We appreciate Dr. Mychaskiw's cautioning words regarding possible negative effects of volatile anesthetics for intensive care unit (ICU) sedation. Perhaps they reflect the apprehension that many anesthetists/intensivists feel regarding the growing body of evidence revealing possible injurious effects of sedatives and anesthetics on the central nervous system. Because these medications are indispensable in modern medicine, we seem to be “damned if we do, damned if we don't.” This may be particularly true in our most vulnerable patients: the very young and very old. We hope to further the discussion with some additional reflections here.

The main purpose of our article was to highlight the clinical impact of sedation strategies on patient outcomes.1This specific case using isoflurane illustrates that volatile anesthetics may be a therapeutic option for deep sedation of intubated ICU patients. Although we grant that isoflurane is relatively unproven for this indication, we would tend not to agree with the assertion that “the use of benzodiazepines, narcotics and intravenous hypnotics, like propofol, for ICU sedation is well-established with an acceptable safety profile.” The cited and worrisome recent findings of neurodegenerative and apoptotic effects have been found to apply as well to barbiturates, ketamine, benzodiazepines, and propofol.2–4To our knowledge, only the α-2-agonists have not been found to cause these changes. Dr. Mychaskiw rightly wonders what significance these animal findings bear on clinical medicine, but at least in the pediatric setting Wilder et al.  have revealed in a large cohort that relatively modest exposure to general anesthesia before the age of 4 yr was related to increased risk of learning disability later in life.5Unfortunately, at our current level of knowledge there is nothing to say that risk is lessened by using one class of drug over another or that inhaled anesthetics are more harmful than intravenous.

In fact, increasing evidence points toward additional clinically relevant problems with commonly used sedative drugs. Benzodiazepines, among the most common drugs in our arsenal, contribute to the development of delirium after ICU sedation.6Delirium is associated with increased hospital length of stay and with increased mortality.7Propofol, common in adult ICUs despite the above mentioned concerns, is not recommended for long-term sedation in children or in higher infusion rates for adults because of the risk of propofol infusion syndrome.8Moreover, long-term use of propofol may contribute to withdrawal.9 

Several studies of volatile anesthetics for sedation purposes in humans—with clinically relevant endpoints—have shown promising results. Rapid pulmonary excretion and limited metabolism of all the modern agents are intrinsically attractive characteristics. Wake-up times are shorter and more predictable than with intravenous sedatives, as is time to cooperation.10,11There may be beneficial cardiac effects of volatile anesthetic sedation.12The memory panorama from the ICU stay, an important patient-related outcome,13also appears to be favorable compared with that of midazolam.14 

Simply put, we need more evidence and knowledge about the advantages and risks of the sedative drugs that we use, be they benzodiazepines and propofol or volatile anesthetics. We advocate for additional evaluation of volatile anesthetics as a promising option for long-term sedation in ventilator-dependent ICU patients. In any case, we can not afford to idly administer routine cocktails of sedatives unaware of the risks we may be taking. Every patient deserves a carefully considered sedation strategy.

*Karolinska University Hospital, Stockholm, Sweden. peter.sackey@karolinska.se

Sackey PV, Eriksson LI, Martling CR, Radell PJ: Tailored sedation to the individual needs of the intensive care unit patient. Anesthesiology 2010; 113:1439–46
Jevtovic-Todorovic V, Benshoff N, Olney JW: Ketamine potentiates cerebrocortical damage induced by the common anaesthetic agent nitrous oxide in adult rats. Br J Pharmacol 2000; 130:1692–8
Young C, Jevtovic-Todorovic V, Qin YQ, Tenkova T, Wang H, Labruyere J, Olney JW: Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol 2005; 146:189–97
Bercker S, Bert B, Bittigau P, Felderhoff-Müser U, Bührer C, Ikonomidou C, Weise M, Kaisers UX, Kerner T: Neurodegeneration in newborn rats following propofol and sevoflurane anesthesia. Neurotox Res 2009; 16:140–7
Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO: Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 2009; 110:796–804
Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, Bernard GR, Ely EW: Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 2006; 104:21–6
Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS: Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004; 291:1753–62
Vasile B, Rasulo F, Candiani A, Latronico N: The pathophysiology of propofol infusion syndrome: A simple name for a complex syndrome. Intensive Care Med 2003; 29:1417–25
Liatsi D, Tsapas B, Pampori S, Tsagourias M, Pneumatikos I, Matamis D: Respiratory, metabolic and hemodynamic effects of clonidine in ventilated patients presenting with withdrawal syndrome. Intensive Care Med 2009; 35:275–81
Röhm KD, Wolf MW, Schöllhorn T, Schellhaass A, Boldt J, Piper SN: Short-term sevoflurane sedation using the Anaesthetic Conserving Device after cardiothoracic surgery. Intensive Care Med 2008; 34:1683–9
Meiser A, Sirtl C, Bellgardt M, Lohmann S, Garthoff A, Kaiser J, Hügler P, Laubenthal HJ: Desflurane compared with propofol for postoperative sedation in the intensive care unit. Br J Anaesth 2003; 90:273–80
Hellström J, Öwall A, Bergström J, Sackey PV: Cardiac outcome after sevoflurane versus  propofol sedation following coronary bypass surgery: A pilot study. Acta Anaesthesiol Scand 2011; 55:460–7
Wunsch H, Kress JP: A new era for sedation in ICU patients. JAMA 2009; 301:542–4
Sackey PV, Martling CR, Carlswärd C, Sundin O, Radell PJ: Short- and long-term follow-up of intensive care unit patients after sedation with isoflurane and midazolam: A pilot study. Crit Care Med 2008; 36:801–6