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- Published: 28 December 2017
Much of what we now do in Critical Care carries an air of urgency, a pressing need to discover and act, with priorities biased toward a reactive response. However, efficacy often depends not simply upon what we do, but rather on whether, when, and how persistently we intervene. The practice of medicine is based upon diagnosis, integration of multiple sources of information, keen judgment, and appropriate intervention. Timing may not be everything, as the well-known adage suggests, but in the intensive care unit (ICU) timing issues clearly deserve more attention than they are currently given. Successfully or not, the patient is continually attempting to adapt and re-adjust to acute illness, and this adaptive process takes time. Knowing that much of what we do carries potential for unintended harm as well as benefit, the trick is to decide whether the patient is winning or losing the adaptive struggle and whether we can help. Costs of modern ICU care is enormous and the trend line shows no encouraging sign of moderation. To sharpen our effectiveness, reduce hazard, and pare cost we must learn to time our interventions, help the patient adapt, and at times withhold treatment rather than jump in on the impulse to rescue and/or to alter the natural course of disease. Indeed, much of the progress made in our discipline has resulted both from timely intervention when called for and avoidance or moderation of hazardous treatments when not. Time-sensitive ICU therapeutics requires awareness of trends in key parameters, respect for adaptive chronobiology, level-headed evaluation of the need to intervene, and awareness of the costs of disrupting a potentially constructive natural response to illness.
- Stages of illness
Patho-physiology of critical illness continually evolves
• Almost all treatments hold potential for injury to both targeted and untargeted organs.
• Selection of treatment, dose, and duration should ideally be based on awareness of underlying dynamism of evolving pathophysiology.
• Thesis: Well-intentioned treatments often frustrate and delay an appropriate adaptive response.
Almost all treatments that we provide to the critically ill patient hold potential for injury to both targeted and non-targeted organs. Ideally, selection of treatment, dose, and duration should be based on awareness of the underlying dynamics of the evolving pathophysiology. It can be reasonably argued that well-intentioned treatments often frustrate and delay an appropriate adaptive response. Moreover, innate responses of the body to critical illness may themselves be inappropriate. Whereas it is an unassailable fact that homeostatic regulation is indispensable during health and moderate illnesses, the same may not be true in the presence of overwhelming challenge.
In his famous book “The Wisdom of the Body”, Walter B. Cannon outlined the intricate feedback mechanisms which allow and modulate appropriate responses to challenges to homeostasis . He and others called attention to the intricacies of innate biorhythms which during health maintain an exquisite balance. Critical illness and treatments disrupt normal physiology and adaptive mechanisms, and often ignore biorhythms, destabilizing and perhaps invalidating normal physiological controls. Increasing evidence indicates that the body does not remain invariably “wise” during catastrophic illness.
Evolution may not have provided for appropriate responses to severe acute injuries. Until recent decades, such illnesses were not survivable. Indeed, to strengthen the gene pool, evolutionary pressures may have been biased toward ensuring an adverse outcome for susceptible individuals. In other words, evolved responses to life-threatening stresses might not be on side. The exuberant “rogue inflammation” response to a septic challenge provides one good example of how an exaggerated, counterproductive reaction may provoke or promote organ damage .
Key characteristics of health and disease
Loss of adaptive reserve
Timing issues in critical illness
• Stage of disease and recovery
• Intensity of management
• Length of application
• Diurnal physiology
Although the underlying and continuously evolving patterns of injury and response usually take place below the threshold of our clinical recognition, our therapeutic interventions influence the eventual outcome due to poorly timed imposition, maintenance, or withdrawal of treatment. Foremost among those that have received recent attention are excessive sedation and enforced bed rest for prolonged periods . Undoubtedly there are others; in fact, I strongly believe that many of our current practices that encourage monotony (e.g., volume controlled ventilation, sustained drug infusions and feedings) or squelch variation (e.g., unnecessarily rigid targeting of isolated hemodynamic variables such as blood pressure) are counterproductive to long-term adaptive response.
In critical care, imprecise definitions and the impersonal approaches of randomized trials threaten to oversimplify management and encourage neglect of personalized physiologic dynamics. Randomized clinical trials, though often instructive and useful for hypothesis generation, often guide decision-making with answers that are interpreted to be ‘all or none’ categorical directives suitable for encoding into care protocols. Although generally helpful for treating the targeted population at large, at times these approaches may conflict with optimized care for the individual. Following such population-based ‘answers’, many critical care practitioners consider low tidal volumes to be appropriate for everyone , conservative fluid therapy invariably to be superior to liberal administration at all phases of acute respiratory distress syndrome (ARDS) , steroids to be inappropriate for all stages and forms of lung injury , etc. In reality, few practice-altering trials have been designed with deep and detailed understanding of the underlying mechanisms or account for individual variation, complexity, biological variation, and the timing of pathophysiology and treatment effects. Our current management approaches can be viewed as rather inflexible and primarily reactive management when, in fact, improved patient health demands proactive, time sensitive, and flexible strategies. The four Ds of drug, dose, duration, and de-escalation are applicable to many ICU interventions, including fluid therapy, antibiotics, and ventilatory support . When facing a complex and evolving problem, the clinician requires appropriate tools, functional probes, and careful reasoning. The need for midcourse corrections should be anticipated and frequently made in response to monitored observations or relevant variables. These decisions must be rooted in physiological understanding. Sadly, however, that educational foundation and skill set has been seriously eroded by the electronically aided, “look it up” medical management structures in which we now work .
Responsiveness to many interventions for ARDS depends on the stage of illness
• Positive end-expiratory pressure (PEEP)
• Prone positioning
• Neuromuscular blockade
The intensity issue is undoubtedly important but frequently ignored. For example, minute ventilation can be considered an intensity variable that determines whether an identical driving pressure for ventilation may cause injury or be well tolerated. The total power that lung tissue must endure is determined by the frequency of breathing as well as the conformation of the individual tidal cycle [26, 27]. The flow profile of each individual breath determines the rate at which alveolar pressure develops, and experimentally has been shown to be important in minimizing ventilator-induced lung injury [28, 29]. At the bedside, however, the inspiratory to expiratory ratio and inspiratory flow profile are given relatively little attention. Extending the duration of inspiration and ‘squaring’ the inspiratory flow profile have been shown in both small and large animal models to blunt the degree of injury inflicted by the same driving pressure. How fast strain is achieved is especially important when the lung is subjected to high stretching forces. In fact a recent experimental study suggests the driving airway or transpulmonary pressures—both based on static variables of plateau and PEEP—did not predict lung outcome when flow rate was altered through a wide range .
It is interesting to consider the question as to why early short-term muscle relaxants administered for a brief period early in ARDS demonstrated benefit which emerged much later with regard to mortality . It is tempting to speculate that by attenuating the intensity of the initial native response we interrupt a catastrophic early feedback sequence which eventually would result in the patient’s demise. Along a similar vein, early sepsis intervention, though obviously important, sometimes may carry unintended consequences in situations where sudden cell lysis under the influence of antibiotics provokes inflammation and threatens survival . Again, the unchecked exuberance of the body’s innate response may not always be helpful; this idea is given further support by demonstrations that early corticosteroids improve all-cause mortality in community-acquired pneumonia and blunt tendency for treatment failure . In fact, early steroids appear to help stabilize severe pneumonia .
We have also learned harsh lessons regarding the appropriate length of application of our drugs and treatments. After the second phase of stabilization, decisions must be made regarding duration of treatment and the program for weaning support. It has been suggested that the reasons why corticosteroids hastened liberation from mechanical ventilator but failed to improve survival in the ARDS Network trial  are linked to inadequate duration of their use; in other words, steroids were stopped too soon. Perhaps the more common problem, however, is that we apply aggressive treatments for too long. It is clear that sustained steroid and neuromuscular blocking agents will weaken or atrophy muscle, producing ventilator-induced diaphragmatic dysfunction and peripheral muscle weakness that delay recovery [35, 36]. Excessive and long-term use of sedation is strongly suspected of contributing to delirium and sustained cognitive impairment in all age groups after critical illness. A link has been established between duration of delirium and long-term impairment of cognition . Perhaps by using less sedation and fewer opiates we may mitigate this process.
One of the most important timing issues of critical illness concerns our interference with the body’s natural adaptive processes. The normal human body has an incredible capacity to adapt to stress. Endurance athletes have completed more than 50 marathons on consecutive days , high-altitude acclimatization has allowed multiple climbers to ascend Mount Everest without oxygen , and extraordinary adaptation to low temperature has been demonstrated by motivated and gradually trained individuals . However, the capacity for the critically ill to adapt to the stresses of acute and subacute disease has not been extensively or systematically probed. Nevertheless, permissive hypercapnia  and more recently graded permissive hypoxemia  appear to offer well-tolerated alternatives to potentially noxious interventions such as high pressure ventilation and high inspired concentrations of oxygen. It has been argued that we should more aggressively encourage adaptation in the ICU by resetting our targets and gradually but methodically reloading the patient’s systems by graded withdrawal of supports required to sustain life during the initial days . Such retargeting might be directed toward goals for blood pressure, hemoglobin, muscular workloads, and position, as well as blood gases. We know little about the advisability of imposing stress for brief periods in a fashion parallel to that of heat shock exposure. It has been shown, however, that adaptive ischemic preconditioning (intentional “stunning”) reduces infarct size in experimental coronary occlusion . It is been suggested that inter-organ adaptive preconditioning (limb stress helping to condition other organs, for example) might also occur via hormonal or neural reflex pathways .
Were encouraging adaptation to critical illness a viable possibility, there would be a modified two-stage approach to management. The initial rescue phase would minimize demands, providing full support, encouraging gentle transitions and tolerance of monotonous supportive treatments such as continuous infusions and fully controlled mechanical ventilation. In the adaptation phase, there would be intermittent stresses in rest periods, with ongoing targeted reductions of vital supports to acclimatize the patient. These would include FiO2, ventilating pressure, vasopressors, and body position. Variability—not monotony—would be encouraged. Although, “ICU conditioning” is attractive in concept, major questions remain unanswered before such an approach can be advocated. These include: Are injured tissues capable of stress conditioning? Or are they hibernating or to injured to respond? Which variables should we monitor to guide the rate of withdrawal of life-sustaining measures? Can we rely on bedside biomarkers of distress and reserve? Can we automatically program or protocolize the graded withdrawal of support? Which conditioning pattern is optimal?
Most organ systems have some degree of brain-influenced circadian rhythm. The supra-chiasmatic nucleus (SCN), which itself is influenced by light exposure, motion, and other cues, is the master clock that regulates the peripheral clocks of other organ systems and sets the circadian rhythms of temperature, sleep-wake cycles, and metabolic, neuroendocrine, and cardiovascular regulations . Melatonin appears to be central to such connections; its activity affects not only wakefulness but also endocrine function such as growth hormone and cortisol regulation, cardiovascular function in terms of heart rate variability and vascular tone, and immune cell function . Melatonin strongly influences the inflammatory response via the antioxidant cascade, reducing oxidative stress when levels are high. The complexity of such interactions will require considerable additional research in the intensive care setting to determine the importance of maintaining appropriate diurnal biorhythms. Whatever the explanation, however, diurnal variation of inflammatory and oxidative sensitivity to lipopolysaccharide (LPS) has been shown in humans as well as experimental animals . Presentation of LPS to rats at the wrong time of their diurnal cycle predisposes to severe injury or death, whereas animals challenged at the opposite time in the diurnal pattern show much greater tolerance.
The therapies that we apply in the ICU cause circadian dysrhythmias [52, 53]. The deleterious effects of noise, artificial light, stress, medical interventions, sedatives, and anesthetics interact with genetic predisposition to cause asynchrony. Innate response to disease blunts normal biorhythms, but we accentuate these tendencies with sustained relief of gravitational stress-reduced activity, steady infusions of drugs, continuous feedings, monotonous ventilation, social isolation, excessive noise, etc. Although this enforced stability may be needed initially, it likely impedes recovery when sustained. There are likely to be multiple contributors to diurnal biorhythm asynchrony. Critical illness alters the amplitude and variability of neuroendocrine hormones, a phenomenon which may contribute to an observed circadian incidence of cardiac arrhythmia such as ventricular tachycardia in critically ill patients, with a greater incidence during the day and lesser incidence at night. Considerable experimental evidence indicates that circadian disruption predisposes to cardiac arrhythmia  and disorders inflammatory responses . Sleep deprivation, a well-recognized problem in critical care units, may itself blunt immune competence . The role of circadian disruption in the generation of delirium has been recently explored by attempting to intervene by imposing diurnal light amplification . Failure of light therapy alone to influence the incidence of delirium simply underscores that many factors contribute to this problem  and, as has already been mentioned, multiple factors apart from light exposure contribute to diurnal biorhythm patterns. Physical activity, auditory cues, and gravitational stresses may help re-establish appropriate diurnal physiology.
New approaches to time sensitive dynamic physiology
• Precisely match patient to treatment
– Gene arrays
– Big data analytics
– Trending of progress and response
• Track the evolution of the underlying physiology
– Functional monitoring
– Follow trends of integrated variables
– Selective biomarkers
• Modulate intensity
• Optimize duration
A two-stage approach to critical care
• Rescue phase
– Minimize demand and establish stability
– Full support/gentle transitions
– Take control (monotony may be needed)
• Adaptation phase
– Intermittent stresses and rest periods
– Ongoing targeted reductions of vital supports (acclimatize)
– Ventilating pressure
– Encourage variability
None declared by author. Publication of this supplement was supported by Fresenius Kabi.
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About this supplement
This article has been published as part of Critical Care Volume 21 Supplement 3, 2017: Future of Critical Care Medicine (FCCM) 2016. The full contents of the supplement are available online at https://ccforum.biomedcentral.com/articles/supplements/volume-21-supplement-3.
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- Herridge MS, Tansey CM, Matté A, Tomlinson G, Diaz-Granados N, Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, Kudlow P, Cook D, Slutsky AS, Cheung AM. Canadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364(14):1293–304.View ArticlePubMedGoogle Scholar
- Cannon WB. The wisdom of the body. New York: W.W. Norton & Co; 1932.Google Scholar
- Hart WH, Jauch KW. Metabolic self-destruction in critically ill patients: origins, mechanisms and therapeutic principles. Nutrition. 2014;30(3):261–7.View ArticleGoogle Scholar
- Lukewich MK, Rogers RC, Lomax AE. Divergent neuroendocrine responses to localised and systemic inflammation. Semin Immunol. 2014;26(5):402–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Ferrer R, Artigas A. Physiologic parameters as biomarkers: what can we learn from physiologic variables and variation? Crit Care Clin. 2011;27(2):229–40.View ArticlePubMedGoogle Scholar
- Noble EG, Milne KJ, Melling CW. Heat shock proteins and exercise: a primer. Appl Physiol Nutr Metab. 2008;33(5):1050–65.View ArticlePubMedGoogle Scholar
- Ribeiro SP, Rhee K, Tremblay L, Veldhuizen R, Lewis JF, Slutsky AS. Heat stress attenuates ventilator-induced lung dysfunction in an ex vivo rat lung model. Am J Respir Crit Care Med. 2001;163(6):1451–6.View ArticlePubMedGoogle Scholar
- Suzuki S, Hotchkiss JR, Toshimichi T, Olson D, Adams AB, Marini JJ. Effect of core body temperature on ventilator-induced lung injury. Crit Care Med. 2004;32(1):144–9.View ArticlePubMedGoogle Scholar
- Morandi A, Brummel NE, Ely EW. Sedation, delirium and mechanical ventilation: the ‘ABCDE’ approach. Curr Opin Crit Care. 2011;17:43–9.View ArticlePubMedGoogle Scholar
- Marini JJ. Lower tidal volumes for everyone: principle or prescription? Intensive Care Med. 2013;39:3–5.View ArticlePubMedGoogle Scholar
- Maccagnan BA, Besen P, Gobatto AL, Melro LM, Maciel AT, Park M. Fluid and electrolyte overload in critically ill patients: an overview. World J Crit Care Med. 2015;4(2):116–29.View ArticleGoogle Scholar
- Peter JV, John P, Graham PL, Moran JL, George IA, Bersten A. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis. BMJ. 2008;336:1006.View ArticlePubMedPubMed CentralGoogle Scholar
- Malbrain ML, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, et al. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014;46(5):361–80.View ArticlePubMedGoogle Scholar
- Varon J, Marik PE. Clinical information systems and the electronic medical record in the intensive care unit. Curr Opin Crit Care. 2002;8(6):616–24.View ArticlePubMedGoogle Scholar
- Broughton G, Janis JE, Attinger CE. The basic science of wound healing. Plast Reconstr Surg. 2006;117(7 Suppl):12S–34S.View ArticlePubMedGoogle Scholar
- Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, Lemeshow S, Osborn T, Terry KM, Levy MM. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017;376(23):2235–44.View ArticlePubMedGoogle Scholar
- Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010;303:865–73.View ArticlePubMedGoogle Scholar
- Gattinoni L, Taccone P, Carlesso E, Marini JJ. Prone position in acute respiratory distress syndrome. Rationale, indications, and limits. Am J Respir Crit Care Med. 2013;188(11):1286–93.View ArticlePubMedGoogle Scholar
- Suzumura EA, Figueiró M, Normilio-Silva K, Laranjeira L, Oliveira C, Buehler AM, Bugano D, Amato MB, Carvalho CR, Berwanger O, Cavalcanti AB. Effects of alveolar recruitment maneuvers on clinical outcomes in patients with acute respiratory distress syndrome: a systematic review and meta-analysis. Intensive Care Med. 2014;40:1227–40.View ArticlePubMedGoogle Scholar
- Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guérin C, Prat G, Morange S, Roch A. ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107–16.View ArticlePubMedGoogle Scholar
- Sessler CN, Gay PC. Are corticosteroids useful in late-stage acute respiratory distress syndrome? Respir Care. 2010;55(1):43–55.PubMedGoogle Scholar
- Hoste EA, Maitland K, Brudney CS, Mehta R, Vincent JL, Yates D, Kellum JA, Mythen MG, Shaw AD, ADQI XII Investigators Group. Four phases of intravenous fluid therapy: a conceptual model. Br J Anaesth. 2014;113(5):740–7.View ArticlePubMedGoogle Scholar
- Boonen E, Van den Berghe G. Endocrine responses to critical illness: novel insights and therapeutic implications. J Clin Endocrinol Metab. 2014;99(5):1569–82.View ArticlePubMedGoogle Scholar
- Preiser JC, van Zanten AR, Berger MM, Biolo G, Casaer MP, Doig GS, Griffiths RD, Heyland DK, Hiesmayr M, Iapichino G, Laviano A, Pichard C, Singer P, Van den Berghe G, Wernerman J, Wischmeyer P, Vincent JL. Metabolic and nutritional support of critically ill patients: consensus and controversies. Crit Care. 2015;19:35.View ArticlePubMedPubMed CentralGoogle Scholar
- Reintam Blaser A, Starkopf J, Alhazzani W, Berger MM, Casaer MP, Deane AM, et al. Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines. Intensive Care Med. 2017;43(3):380–98.View ArticlePubMedPubMed CentralGoogle Scholar
- Gattinoni L, Tonetti T, Cressoni M, Cadringher P, Herrmann P, Moerer O, Protti A, Gotti M, Chiurazzi C, Carlesso E, Chiumello D, Quintel M. Ventilator-related causes of lung injury: the mechanical power. Intensive Care Med. 2016;42(10):1567–75.View ArticlePubMedGoogle Scholar
- Marini JJ, Jaber S. Dynamic predictors of VILI risk: beyond the driving pressure. Intensive Care Med. 2016;42(10):1597–600.View ArticlePubMedGoogle Scholar
- Rich PB, Reickert CA, Sawada S, Awad SS, Lynch WR, Johnson KJ, Hirschl RB. Effect of rate and inspiratory flow on ventilator-induced lung injury. J Trauma. 2000;49(5):903–11.View ArticlePubMedGoogle Scholar
- Maeda Y, Fujino Y, Uchiyama A, Matsuura N, Mashimo T, Nishimura M. Effects of peak inspiratory flow on development of ventilator-induced lung injury in rabbits. Anesthesiology. 2004;101(3):722–8.View ArticlePubMedGoogle Scholar
- Protti A, Maraffi T, Milesi M, Votta E, Santini A, Pugni P, Andreis DT, Nicosia F, Zannin E, Gatti S, Vaira V, Ferrero S, Gattinoni L. Role of strain rate in the pathogenesis of ventilator-induced lung edema. Crit Care Med. 2016;44(9):e838–45.View ArticlePubMedGoogle Scholar
- Nau R, Eiffert H. Modulation of release of proinflammatory bacterial compounds by antibacterials: potential impact on course of inflammation and outcome in sepsis and meningitis. Clin Microbiol Rev. 2002;15(1):95–110.View ArticlePubMedPubMed CentralGoogle Scholar
- Blum CA, Nigro N, Briel M, Schuetz P, Ullmer E, Suter-Widmer I, Winzeler B, Bingisser R, Elsaesser H, Drozdov D, Arici B, Urwyler SA, Refardt J, Tarr P, Wirz S, Thomann R, Baumgartner C, Duplain H, Burki D, Zimmerli W, Rodondi N, Mueller B, Christ-Crain M. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2015;385:1511–8.View ArticlePubMedGoogle Scholar
- Torres A, Sibila O, Ferrer M, Polverino E, Menendez R, Mensa J, Gabarrús A, Sellarés J, Restrepo MI, Anzueto A, Niederman MS, Agustí C. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA. 2015;313(7):677–86.View ArticlePubMedGoogle Scholar
- Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, Thompson BT, Ancukiewicz M, National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354(16):1671–84.View ArticlePubMedGoogle Scholar
- Petrof BJ, Hussain SN. Ventilator-induced diaphragmatic dysfunction: what have we learned? Curr Opin Crit Care. 2016;22(1):67–72.View ArticlePubMedGoogle Scholar
- Mehta S, Cook D, Devlin JW, Skrobik Y, Meade M, Fergusson D, Herridge M, Steinberg M, Granton J, Ferguson N, Tanios M, Dodek P, Fowler R, Burns K, Jacka M, Olafson K, Mallick R, Reynolds S, Keenan S, Burry L. SLEAP Investigators; Canadian Critical Care Trials Group. Prevalence, risk factors, and outcomes of delirium in mechanically ventilated adults. Crit Care Med. 2015;43(3):557–66.Google Scholar
- Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, Brummel NE, Hughes CG, Vasilevskis EE, Shintani AK, Moons KG, Geevarghese SK, Canonico A, Hopkins RO, Bernard GR, Dittus RS, Ely EW, BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369(14):1306–16.View ArticlePubMedPubMed CentralGoogle Scholar
- Gorney C. On the Road again and again, Runners World. 2006. p. 68–74.Google Scholar
- Bailey DM. The last “oxygenless” ascent of Mt. Everest. Br J Sports Med. 2001;35(5):294–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Castellani JW, Young AJ. Human physiological responses to cold exposure: acute responses and acclimatization to prolonged exposure. Auton Neurosci. 2016;196:63–74.View ArticlePubMedGoogle Scholar
- Marhong J, Fan E. Carbon dioxide in the critically ill: too much or too little of a good thing? Respir Care. 2014;59(10):1597–605.View ArticlePubMedGoogle Scholar
- Martin DS, Grocott MP. Oxygen therapy in critical illness: precise control of arterial oxygenation and permissive hypoxemia. Crit Care Med. 2013;41(2):423–32.View ArticlePubMedGoogle Scholar
- Marini JJ. Too much for too long—wrong targets, wrong timing? Crit Care Med. 2013;41(2):664–5.View ArticlePubMedGoogle Scholar
- Kloner RA, Jennings RB. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2. Circulation. 2001;104(25):3158–67.View ArticlePubMedGoogle Scholar
- Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc Res. 2008;79(3):377–86.View ArticlePubMedGoogle Scholar
- Billings ME, Watson NF. Circadian dysrhythmias in the intensive care unit. Crit Care Clin. 2015;31(3):393–402.View ArticlePubMedGoogle Scholar
- Pavlov VA, Tracey KJ. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat Neurosci. 2017;20(2):156–66.View ArticlePubMedGoogle Scholar
- Blanch L, Villagra A, Sales B, Montanya J, Lucangelo U, Luján M, García-Esquirol O, Chacón E, Estruga A, Oliva JC, Hernández-Abadia A, Albaiceta GM, Fernández-Mondejar E, Fernández R, Lopez-Aguilar J, Villar J, Murias G, Kacmarek RM. Asynchronies during mechanical ventilation are associated with mortality. Intensive Care Med. 2015;41(4):633–41.View ArticlePubMedGoogle Scholar
- Husse J, Eichele G, Oster H. Synchronization of the mammalian circadian timing system: light can control peripheral clocks independently of the SCN clock: alternate routes of entrainment optimize the alignment of the body's circadian clock network with external time. Bioessays. 2015;37(10):1119–28.View ArticlePubMedPubMed CentralGoogle Scholar
- Papaioannou V, Mebazaa A, Plaud B, Legrand M. ‘Chronomics’ in ICU: circadian aspects of immune response and therapeutic perspectives in the critically ill. Intensive Care Med Exp. 2014;2(1):18.View ArticlePubMedPubMed CentralGoogle Scholar
- Castanon-Cervantes O, Wu M, Ehlen JC, Paul K, Gamble KL, Johnson RL, Besing RC, Menaker M, Gewirtz AT, Davidson AJ. Dysregulation of inflammatory responses by chronic circadian disruption. J Immunol. 2010;185(10):5796–805.View ArticlePubMedPubMed CentralGoogle Scholar
- Delle Karth G, Reinelt P, Buberl A, Geppert A, Huelsmann M, Berger R, Heinz G. Circadian variation in ventricular tachycardia and atrial fibrillation in a medical-cardiological ICU. Intensive Care Med. 2003;29(6):963–8.View ArticlePubMedGoogle Scholar
- Brainard J, Gobel M, Bartels K, Scott B, Koeppen M, Eckle T. Circadian rhythms in anesthesia and critical care medicine: potential importance of circadian disruptions. Semin Cardiothorac Vasc Anesth. 2015;19(1):49–60.View ArticlePubMedGoogle Scholar
- McClintick J, Costlow C, Fortner M, White J, Gillin JC. Partial night sleep deprivation reduces natural killer and cellular immune responses in humans. FASEB J. 1996;10(5):643–53.PubMedGoogle Scholar
- Simons KS, Laheij RJ, van den Boogaard M, Moviat MA, Paling AJ, Polderman FN, Rozendaal FW, Salet GA, van der Hoeven JG, Pickkers P, de Jager CP. Dynamic light application therapy to reduce the incidence and duration of delirium in intensive-care patients: a randomised controlled trial. Lancet Respir Med. 2016;4(3):194–202.View ArticlePubMedGoogle Scholar
- Annane D. Light therapy and chronobiology in critical illness. Lancet Respir Med. 2016;4(3):167–8.View ArticlePubMedGoogle Scholar
- Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT, Taichman DB, Dunn JG, Pohlman AS, Kinniry PA, Jackson JC, Canonico AE, Light RW, Shintani AK, Thompson JL, Gordon SM, Hall JB, Dittus RS, Bernard GR, Ely EW. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008;371(9607):126–34.View ArticlePubMedGoogle Scholar
- Mekontso-Dessap A, Roche-Campo F, Kouatchet A, Tomicic V, Beduneau G, Sonneville R, Cabello B, Jaber S, Azoulay E, Castanares-Zapatero D, Devaquet J, Lellouche F, Katsahian S, Brochard L. Natriuretic peptide-driven fluid management during ventilator weaning: a randomized controlled trial. Am J Respir Crit Care Med. 2012;186(12):1256–63.View ArticlePubMedGoogle Scholar
- Marini JJ, Vincent JL, Annane D. Critical care evidence—new directions. JAMA. 2015;313(9):893–4.View ArticlePubMedGoogle Scholar
- Drewry AM, Fuller BM, Bailey TC, Hotchkiss RS. Body temperature patterns as a predictor of hospital-acquired sepsis in afebrile adult intensive care unit patients: a case-control study. Crit Care. 2013;17(5):R200.View ArticlePubMedPubMed CentralGoogle Scholar
- Celi LA, Mark RG, Stone DJ, Montgomery RA. “Big data” in the intensive care unit. Closing the data loop. Am J Respir Crit Care Med. 2013;187(11):1157–60.View ArticlePubMedGoogle Scholar
- Maslove DM, Lamontagne F, Marshall JC, Heyland DK. A path to precision in the ICU. Crit Care. 2017;21(1):79.View ArticlePubMedPubMed CentralGoogle Scholar