Compared with manual control, automated systems increased the percentage of time a given variable was maintained in a desired range by 21.2% (95% CI, 11.5%−30.9%; I 2 = 0.96, P = 0.001 as shown in Figure 4). In all studies, the length of time was longer in the automated control group. This difference reached statistical significance in 6 trials.22,29,32,43,44,46 All articles provided data corresponding to the secondary outcome of this review. In 3 articles,22,42,44 the authors found a statistically significant reduction of episodes of hypoglycemia in the automated group. In the remaining articles, even if not statistically significant, the number of episodes of hypoglycemia or hyperglycemia was higher in the control groups. Performing subgroup analyses, we observed that automated systems decreased the percentage of time of inadequate control (below or above the target range) of BG compared with the manual group by −6.5 % (95% CI, −11.3% to −1.8%, I 2 = 0.92, P = 0.010; Figure 5).
Compared with manual control, automated systems increased the number of measurements that were within the target range (odds ratio, 1.44; 95% CI, 1.04–2.0; I 2 = 0.77, P < 0.0001). The number of patients with 1 or more episodes of hypotension or hypertension was similar between the manual and automated group in 1 trial.34 In the other trial,49 the number of patients with hypotension was significantly higher in the manual group (P = 0.001).
In this systematic review and meta-analysis of randomized clinical trials, we evaluated the accuracy and safety of closed-loop systems compared with manual control. Automated systems increased the length of time that a given variable was maintained in the desired range compared with manual control. This difference reached statistical significance in the majority of trials (28 of 36). This likely suggests that automated systems can obtain a better control of depth of anesthesia, BG level, and ventilation. Because of the limited number of studies gathered, no conclusion could be drawn concerning automated systems for vasopressor administration and for insulin infusion in ICU patients. The incidence of overshooting or undershooting a given control target was reduced during automated control or was at least similar between the groups in all trials reporting this outcome (29 of 36).
To assess the clinical significance of the control aspect of closed-loop systems, we can deduct from this meta-analysis that there is a significant improvement in the percentage of time of “desired” control (parameter in the predefined range of target control). Interestingly, this improvement ranged from 12% for the maintenance of specific ventilation parameters (Figure 6), to 17% for maintenance of a target level of anesthesia (Figure 2) and to 21% of maintenance of a target level of BG level in patients with diabetes mellitus (Figure 4). As an example, for 1-hour duration of anesthesia, the targeted level of anesthesia would be maintained for 10 minutes longer than with manual control: these authors would regard this as a significant clinical advantage.
We chose undershooting or overshooting as a parameter of safety assessment: for example, we would consider undershooting a given BIS target as putting the patients at risk of either waking up or having periods of awareness. The improvement ranged from 7% for avoidance of overshooting or undershooting parameters of ventilation and avoidance of either hypoglycemia or hyperglycemia (Figure 5) to 12% for avoidance of undershooting or overshooting a given level of anesthesia. If one considers that undershooting a given level of anesthesia, too light a level of hypnosis, puts the patient at risk of awareness, whereas overshooting might be related to worse outcome, 5 to 6 minutes less time during 1 hour of anesthesia of exposure to these risks is a significant clinical improvement of closed-loop systems compared with manually administered anesthesia.
There are several limitations to our review. First, we decided to perform a review and meta-analysis focusing on the comparison between automated systems and manual control in different medical fields. As a consequence, we analyzed different kinds of closed-loop systems. We cannot draw any conclusion about the superiority of one technological system compared with another. A second limitation was the limited number of studies retrieved for automated insulin delivery in ICU patients and closed-loop systems for vasopressor administration. Third, the overwhelming majority of trials qualified for an intermediate quality score. Only 1 study49 reported a proper blinding procedure. Another limitation was the high heterogeneity of the studies. This marked heterogeneity can be explained by multiple factors. We included trials that investigated both pediatric and adult patients. Moreover, regarding closed loop for insulin administration, the desired target range for the BG concentration varied widely within the studies (as shown in Table 1). The high heterogeneity likely reflects the different durations of the observational period selected by the authors (eg, 36 hours,29 6 weeks44). The choice of comparing differently designed and engineered automated systems might have increased the heterogeneity.
Another limitation of the review is related to the type of studies published: no studies focused on the influence of closed-loop systems on patient outcome such as reduced length of stay, reduced morbidity, or mortality.
In summary, automated systems increased the length of time that a given variable was maintained in the desired range compared with manual control. The incidence of overshooting or undershooting a given control target was reduced during automated control or was at least similar between the groups in all trials reporting this outcome.
1. Schwilden H, Schüttler J, Stoeckel H. Closed-loop feedback control of methohexital anesthesia by quantitative EEG analysis in humans. Anesthesiology 1987;67:341–7.
2. Schwilden H, Stoeckel H, Schüttler J. Closed-loop feedback control of propofol anaesthesia by quantitative EEG analysis in humans. Br J Anaesth 1989;62:290–6.
3. Puri GD, Kumar B, Aveek J. Closed-loop anaesthesia delivery system (CLADS) using bispectral index: a performance assessment study. Anaesth Intensive Care 2007;35:357–62.
4. Kenny GN, Mantzaridis H. Closed-loop control of propofol anaesthesia. Br J Anaesth 1999;83:223–8.
5. Mortier E, Struys M, De Smet T, Versichelen L, Rolly G. Closed-loop controlled administration of propofol using bispectral analysis. Anaesthesia 1998;53:749–54.
6. Liu N, Chazot T, Trillat B, Pirracchio R, Law-Koune JD, Barvais L, Fischler M. Feasibility of closed-loop titration of propofol guided by the Bispectral Index for general anaesthesia induction: a prospective randomized study. Eur J Anaesthesiol 2006;23:465–9.
7. Simanski O, Janda M, Schubert A, Bajorat J, Hofmockel R, Lampe B. Progress of automatic drug delivery in anaesthesia-the ‘Rostock assistant system for anaesthesia control (RAN)’. Int J Adapt Contr Signal Process 2009;23:504–21.
8. Hemmerling TM, Arbeid E, Wehbe M, Cyr S, Taddei R, Zaouter C. Evaluation of a novel closed-loop total intravenous anaesthesia drug delivery system: a randomized controlled trial. Br J Anaesth 2013;110:1031–9.
9. Hemmerling TM. Automated anesthesia. Curr Opin Anaesthesiol 2009;22:757–63.
10. Dussaussoy C, Peres M, Jaoul V, Liu N, Chazot T, Picquet J, Fischler M, Beydon L. Automated titration of propofol and remifentanil decreases the anesthesiologist’s workload during vascular or thoracic surgery: a randomized prospective study. J Clin Monit Comput 2014;28:35–40.
11. Rose L, Schultz MJ, Cardwell CR, Jouvet P, McAuley DF, Blackwood B. Automated versus non-automated weaning for reducing the duration of mechanical ventilation for critically ill adults and children. Cochrane Database Syst Rev 2014;6:CD009235.
12. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. BMJ 2009;339:b2700.
13. Moher D, Jadad AR, Nichol G, Penman M, Tugwell P, Walsh S. Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists. Control Clin Trials 1995;16:62–73.
14. Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions. 2008Wiley Online Library.
15. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005;5:13.
16. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–58.
17. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60.
18. Ledolter J, Dexter F. Analysis of interventions influencing or reducing patient waiting while stratifying by surgical procedure. Anesth Analg 2011;112:950–7.
19. IntHout J, Ioannidis JP, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med Res Methodol 2014;14:25.
20. Agarwal J, Puri GD, Mathew PJ. Comparison of closed loop vs. manual administration of propofol using the Bispectral index in cardiac surgery. Acta Anaesthesiol Scand 2009;53:390–7.
21. Biswas I, Mathew PJ, Singh RS, Puri GD. Evaluation of closed-loop anesthesia delivery for propofol anesthesia in pediatric cardiac surgery. Paediatr Anaesth 2013;23:1145–52.
22. Breton M, Farret A, Bruttomesso D, Anderson S, Magni L, Patek S, Dalla Man C, Place J, Demartini S, Del Favero S, Toffanin C, Hughes-Karvetski C, Dassau E, Zisser H, Doyle FJ 3rd, De Nicolao G, Avogaro A, Cobelli C, Renard E, Kovatchev B; International Artificial Pancreas Study Group. Fully integrated artificial pancreas in type 1 diabetes: modular closed-loop glucose control maintains near normoglycemia. Diabetes 2012;61:2230–7.
23. Cavalcanti AB, Silva E, Pereira AJ, Caldeira-Filho M, Almeida FP, Westphal GA, Beims R, Fernandes CC, Correa TD, Gouvea MR, Eluf-Neto J. A randomized controlled trial comparing a computer-assisted insulin infusion protocol with a strict and a conventional protocol for glucose control in critically ill patients. J Crit Care 2009;24:371–8.
24. Claure N, Gerhardt T, Everett R, Musante G, Herrera C, Bancalari E. Closed-loop controlled inspired oxygen concentration for mechanically ventilated very low birth weight infants with frequent episodes of hypoxemia. Pediatrics 2001;107:1120–4.
25. Claure N, Bancalari E, D’Ugard C, Nelin L, Stein M, Ramanathan R, Hernandez R, Donn SM, Becker M, Bachman T. Multicenter crossover study of automated control of inspired oxygen in ventilated preterm infants. Pediatrics 2011;127:e76–83.
26. Dauber A, Corcia L, Safer J, Agus MS, Einis S, Steil GM. Closed-loop insulin therapy improves glycemic control in children aged <7 years: a randomized controlled trial. Diabetes Care 2013;36:222–7.
27. De Smet T, Struys MM, Neckebroek MM, Van den Hauwe K, Bonte S, Mortier EP. The accuracy and clinical feasibility of a new bayesian-based closed-loop control system for propofol administration using the bispectral index as a controlled variable. Anesth Analg 2008;107:1200–10.
28. Dojat M, Harf A, Touchard D, Lemaire F, Brochard L. Clinical evaluation of a computer-controlled pressure support mode. Am J Respir Crit Care Med 2000;161:1161–6.
29. Elleri D, Allen JM, Kumareswaran K, Leelarathna L, Nodale M, Caldwell K, Cheng P, Kollman C, Haidar A, Murphy HR, Wilinska ME, Acerini CL, Dunger DB, Hovorka R. Closed-loop basal insulin delivery over 36 hours in adolescents with type 1 diabetes: randomized clinical trial. Diabetes Care 2013;36:838–44.
30. Hallenberger A, Poets CF, Horn W, Seyfang A, Urschitz MS; CLAC Study Group. Closed-loop automatic oxygen control (CLAC) in preterm infants: a randomized controlled trial. Pediatrics 2014;133:e379–85.
31. Hemmerling TM, Charabati S, Zaouter C, Minardi C, Mathieu PA. A randomized controlled trial demonstrates that a novel closed-loop propofol system performs better hypnosis control than manual administration. Can J Anaesth 2010;57:725–35.
32. Hovorka R, Allen JM, Elleri D, Chassin LJ, Harris J, Xing D, Kollman C, Hovorka T, Larsen AM, Nodale M, De Palma A, Wilinska ME, Acerini CL, Dunger DB. Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial. Lancet 2010;375:743–51.
33. Johannigman JA, Branson R, Lecroy D, Beck G. Autonomous control of inspired oxygen concentration during mechanical ventilation of the critically injured trauma patient. J Trauma 2009;66:386–92.
34. Kee N, Khaw KS, Ng FF, Tam YH. Randomized comparison of closed-loop feedback computer-controlled with manual-controlled infusion of phenylephrine for maintaining arterial pressure during spinal anaesthesia for caesarean delivery. Br J Anaesth 2013;110:59–65.
35. Le Guen M, Liu N, Bourgeois E, Chazot T, Sessler DI, Rouby JJ, Fischler M. Automated sedation outperforms manual administration of propofol and remifentanil in critically ill patients with deep sedation: a randomized phase II trial. Intensive Care Med 2013;39:454–62.
36. Leelarathna L, English SW, Thabit H, Caldwell K, Allen JM, Kumareswaran K, Wilinska ME, Nodale M, Mangat J, Evans ML, Burnstein R, Hovorka R. Feasibility of fully automated closed-loop glucose control using continuous subcutaneous glucose measurements in critical illness: a randomized controlled trial. Crit Care 2013;17:R159.
37. Lellouche F, Bouchard PA, Simard S, L’Her E, Wysocki M. Evaluation of fully automated ventilation: a randomized controlled study in post-cardiac surgery patients. Intensive Care Med 2013;39:463–71.
38. Liu N, Chazot T, Genty A, Landais A, Restoux A, McGee K, Laloë PA, Trillat B, Barvais 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.
39. Liu N, Chazot T, Hamada S, Landais A, Boichut N, Dussaussoy C, Trillat B, Beydon L, Samain E, Sessler DI, Fischler M. Closed-loop coadministration of propofol and remifentanil guided by bispectral index: a randomized multicenter study. Anesth Analg 2011;112:546–57.
40. Liu N, Le Guen M, Benabbes-Lambert F, Chazot T, Trillat B, Sessler DI, Fischler M. Feasibility of closed-loop titration of propofol and remifentanil guided by the spectral M-Entropy monitor. Anesthesiology 2012;116:286–95.
41. Locher S, Stadler KS, Boehlen T, Bouillon T, Leibundgut D, Schumacher PM, Wymann R, Zbinden AM. A new closed-loop control system for isoflurane using bispectral index outperforms manual control. Anesthesiology 2004;101:591–602.
42. Ly TT, Breton MD, Keith-Hynes P, De Salvo D, Clinton P, Benassi K, Mize B, Chernavvsky D, Place J, Wilson DM, Kovatchev BP, Buckingham BA. Overnight glucose control with an automated, unified safety system in children and adolescents with type 1 diabetes at diabetes camp. Diabetes Care 2014;37:2310–6.
43. Nimri R, Danne T, Kordonouri O, Atlas E, Bratina N, Biester T, Avbelj M, Miller S, Muller I, Phillip M, Battelino T. The “Glucositter” overnight automated closed loop system for type 1 diabetes: a randomized crossover trial. Pediatr Diabetes 2013;14:159–67.
44. Nimri R, Muller I, Atlas E, Miller S, Fogel A, Bratina N, Kordonouri O, Battelino T, Danne T, Phillip M. MD-Logic overnight control for 6 weeks of home use in patients with type 1 diabetes: randomized crossover trial. Diabetes Care 2014;37:3025–32.
45. Plank J, Blaha J, Cordingley J, Wilinska ME, Chassin LJ, Morgan C, Squire S, Haluzik M, Kremen J, Svacina S, Toller W, Plasnik A, Ellmerer M, Hovorka R, Pieber TR. Multicentric, randomized, controlled trial to evaluate blood glucose control by the model predictive control algorithm versus routine glucose management protocols in intensive care unit patients. Diabetes Care 2006;29:271–6.
46. Renard E, Place J, Cantwell M, Chevassus H, Palerm CC. Closed-loop insulin delivery using a subcutaneous glucose sensor and intraperitoneal insulin delivery: feasibility study testing a new model for the artificial pancreas. Diabetes Care 2010;33:121–7.
47. Schädler D, Engel C, Elke G, Pulletz S, Haake N, Frerichs I, Zick G, Scholz J, Weiler N. Automatic control of pressure support for ventilator weaning in surgical intensive care patients. Am J Respir Crit Care Med 2012;185:637–44.
48. Madhavan JS, Puri GD, Mathew PJ. Closed-loop isoflurane administration with bispectral index in open heart surgery: randomized controlled trial with manual control. Acta Anaesthesiol Taiwan 2011;49:130–5.
49. Sng BL, Tan HS, Sia AT. Closed-loop double-vasopressor automated system vs manual bolus vasopressor to treat hypotension during spinal anaesthesia for caesarean section: a randomised controlled trial. Anaesthesia 2014;69:37–45.
50. Solanki A, Puri GD, Mathew PJ. Bispectral index-controlled postoperative sedation in cardiac surgery patients: a comparative trial between closed loop and manual administration of propofol. Eur J Anaesthesiol 2010;27:708–13.
51. Struys MM, De Smet T, Versichelen LF, Van De Velde S, Van den Broecke R, Mortier EP. Comparison of closed-loop controlled administration of propofol using Bispectral Index as the controlled variable versus “standard practice” controlled administration. Anesthesiology 2001;95:6–17.
52. Urschitz MS, Horn W, Seyfang A, Hallenberger A, Herberts T, Miksch S, Popow C, Müller-Hansen I, Poets CF. Automatic control of the inspired oxygen fraction in preterm infants: a randomized crossover trial. Am J Respir Crit Care Med 2004;170:1095–100.
53. Burns KE, Lellouche F, Nisenbaum R, Lessard MR, Friedrich JO. Automated weaning and SBT systems versus non-automated weaning strategies for weaning time in invasively ventilated critically ill adults. Cochrane Database Syst Rev 2014;9:CD008638.