Hypothesis: Fever control, a niche for alpha-2 agonists in the setting of septic shock and severe acute respiratory distress syndrome?

Abstract

During severe septic shock and/or severe acute respiratory distress syndrome (ARDS) patients present with a limited cardio-ventilatory reserve (low cardiac output and blood pressure, low mixed venous saturation, increased lactate, low PaO2/FiO2 ratio, etc.), especially when elderly patients or co-morbidities are considered. Rescue therapies (low dose steroids, adding vasopressin to noradrenaline, proning, almitrine, NO, extracorporeal membrane oxygenation, etc.) are complex. Fever, above 38.5-39.5°C, increases both the ventilatory (high respiratory drive: large tidal volume, high respiratory rate) and the metabolic (increased O2 consumption) demands, further limiting the cardio-ventilatory reserve. Some data (case reports, uncontrolled trial, small randomized prospective trials) suggest that control of elevated body temperature ("fever control") leading to normothermia (35.5-37°C) will lower both the ventilatory and metabolic demands: fever control should simplify critical care management when limited cardio-ventilatory reserve is at stake. Usually fever control is generated by a combination of general anesthesia ("analgo-sedation", light total intravenous anesthesia), antipyretics and cooling. However general anesthesia suppresses spontaneous ventilation, making the management more complex. At variance, alpha-2 agonists (clonidine, dexmedetomidine) administered immediately following tracheal intubation and controlled mandatory ventilation, with prior optimization of volemia and atrio-ventricular conduction, will reduce metabolic demand and facilitate normothermia. Furthermore, after a rigorous control of systemic acidosis, alpha-2 agonists will allow for accelerated emergence without delirium, early spontaneous ventilation, improved cardiac output and micro-circulation, lowered vasopressor requirements and inflammation. Rigorous prospective randomized trials are needed in subsets of patients with a high fever and spiraling toward refractory septic shock and/or presenting with severe ARDS.

Keywords: acute respiratory distress syndrome; clonidine; dexmedetomidine; fever control; high PEEP; hyperthermia; hypothermia; septic shock; spontaneous breathing; sympathetic system.

Figure 1.

A niche for normothermia in the critical care setting? Suggested impact of fever control on outcome according to clinical context: obviously fever control is to be restricted to niches (cost of pyrexia>benefit : left part of schema) in which the benefit is superior to the cost for the patient : severe septic shock, severe ARDS, circulatory insufficiency. Abbreviations: ARDS: acute respiratory distress syndrome; CNS: central nervous system. Reused from Doyle, Crit Care, 2016, 20: 303 [7] under Creative Commons attribution license 4.0.

Figure 2.

Raw electromyogram (EMG) from quadriceps femoris muscle. The rat is chronically spinalized to suppress descending control. This will allow one to assess absence or presence of peripherally-evoked tremor. Note the increase in EMG after administration of 5-hydroxy-tryptophan (5HTP) and the reduction after systemic administration of an alpha-2 agonist, clonidine. Phasic bursting persists after clonidine, as observed in another setting [58]. The observation of reduced muscular activity is key to understand reduced VO2 and enlarged cardio-ventilatory reserve, after alpha-2 agonists. Reused from Tremblay, Neuropharmacology, 1986, 25, 41–46 [41] under Elsevier reuse free agreement (Dec, 06, 2017) with thanks.

Figure 3.

Reduced oxygen consumption following administration of an alpha-2 agonist (clonidine (900 μg i.v.) during withdrawal from remifentanil-propofol sedation, while depth of sedation decreased (Ramsay score: from ≈3.5 under remifentanil-propofol to ≈2.2 after clonidine). Abbreviations: VO2: O2 consumption; VCO2: CO2 production; RR: respiratory rate; VE: minute ventilation. Note a) the normalized tachypnea and increased Vt after clonidine relative to pre-interruption of remifentanil-propofol administration b) some patients need very high dose of clonidine (2700 μg, i.e. 1.6 μg.kg-1.h-1) to lower VO2. These very high requirements of alpha-2 agonists fit with similar observation in a minority of patients in which sympathetic activity has been increased for an extended period of time, or in patients presenting with addiction and/or delirium tremens or Gayet-Wernicke (Pichot and Quintin, unpublished data). Reused from Liatsi, Intens Care Med, 2009, 35, 271–81 [45] with paid agreement from Springer (Dec, 7, 2017).

Figure 4.

Effect of seated position on PaO2/FiO2 (P/F) in moderate and severe ARDS. P/F increased from ≈125 to ≈155 in moderate and severe ARDS. Four epochs were studied: supine1, semi-recumbent, seated, supine 2 (not shown). Blue boxes represent moderate & severe ARDS defined as PaO2/FiO2 = P/F<200. Note the statistically significant, and clinically relevant, changes for moderate and severe ARDS when seated is compared to supine. Modified from Dellamonica, Intens Care Med, 2013, 39 : 1121–7 (figure in electronic supplement, panel B) under Springer reuse free agreement (Dec, 7, 2017) with thanks.

Figure 5.

Inflammatory responses in sepsis. Immune responses in sepsis are determined by many factors including pathogen virulence, size of the bacterial inoculum, comorbidities, etc.

Figure 6.

Immune dysregulation in sepsis. New insights into immune dysregulation were achieved using samples from deceased septic patients and severely injured trauma patients. An enduring inflammatory state driven by an upregulated innate and a suppressed adaptative immunity culminates in persistent organ injury and death. Accordingly, 80% of patients presented unresolved septic foci observed during a post mortem study (Torgensen 2009 quoted from [223]. The unabated initial inflammatory process contributes to organ failure and early mortality. This maladative syndrome is improved by newer “analytic” management. However, considering that the vast majority of sepsis survivors are elderly patients with multiple comorbidities, the short-term gain in survival have been merely pushed back by months or years. The widespread consensus is that persistent derangement in innate and adaptive immune systems are the main culprits driving long-term mortality. This raises the question: does normalized sympathetic hyperactivity would in turn normalize a dysfunctional innate immune system? Reused from Delano, J Clin Investigation, 2016, 126, 23–31 [224] under American Society of Clinical Investigation paid agreement (Dec, 6, 2017).

Figure 7.

Dysfonctionnal response following shock or trauma (“reaction oscillante post aggressive”). Modified from Laborit, Therapie, 1951, 6, 207–10 [237] with free permission of Therapie and Societe Française de Pharmacologie et Therapeutique (Dec, 8, 2017) with thanks. Excessive catabolism may lead to prolonged, exaggerated disorders, multiple organ failure and death (“reaction dysharmonique”: dysfunctionnal response. The author [237] questioned the excessive use of sympathomimetic drugs. This led him to use of phenothiazines (“lytic cocktails”: chlorpromazine, promethazine, meperidine) to evoke hypothermia (“artificial hibernation”) [1]. Do alpha-2 agonists represent a tool more specific than phenothiazines to normalize early the sympathetic hyperactivity back to baseline levels?