Kate Leslie, MBBS, MD, MEpi, FANZCA,* Paul S. Myles, MBBS, MD, MPH, FANZCA, FCARSCI, FRCA,†Matthew T. 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**

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.

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.

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.

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.

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).

 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.

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.

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).

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).

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.

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.

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.

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.

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.

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

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).

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.

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.

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.

Present day surgical robotic systems

3 main types of surgical robots available: Supervisory-controlled Robotic Surgery Systems ROBODOC® system from CUREXO Technology

Corporationmost 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.

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.

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.

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.

Robot Assisted Surgeries

Anaesthetic ConsiderationsGeneral 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.

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.

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.

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.

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.

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.

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.

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.

(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.

(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.

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.