Closed Loop Anaesthesia Delivery System (CLADS)

- Anaesthesia Robot

Prof. G. D. Puri

Keywords: Anaesthesia, closed loop anaesthesia, propofol, EEG, BIS

Anaesthesia practice in operating room primarily involves giving anaesthetics drugs to

patients to produce unconsciousness and ensuring safe surgery without any untoward incidence.
Some of these processes and procedures are fixed and predetermined and some are based on the
patients’ response to the interventions like altering anaesthetic drug infusions or inhaled
concentrations, giving drugs and infusions to maintain hemodynamic etc. The processes which are
repetitive and require constant attention of the anaesthetist are always prone for human errors.
Putting an intravenous line, checking the machine and equipment, monitoring, giving anaesthetic
drugs, titrating the drugs, securing an airway, maintaining the respiration and hemodynamic and
giving intravenous fluids and blood products, keeping an eye on the surgical field and monitors,
altering the dosages of potent drugs based on patients’ requirement and responses, are some of the
activities which an anaesthesiologist is supposed to be doing routinely day in and day out while
anaesthetizing the patients. Though the incidences of errors in these may be low, the risk involved is
high. This has been shown and proven number of time in different industries and is the reason
automation has been adopted as safety measures in these industries. One such example is airline
industry. Induction, maintenance as well as recovery from anaesthesia can be compared to take off,
flying and landing of the aero plane. In view of this there is need to automate some of the
processes related to anaesthesia so that the human error can be minimized, distractions from
routine repetitive activities can be minimized and anaesthetist can have more time for direct patient
care. The Department of Anaesthesia and Intensive Care at Post Graduate Institute of Medical
Education and Research Chandigarh has made great strides in developing automated anaesthesia
system that is predicted to be the future of standard anaesthesia care.

Figure 1 Complex operating room environment and its interaction with human physiology

With the development of computers attempts at automating the delivery of anaesthetics and
related drugs were made using the apparent relationship between the depth of anaesthesia and
changes in the EEG to control the delivery of intravenous anaesthetic drugs. Investigators have
used simple electronic circuits with analog systems for data acquisition and conversions to
mechanical outputs for the delivery of a drug. With the advances in microprocessor technology and
miniaturisation of electronic sensors the EEG signals picked from the head of the patients can be
used for development of objective parameters of measurements of depth of anaesthesia. As
anaesthetic requirement variability requires the titration of drugs based on patient’s response, these
objective anaesthetic depth monitors have hugely opened the possibility of automation of
anaesthetic delivery based on these parameters and probability of closing the loop of this drug
delivery has increased recently.
Automated drug delivery consists of computer programs designed to maintain a targeted
effect by adapting/ varying the administered amounts of drug based on the feedback of effect of the
drugs on the specific body functions which it has been given to alter. A closed-loop system is the
ideal means of automated drug delivery.

Measures level of output

Fig 2 Broad framework of Closed loop systems in the clinical medicine

A closed-loop system senses the level of output, feedbacks this information, compares it to
a set point that defines the desired output level and uses the difference to push the output towards
the set point. Such systems are referred to as feedback control systems. Because of more frequent
sampling of the control variable and more frequent changes to the rate of drug delivery than with
manually delivered anaesthesia, the stability of the control variable may be greater. At the same
time, the dose delivered is customized to meet the exact requirements of each patient, thereby
overcoming the problems of inter-individual differences and differing levels of surgical stimulation.
The advantage of closed-loop anaesthesia delivery system is that the control is continuous and
responsive that may improve the quality of care as compared with intermittent control practiced
routinely. Recovery times and the risk of inadvertent awareness may thereby be decreased. The
advantages of closed loop systems are more apparent in complex situations like open heart surgery
where not only a large number of drugs are being administered simultaneously but their
requirements also change on a minute to minute basis.

The pharmacodynamic feedback guided automated anaesthesia delivery systems, also

known as closed loop systems, have been shown to outperform the traditional manual drug delivery
of anaesthetic agents1,2. Such pharmacodynamic feedback to control anaesthesia may be superior
in situations of altered pharmacokinetics such as those encountered during cardiopulmonary bypass
(CPB) and hypothermia. CLADS(Closed Loop Anaesthesia Delivery System) is a BIS guided closed
loop anaesthesia delivery system developed at PGIMER, Chandigarh and has been used
successfully for administration of propofol, an intravenous anaesthetic, in various situations, like
non-cardiac surgery3, cardiac surgery4, post-operative sedation5 and high altitude6. CLADS had the
uniqueness of using simple syringe pumps to control the intravenous anaesthetic drug delivery and
for the first time using closed loop administration of anaesthetics both for induction as well as
maintenance of anaesthesia. It has been in use since last more than 10 years and has been used
on more than 6000 patients including patients with cardiac, liver and renal dysfunctions both for
cardiac surgery as well as non cardiac surgery and its usefulness and safety has been well proved
in different groups of surgical patients. During last 10 years the system has been continuously
refined and upgraded to incorporate a number of safety features including hemodynamic control as
well as user friendly options of using both intravenously as well as inhalational anaesthetic agents
depending upon user’s choice and interchange of these anaesthetic agents during active
anaesthesia. IAADS (Improved Anaesthetic Agent Delivery System), an improved version of CLADS
with a number of safety features of hemodynamic control and which can administer isoflurane 7 and
muscle relaxants besides propofol in adults and children not only encompasses the induction and
maintenance of intravenous anaesthesia but also controls the muscle relaxant delivery based on the
feedback from neuromuscular junction monitoring and analgesic delivery based on the preset rate
of delivery along with as and when required based on the hemodynamic and EEG responses. The
ultimate goal for closed-loop controllers is their general acceptance in clinical practice for which
multicenter study has been completed successfully.

Fig 3 Line diagram of CLADS / IAADS showing interfacing of different monitors and drug infusing
syringe pumps with algorithm in the computer to control the drug infusions based on the feedback
from the patient monitors.

CLADS / IAADS system can operate in various modes. In “monitor” mode, it requests an
update of the latest BIS and other vital sign data at user-defined intervals, provides a graphic display
of current and trend values and records them on the hard disc of the computer (PC). In “manual”
mode, the user can also control the propofol infusion rate manually, using the keyboard / mouse /
screen of the PC. The PC displays a graph of the propofol delivery rate and trends the BIS and
other vital signs values. When the system is in “automatic” mode, in addition to the functions already
described, it also automatically controls the anaesthetic agent, muscle relaxant and narcotic
infusion, according to mode selected as induction, maintenance or induction and maintenance
combined. User need to enter a target BIS value, maximum allowable anaesthetic infusion rate, a
starting infusion rate in case of maintenance mode and status of the patients- Low Risk (ASA I-III),
High Risk (ASA IV, NYHA class 3), Very high risk (ASA IV-V, NYHA IV), Children.

The ‘control algorithm’ is based on the relationship between various rates of propofol
infusion (producing different plasma concentrations) and BIS, taking into consideration the
pharmacokinetic variables (distribution and clearance) that were established in the developmental
stage of CLADS. The system also incorporates an algorithm for children, which takes into account
the alteration in pharmacokinetics, mainly change in the distribution compartment and clearance
(age-wise) of anaesthetic drugs in them. This allows the system to be used for induction and
maintenance of anaesthesia in paediatric patients. The system also notifies the anaesthesiologist
deviations in blood pressure, heart rate or changes in the end tidal CO 2 concentration. The system
stops administering agents automatically if there is deterioration in vital parameters beyond the
limits set by the anaesthesiologist. It uses voice clips in addition to visual display to notify the
anaesthesiologist deviations in vital parameters, cut-off of anaesthetic agents, high EMG activity, etc
and also provides possible suggestions, such as, “give atropine”, “give muscle relaxant”, “start
inotropes”, etc. for managing haemodynamic disturbances.
 Check Validity of Valid BIS Error (PB-TB) Yes Set new Propofol
BIS using SQI >+5 or <-5 infusion rate

Invalid No

See previous BIS trends

BIS Safe and accordingly ↑ or ↓ the
collect Mode propofol infusion rate

Wait for effect site delay

Fig 3 Basic algorithm of ‘CLADS’. Signal quality index is checked before accepting the BIS numbers as valid for
taking action on these. Effect site delay is based on the time needed for the Propofol to produce effect on BIS. PB
= present or current BIS at any given time point, TB = target BIS set by the user, BIS error is the difference between
the PB and TB.

Fig 4 Broad algorithm of CLADS for inhalational anaesthetic delivery. CV = circuit volume; DOA =
duration of anaesthesia; FRC = functional residual capacity; HT = height; IAA – Inhalational
anaesthetic uptake; PB = present BIS; PC = present concentration; ROTCA = rapidity of target
concentrations achievement; RB = Target BIS; TC = target concentration; WT = weight of patient.
Fig 5 Screen shot of CLADS showing different monitored variables as well as controlled variables
like BIS trends

The success of the system to administer propofol4 and isoflurane7 anaesthesia has been
demonstrated in both adults and children and both cardiac and non cardiac surgery. CLADS as well
as IAADS are able to achieve induction in all patients without major hemodynamic instability and
within acceptable period of time. The induction dose needed and the BIS overshoot during induction
are both significantly less while using closed loop systems of anaesthesia. This is because of more
frequent and smaller dose adjustments made by CLADS/ IAADS based on more frequent feedback
updates of BIS data from the patient. Absence of any major hemodynamic fluctuations in the
patients during induction is explained by finer tuning of propofol dose by IAADS and automatic cut-
off of propofol delivery in the event of a major drop in hemodynamic. Following a smooth induction,
the CLADS/ IAADS is able to maintain clinically adequate anaesthesia in all the patients during the
period of automatic control.

CPB and hypothermia alters the pharmacokinetics and pharmacodynamics of propofol

8,9 10
unpredictably . Moreover, propofol pharmacokinetics differs in children from that in adults .
Therefore, controlling the pharmacodynamic effect of propofol may be superior to target-controlled
infusions based on serum or effect-site concentrations. Various investigators have demonstrated
good correlation between predicted plasma propofol concentration and BIS in children11-13. Since
BIS is the controlled parameter in our system, the variations in pharmacokinetics that affect propofol
requirements during CPB may be overcome in this pharmacodynamic based closed loop control.
CLADS / IAADS has been successfully evaluated even in open heart surgery for children14.

Hemodynamic stability is better maintained using IAADS than manual control- which is very
much desired in open heart surgery. This may probably be because the anaesthesiologist often gets
distracted from the accuracy of anaesthetic delivery for want of paying attention to other aspects of
anaesthetic management like coagulation/blood gas monitoring/ventilation, etc. This may have led
to a late detection of increased propofol delivery rate and subsequent adjustments of hemodynamic.
Also, the frequent dose adjustments that were required in the manual group to obtain good stability
of anaesthetic depth involved substantial involvement of anaesthesia human resources. Use of
IAADS could enable the anaesthesiologist to pay attention to other aspects of anaesthesia, e.g,
hemodynamic control, performance of trans-esophageal echocardiography, etc.

Cost effectiveness is an important measure of efficiency in assessment of quality of health

care services provided these days. Closed loop anaesthesia system CLADS / IAADS use
significantly lesser amounts of propofol during induction and maintenance and also conserves
isoflurane during inhalational anaesthesia delivery for maintenance of anaesthetic depth as
compared to the manual control7. This was achieved because of the frequent alterations done by the
IAADS to maintain the optimal depth of anaesthesia judged by BIS and thus avoiding either very
deep or light planes of anaesthesia. Although the difference in consumption of anaesthetic agent
 appears small, the cumulative difference if used for long duration surgeries and multiple surgeries
can result in cost effective anaesthetic administration. Moreover, the number of times isoflurane dial
settings were changed manually translates to an involvement of anaesthesia human resource in
maintaining appropriate depth of anaesthesia. Use of CLADS and IAADS has also better
hemodynamic stability in critically ill cardiac surgery patients.

In conclusion closed loop systems have an important role in the future clinical management
during anaesthesia and CLADS as an indigenous system of automated anaesthesia has a great
potential.

References

1. Struys MM, De Smet T, Versichelen LF. Comparison of closedloop controlled administration of propofol
using Bispectral Index as the controlled variable versus ‘‘standard practice’’ controlled administration.
Anaesthesiology 2001; 95: 6–17.
2. Liu N, Chazot T, Genty A, Landais A, Restoux A, McGee C, Laloe PA, Trillat B, Barvois L, Fischler M.
Titration of propofol for anesthetic induction and maintenance guided by the Bispectral Index: closed-loop
versus manual control – a prospective, randomized, multicenter study. Anesthesiology 2006; 104: 686–95.
3. Puri G D, Kumar B, Aveek J. Closed-loop anaesthesia delivery system (CLADS™) using bispectral index: a
performance assessment study. Anaesthesia and Intensive Care 2007; 35: 357-367.
4. Agarwal J, Puri G D, Mathew P J. Comparison of closed loop vs manual administration of propofol using the
bispectral index in cardiac surgery. Acta Anaesthesiologica Scandinavica 2009; 53: 390-397.

5. Solanki A, Puri G D, Mathew P J. Bispectral index controlled post operative sedation in cardiac surgery
patients: A comparative trial between closed loop and manual administration of propofol. Eur J Anaesthesiol
2010; 27(8): 708-713.

6. Puri Goverdhan D, Jayant Aveek, Dorje Motup, Tashi Motup. Performance of Closed Loop Anaesthesia
Delivery System in high altitude. Indian Journal of Anaesthesia 2012; 56(3): 238-242.
7. Madhavan JS, Puri G D, Mathew PJ. Closed-loop isoflurane administration with bispectral index in open
heart surgery: Randomized controlled trial with manual control.
Acta Anaesthesiol Taiwan 2011; 49(4):130-5.

8. Hynynen M, Hammaren E, Rosenberg PH. Propofol sequestration within the extracorporeal circuit. Can J
Anaesth 1994; 41: 583–8.

9. Massey NJA, Sherry KM, Oldroyd S, Peacock JE. Pharmacokinetics of an infusion of propofol during cardiac
surgery. Br J Anaesth 1990; 65: 475–9.

10. McFarlan CS, Anderson BJ, Short TG. The use of propofol infusions in paediatric anaesthesia: a practical
guide. Pediatric Anesthesia 1999; 9: 209-216.

11. Jeleazcov C, Schmidt J, Schmitz B, Becke K, Albrecht S. EEG variables as measures of arousal during
propofol anaesthesia for general surgery in children: rational selection and age dependence. Br J Anaesth
2007. 99(6): 845-54.

12. Riqouzzo A et al. The relationship between bispectral index and propofol during target-controlled infusion
anesthesia: a comparative study between children and young adults. Anesth Analg 2008; 106(4): 1109-16.

13. Munoz HR, Cortinez LI, Ibacache ME, Leon PJ. Effect site concentrations of propofol producing hypnosis in
children and adults: comparison using the bispectral index. Acta Anaesthesiol Scand 2006; 50(7): 882-7.

14. Biswas I, Mathew PJ, Singh RS, Puri GD Evaluation of closed-loop anesthesia delivery for propofol
anesthesia in pediatric cardiac surgery.. Paediatr Anaesth. 2013 Dec;23(12):1145-52
- Presentation Title Closed Loop Anaesthesia Delivery System (CLADS) Anaesthesia Robot

• Author’s Name. Prof G D Puri

• Author’s biography (200 words) ; already sent

• Author’s postal and email address

Prof Incharge Cardiac Anaesthesia,

Department of Anaesthesia & Intensive Care
Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
gdpuri007@hotmail.com

Abstract
With the advancement in microprocessor technology and development of objective anaesthesia
depth indicators, the use of automated anaesthesia deliver system using feedback from different
EEG derived parameters has become a reality. The anaesthetic drugs can be delivered based on
patients’ individual requirement using computer controlled syringe infusion pumps. CLADS is an
indigenously developed closed loop anaesthesia delivery system which can control delivery of both
intravenous as well as inhalational anaesthetics depending upon patient requirement with
continuous feedback from the patient. The system has been developed at PGIMER Chandigarh and
is in use for last more than 10 years and its performance has been successfully evaluated in
patients undergoing both cardiac as well as non-cardiac surgery in adult as well as paediatric
patients. It can control neuromuscular blocking agents in addition to anaesthetics as well as
analgesic drugs. With this automated anaesthesia has become a reality with optimum anaesthetic
drug control and improved hemodynamic stability intraoperatively.