1st developed by NASA for use in
space exploration.
 Today's medical robotic systems - US Department of Defence's
desire to decrease war casualties with development of
'telerobotic surgery'.
 ‘Master-slave' telemanipulator concept - developed for medical
use in early 90s where surgeon's (master) manual movements
were transmitted to end-effector (slave) instruments at remote
site.
 Since then, massive transformation and the future is even
brighter.
 The person who bears the brunt of complications or benefit from
a new invention is 'Patient'.
 As anaestheists we should be prepared for screening & selection
of pts in different perspective (keeping in mind long sx hrs,
extreme positioning etc).

22. Development of Surgical Robotics
 Of all wounded soldiers in Vietnam War, 1/3 total deaths were due to
exsanguinating hge that had potential to survive if treated in time.
 In 1985, NASA instituted research program in Telerobotics to develop
technology for US Space program.
 Early developments were confined to fields of nuclear, underwater
and space applications.
 Relevant studies also carried out by German Aerospace Center &
Japanese Space Agency.
 1st documented use of a robot assisted surgical procedure was in 1985
when PUMA 560 robotic surgical arm was used to take neurosurgical
biopsy.
 In 1990, FDA approved Automated Endoscopic System for Optimal
Positioning (AESOP) arm for lap sx to achieve precise & consistent
movements of camera during surgery.
 1st telemanipulative robotic assisted lapchole was performed by
Jacques Himpens & Guy Cardiere in 1997 in Brussels, Belgium.


23. Advantages
 Robots allow unprecedented control
& precision of surgical instruments in
minimally invasive procedures &
microsurgery [e.g. Trans Oral
Robotic Surgery (TORS), natural
orifice transluminal endoscopic
surgery (NOTES), eye operations,
intrauterine fetal surgery].
 Robot can filter surgeon's hand
tremor & scale movements of
instruments.
 Present day Robotic surgical
systems have 7 degrees of freedom
in contrast to lap arm providing only
4 degrees
 Robot motions & tasks are
reproducible, immune to fatigue.

24. Limitations of Robot assisted
surgery
 Concerns about pt safety in event of Robot malfunction is an issue that OT
staff should be aware of.
 Complex inventions which need lot of practice & technical expertise.
 Preparation needs longer OT time compared to conventional surgeries.
 Several pieces of equipment, extremely bulky require large OT space.
 For the anaesthesiologist, invasion of anaesthesia work space & difficulty
in accessing pt intra op.
 staff must be trained & prepared to quickly detach & remove robot in
emergency.
 lack tactile feedback from instruments.
 Surgeons have to rely on visual clues to modulate amount of tension,
pressure applied to tissues to avoid organ damage.
 Latent time - time taken to send an electrical signal from hand motion to
actual visualization of motion on a remote screen. Humans can
compensate for delays of <200 msec. Longer delays compromise surgical
accuracy.

25. Present day surgical robotic
systems
3 main types of surgical robots available:
 Supervisory-controlled Robotic Surgery Systems
ROBODOC® system from CUREXO Technology Corporation
most automated surgical robot available till date. Surgeons
can plan surgery preop in 3-D virtual space & then execute
surgery exactly as planned in OT.
 Shared-control Robotic Surgery Systems:
robots aid surgeons during surgery, but human does most of
work.
 Telesurgical devices:
surgeon directs the motions of the robot. e.g. the da Vinci
Robotic system, the ZEUS Surgical System.

26. The da Vinci system
 product of Intuitive Surgical, falls under category of telesurgical devices.
 On July 11, 2000, FDA approved da Vinci Surgical System for lap
procedures.
3 generations of da Vinci surgical systems have developed so far:
 da Vinci surgical system (1999)
It consists of 3 components: viewing & control console, surgical arm unit
(3/4 arms depending on model) & Optical 3D vision tower
 da Vinci S HD surgical system (2006)
2nd generation surgical robot equipped with wide range of motion of
robotic arms & extended length instruments, interactive video displays
and touch screen monitor.
 da Vinci Si HD surgical system (2009)
dual console capability to support training and collaboration, advanced
3D HD visualization with up to 10× magnification, 'EndoWrist'®
instrumentation with dexterity & range of motion more than human hand
& 'Intuitive®
motion technology', which replicates experience of open
surgery by preserving natural eye-hand-instrument alignment.

28. Operating with a da Vinci surgical
system After positioning pt, surgeon makes 3/4 small incisions
(depending on no. of arms) on pt's body.
 1 port accommodates 2 endoscopic cameras in single rod &
provides stereoscopic image, while other ports dedicated
for surgical instruments for dissection & suturing.
 At console, surgeon actually looks at 2 separate monitors;
each eye sees through independent camera channel -
creates virtual 3D stereoscopic image.
 surgeon uses joystick-like controls located underneath
screen to manipulate instruments.
 Each time surgeon moves joysticks, computer sends an
electronic signal to instruments, moves in sync with
surgeon's hands.
 To work on miniature scale, 'frequency filter' eliminates
hand tremor >6 Hz & 'motion scaling device' scales down
surgeon's hand movements upto ratio of 5:1.

30. The ZEUS surgical system
(Computer Motion Inc)
 ZEUS surgical system made up of surgeon
control console & 3 Table-mounted robotic
arms , which perform surgical tasks and
provide steady visualization using AESOP
technology.
 In 2003, Intuitive Surgical merged with
Computer Motion Inc and the ZEUS system
was phased out gradually in favor of the da
Vinci system.

31. Robot Assisted Surgeries

32. Anaesthetic Considerations
General considerations
A)Patient selection
 depends on clinical judgement & assessment as to
whether pt could withstand a prolonged period in
extreme position.
 h/o significant CVS comorbidity, cerebrovascular
disease, poor pulmonary function, pulmonary
HTN & glaucoma - independent risk factors for
Robot assisted surgeries.

33. B) Intraoperative preparation
 2 wide bore IV cannulae with extension tubings placed to administer
anaesthetic drugs & fluids intraop
 Antisialogouges used in pts requiring extreme patient positioning.
 Monitoring includes ECG, NIBP, SpO2, ET CO 2 , UO.
 UO not a good guide of end organ perfusion in procedures involving
manipulation & dissection of urinary tract.
 CVP catheter in certain procedures with major fluid shifts.
 arterial line for continuous arterial pressure dictated by nature of sx &
preop functional status.
 pt should be well strapped to Table to prevent sliding & trial run of final
position should be done to check for strain on monitoring cables, circuit
& IV tubings.
 imp to record baseline CVP & BP after patient positioning as the
extreme positioning may render single isolated readings (especially of
CVP) inconclusive.
 recommended zero reference level for transducer positioning is Angle of
Louis
 DVT prophylaxis should be followed strictly as per protocol.

34.  assisting surgeon creates pneumoperitoneum & makes ports in
pt's body.
 robotic arms are docked into ports & chief surgeon starts
operating by controlling robotic arms from console which is kept
little away from pt.
 Size & bulk of robot over pt & significant draping on both robot
& pt make it difficult to access intraop.
 Some procedures require pt's airway to be at distance from
anaesthesiologist & machine/monitor.
 more challenging if 1-lung ventilation required, since frequent
use of fiberoptic bronchoscope may be necessary.
 important to have all monitors & safety devices (defibrillator pad,
TEE, left precordial stethoscope in pediatric pts to detect
inadvertent right bronchial intubation) in place before Robot is
docked.
 Careful attention given to prevent robotic arms from injuring pt.
 Cameras & light sources should never be kept directly on drapes
or pt's skin.

35. C) Patient positioning
 steep Trendelenburg with legs apart for prostatectomy
 supine/ slight lateral decubitus (raising one side 15° to 30°) position for
anterior mediastinum pathology
 90° lateral position for hilar mass and lobectomy
 nearly prone position for posterior mediastinal mass.
 difficult to change pt's position once Robot is docked. So, proper patient
positioning should be confirmed beforehand with surgical team.
 highly recommended that anaesthesiologist is well versed with various
patient positions and their implications.
 Proper padding/cushions over pressure points should be used to avoid
tissue and nerve impingement.
 restraints must be used to prevent the risk of anaesthetized patient
sliding off the Table.
 cause endotracheal tube migration into the main stem bronchus.,
therefore before docking Robot, tube position must be confirmed.
 Insignificant changes in cardiac output or stroke volume were noted [31]
in
spite of increase in MAP & SVR.

36.  Cerebral oxygenation was shown to increase slightly provided PaCO 2
was kept within normal limit.
 IOP can increase on an average 13 mm Hg higher than baseline.
Surgical duration and ETCO 2 are significant predictors of IOP increase in
the Trendelenburg position.
 Severe oral ulceration and conjunctival burns may occur from reflux of
stomach acid onto face. As precautionary measure, stomach should be
decompressed by NGT & pts' face kept visible intraoperatively. [28]
D) Anaesthetic technique
 O2-air mixture with inhalational & Fentanyl/Remifentanil infusion for
maintenance of anaesthesia.
 Sevoflurane preferred agent in view of recovery profile & lack of
significant CNS effects.
 However we do recommend placement of an epidural catheter &
epidural infusion for intra & postop pain relief & gut volume reduction.

37.  Epidural test dose and initial bolus should be given well before patient
positioning.
 Continuous uniform depth of muscle relaxation is of prime importance
in avoiding any movements by patient while surgical instruments are in
place and starting an infusion of muscle relaxant is recommended. Fluid
replacement: Initial fluid loading inappropriate in extreme positioning &
surgeries needing urethral anastomoses.
 Suction, made up of a mixture of flush (saline), blood and urine, is not a
reliable measure of blood loss.
 In long operations and when there was evidence of excessive blood loss,
not tallying with the suction, intraoperative haematocrit may give a
rough guide.
 Diuresis: Mannitol 1-2 g/kg or Furosemide can be used. The rationale is
3fold: to promote urine flow to flush out & maintain urinary tract
patency, to conserve renal function, & prophylaxis against cerebral
swelling in extreme Trendelenburg position.
 Cerebral protection: Fluid restriction, maintaining intraoperative ETCO
2 , using minimal insufflation pressures and use of diuretics towards the
end of the procedure are some of the techniques commonly employed
for avoiding cerebral oedema.

38.  Reversal: Cognitive recovery may be delayed because of cerebral
oedema & raised ICT, especially after a long surgery in steep head
down position.
 So, early discontinuation of anaesthetic agents may be necessary as
soon as Robot is withdrawn.
 With more experience and skill and reduced operating time, the
issue of delayed cognitive recovery may be resolved.
 There have been reports of stridor after extubation, following
laryngeal oedema due to prolonged steep Trendelenburg &
overjudicious fluid administration.
 Presence of peri-orbital oedema should alert Anaesthetist of
possibility of concomitant airway oedema.
 Maintenance of airway & prevention of aspiration should be taken
care of.
 Reports of compartment syndrome in the calves after prolonged
lithotomy, necessitating routine checks for calf tightness and
tenderness.

39. Important issues related to
specific surgeries
(A)Cardiac surgery
 Robotic surgery may require unprecedented, prolonged one-lung
ventilation.
 This tests the limits of our knowledge and understanding of one lung
anaesthesia.
 Confirmed placement of left DLT is necessary to allow single left-sided
ventilation required for cardiac exposure.
 DLT is preferred to Bronchial blockers in robot assisted cardiac surgery
because intermittent right lung inflation is necessary for adequate
oxygenation during weaning from Cardiopulmonary Bypass (CPB).
 Moreover, isolation of the right lung may again be necessary to check
for bleeding post CPB.
 Knowledge of TEE is a must in robot assisted surgeries.

40. (B)Thoracic surgery
 principles that apply for thoracoscopic surgery apply for robotic
assisted thoracic surgery.
 combination of pt position, 1 lung anaesthesia, surgical
manipulation alter ventilation and perfusion profoundly.
 Frequently robotic assisted surgeries require insufflation of CO 2
in the chest (CO 2 pneumothorax).
 may lead to an increase in the airway pressures and
haemodynamic instability secondary to decrease venous return
and cardiac compliance.
 rate of CO 2 elimination is difficult to match with the rate of CO 2
absorption and production during one lung anaesthesia as
minute ventilation may already be maximized.
 Iatrogenic injury to the contra lateral pleura can result in occult
blood loss and a tension pneumothorax on the dependent chest.

41. (C)Urological procedures
 principles involved are already described in general
section.
(D)Paediatric surgery
 left-sided precordial stethoscope placed beforehand
monitors for inadvertent rt mainstem intubation.
 Fibreoptic Bronchoscope may be used to verify tube
position.
 In infants, confirming proper ETT positioning with
fluoroscopy may help prevent an airway emergency.

42. Scenerio of Robot Asisted Surgery
in India
 In our country the availability of surgical Robot is limited to only a
couple of centers.
 The costs of the machine as well as the operative cost are the main
deterrents to its popularity.
 Escorts Heart Institute and Research Centre was the first institute in
India to acquire a surgical robot (da Vinci surgical system).
 In India the first robotic urology surgery was performed in April,
2005 and first robotic thoracic surgery (thoracoscopic thymectomy)
in 2008.
 Recently, CARE Foundation in collaboration with Indian Institute of
Information Technology (IIIT) Hyderabad has undertaken the task of
developing indigenous robotic surgical systems.
 It is envisaged that such systems would be required at large numbers
in India in the near future.