Hypnomidate was widely used due to its hemodynamic properties. However, its metabolic effects (blockade of the 11beta-hydroxylase and adrenal insufficiency) with potential harm in the critically ill patient made its use controversial [3]. A meta-analysis including about 1000 patients concluded that its administration for rapid sequence intubation was associated with higher rates of adrenal insufficiency and mortality in patients with sepsis (RR 1.33; 95% CI 1.22–1.46 and RR 1.20; 95% CI 1.02–1.42, respectively) [4]. However, the conclusion of this meta-analysis has been discussed because of the data heterogeneity.

The metabolic effect of this drug was confirmed. Retrospective study of a large electronic intensive care unit (ICU) database [5] in 2013 shows no difference in ICU and hospital mortality, ICU and hospital length of stay, and vasopressor use and duration of mechanical ventilation. However, more patients in the hypnomidate group received steroids before and after intubation (52.9% vs. 44.5%, p < 0.001). A multicenter, retrospective, propensity-matched cohort study [6] found that the use of hypnomidate for intubation of septic patients did not increase vasopressor requirements within 72 h after intubation (primary outcome), ICU length of stay, and in-hospital mortality (secondary outcomes). A prospective controlled double blind study [7] found no benefit on ICU length of stay and mortality of a moderate-dose hydrocortisone therapy throughout the period of hypnomidate-related adrenal insufficiency in critically ill patients without septic shock. These findings are consistent with a meta-analysis compelling 5000 patients. This study concluded that hypnomidate administration was associated with an adrenal insufficiency (RR 1.42; 95% CI, 1.22–1.64; p 0.00001) but not with a higher rate of mortality (RR 1.20; 95% CI 0.84–1.72) [8]. However, these findings largely rely on data from observational studies with a potential selection bias.

Current data do not allow to decide for or against hypnomidate for septic shock patients. However, its pharmacodynamic profile is potentially harmful, and other anesthetic drugs with identical or better hemodynamic properties are available.

Due to its excellent safety features, propofol is the most widely used drug in elective anesthesia. Propofol contains a phenolic hydroxyl group that donates electrons to the free radicals, thus acts as an antioxidant. Many studies highlighted the effects of propofol on the inflammatory pathways. Pretreatment with propofol reduced the mortality rate of rats and attenuated the pro-inflammatory cytokine responses (interleukin-6 and tumor necrosis factor-α) in an endotoxin shock model [9] through an inhibiting induction of high mobility group box 1 protein. In a porcine endotoxemia model [10], propofol reduced enzymatic and nonenzymatic endotoxin-induced lipid peroxidation, improving arterial oxygen tension.

At concentrations used during clinical anesthesia, propofol protects human umbilical vein endothelial cells against arachidonylethanolamine-induced injury, in part by suppressing apoptosis [11]. Propofol also downregulates macrophage nitrous oxide biosynthesis via inhibiting iNOS gene expression [12].

Nevertheless, propofol has significant hemodynamic effects. It suppresses the sympathetic response, decreasing systemic vascular resistance, cardiac contractility, and preload. Hence, it may lead to adverse effects if used in septic patients, in which the sympathetic response is already impaired.

An analysis of anesthesia records of 4096 patients reported predictors of hypotension after anesthetic induction [13]: ASA III–V, baseline mean arterial pressure <70 mmHg, age >50 years, use of propofol for induction, and increasing induction dosage of fentanyl. The authors recommended avoiding propofol induction in patients with baseline mean arterial pressure <70 mmHg. An animal study showed that propofol is the anesthetic drug with the most pronounced direct cardiac effect during sepsis, with a significant decrease in contractility of −38%, a reduction in lusitropy of −44%, and a direct vasodilator effect by increasing coronary flow by +29 [14].

Compared with midazolam, propofol increases preload dependency in septic shock patients [15]. Compared with dexmedetomidine, propofol increases preload dependency in endotoxemic rabbit model with fluid nonresponsiveness and norepinephrine infusion [16]. Despite its anti-inflammatory properties, who are yet to be confirmed by human studies, the hemodynamic effects of propofol make it unsuitable for the anesthesia of patients with septic shock.

Thiopental remains the gold standard for rapid-sequence induction thanks to its rapid onset. Nevertheless, its negative hemodynamic [17] and inflammatory properties [18] (elevation of IL-10 from peripheral blood mononuclear cells in the presence of lipopolysaccharide) make it unsuitable for anesthesia of the patient with septic shock.

Ketamine seems to be the most valuable choice for the anesthesia of patients with septic shock. Unfortunately, there is a lack of reliable data on its efficiency and safety. Nevertheless, several studies provided data showing that ketamine is the drug of choice in septic shock. The abolition of sympathetic vascular tone is an effect shared by most hypnotics. Hoka et al. [19] showed the preservation of baroreflex control of vascular resistance when using ketamine in rats. The authors wrote that “ketamine may contribute significantly to the maintenance of blood pressure in the subjects with hemorrhagic hypovolemia, since arterial baroreflex is considered to play an important compensatory role in such condition.” In vivo, ketamine acts as a sympathomimetic, increasing heart rate, arterial pressure, and cardiac output [17].

The KETASED Collaborative Study Group produced a randomized, controlled, single-blind trial [20], involving 655 patients who needed sedation for emergency intubation. They compared the administration of 0.3 mg/kg of hypnomidate or 2 mg/kg of ketamine for tracheal intubation. The investigators found no difference in the maximum severity score during the first 3 days in the ICU, concluding that ketamine is a safe and valuable alternative to hypnomidate for endotracheal intubation in critically ill patients. Ketamine induces cardiovascular stability over a wide range of concentration in an isolated septic rat heart model, as compared with propofol, hypnomidate, and midazolam [14]. No data is available about the clinical use of ketamine for septic patients, but several studies strongly advocate its use for hemodynamically unstable patients and in emergency settings [21].

Another point of interest is the immunologic effects of ketamine. These effects have been summarized in a review article [22]. In brief, the mechanism is based on a ketamine-involved regulation of pro-inflammatory gene expression. Thus, ketamine suppressed the production of TNF-α, IL-1, and IL-6. Due to its hemodynamic and immunologic properties, and despite the lack of large-scale prospective randomized trials, ketamine seems to be the drug of choice for induction of general anesthesia for patients in septic shock.

Due to its pharmacokinetic properties (short duration of action, hemodynamic stability), midazolam is widely used for the sedation of ICU patients. Propofol may also be used but because of its cumulative toxicity (PRIS syndrome), its use is reserved for limited duration sedation.

Dexmedetomidine, an α-2 agonist, is more and more commonly used in ICU for cooperative sedation. Dexmedetomidine seems to have intrinsic anti-inflammatory properties, suppressing pro-inflammatory mediators. In a murine endotoxemia model, it reduced mortality rate with an inhibitory effect on inflammatory response [23]. In another model, the shift of sedation regimen from propofol to midazolam was associated with an improvement in sublingual microcirculatory perfusion [24].

In the operating room, volatile anesthetics are a valid choice for maintenance of general anesthesia in the critically ill patients, due to their pharmacologic properties. They are easily titrated to obtain a satisfactory level of sedation with little hemodynamic repercussion. Their short half-life allows a rapid reversal. However, no data from large-scale studies are available to confirm those assertions.

Volatile anesthetics as sevoflurane are used in cardiac surgery in a preconditioning strategy, since this drug decreases ischemia-reperfusion injuries in those patients thanks to its inhibitory action on the inflammatory pathway [25]. Studies have been performed in septic conditions to assess the protective effect of volatile anesthetics. Due to an attenuated inflammatory response, lipid peroxidation, and oxidative stress, sevoflurane, desflurane, and isoflurane significantly improved survival rate in murine models of cecal ligation-puncture-induced sepsis [26]. Those findings are consistent with those in the cardiac surgery preconditioning setting. Even if there is a lack of data regarding hemodynamic safety of volatile anesthetics, the profile of volatile anesthetics seems beneficial.

Identifying the best dosage of drugs remains challenging due to the cardiovascular effects of anesthetics, the change in pharmacokinetics due to fluid therapy, and the alterations of pharmacodynamics due to hypermetabolism. In routine, the dosages are lowered to prevent adverse effects although they must be sufficient to maintain an adequate level of sedation and analgesia.

Bispectral index monitoring with a goal between 40 and 60 is efficient to prevent awareness during surgery and to improve sedative drug delivery and postoperative delivery [27]. There is no study evaluating the effect of bispectral index monitoring specifically for septic patient. However, bispectral index monitoring was associated with a decrease of sedative drug doses, recall, and time to wake-up [28]. Furthermore, it could detect inadequate sedation during therapeutic or preoperative paralysis [29].

Guidelines on neuromuscular blockade stress on the train-of-four monitoring to prevent excessive dose infusion leading to prolonged skeletal muscle weakness or remaining blockade leading to respiratory failure after extubation [29]. In septic patients, cisatracurium pharmacokinetics is deeply altered due to both body fluid distribution and organ dysfunction leading to change in volume of distribution, elimination, and effect of neural transmission. These alterations result in a slower response with reduced effect, strengthening the need of paralysis monitoring [30].

Shock is defined as an acute circulatory failure associated with inadequate oxygen utilization by the cells. Circulation remains unable to deliver sufficient oxygen to meet demands of the tissues. Clinical examination and standard monitoring fail to assess fluid responsiveness during circulatory shock. Invasive monitoring of cardiac output is the cornerstone of an efficient hemodynamic optimization. Biomarkers such as blood lactates or central venous oxygen saturation (ScvO₂) should be used to detect inadequate tissue perfusion even without hypotension. A close monitoring is mandatory in the septic shock patient in the operating room, since fluid loss due to bleeding, inflammation related to surgical insult, and hemodynamic impairment due to deep anesthesia make her or his management challenging.

Fluid resuscitation is the first intervention for the management of a patient with shock. Preload is an important determinant of cardiac output (such as afterload and contractility). Preload can be optimized with fluid resuscitation to improve cardiac output, but excess of fluid results in adverse effects [31]. Fluid responsiveness can be defined by improvement of 15% of cardiac output after a 500 mL fluid infusion [32]. During shock, clinician should be able to predict fluid responsiveness before fluid administration. Static index such as central venous pressure (CVP) or pulmonary artery occlusion pressure (PAPO) is not reliable enough to guide a fluid resuscitation [33]. Dynamic index is a more reliable criterion than static index. These are based on changes in the relation between heart function and intrathoracic pressure during mechanical ventilation cycles. Pulse pressure variation (PPV) and stroke volume variation (SVV) are classically assessed via an arterial line. In a seminal study, the area under receiver operating characteristic curve was 0.89 (95% CI: 0.86–0.92) for PPV, compared with 0.57 (95% CI: 0.54–0.59) for central venous pressure. The authors defined a gray zone of PPV ranging from 9 to 13% for which fluid responsiveness could not be predicted reliably [34].

The assessment of aortic blood flow variation using a transesophageal Doppler is probably the method with the highest level of evidence. The use of noninvasive inflatable finger cuffs and variation of vena cava (inferior or superior) with echocardiography are other options. This strategy may prevent fluid overload [35]. Dynamic measures have several limitations because they require a sedated, mechanically ventilated patient in sinus rhythm.

Cardiac output monitoring is critical. However, a single value of cardiac output cannot be used to assess the global hemodynamic state. The cardiac output must be integrated with data about tissue perfusion (lactate clearance, ScvO₂, and clinical signs of shock). The best level of cardiac output is not a quantitative value but a confrontation between the patient needs and her or his cardiovascular performance. One should always keep in mind that supramaximal cardiac output using inotropic medication leads to complications and increased mortality [36].

Industry proposes several devices to measure cardiac output. All devices based on pulse contour analysis are considered as inaccurate in patients with septic shock. Their use can be discussed in emergent situations to follow the variations rather than absolute values. Similarly, volume clamp system using inflatable cuff wrapped around the finger to generate a real-time pulse contour analysis is not reliable in those patients due to the spontaneous vasoconstriction of finger arteries [37].

In our opinion, thermodilution is the gold standard for hemodynamic assessment. Continuous monitoring of cardiac output is available with new types of pulmonary artery catheter. This device provides information on other hemodynamic variables (CVP, PAPO) and tissue perfusion (SVO₂, oxygen utilization, oxygen delivery). However, this system did not demonstrate a positive effect on the outcome of patients [38].

Thermodilution provides intermittent measurements of cardiac output after infusion of cold bolus through the superior vena cava central line and its detection in the femoral artery by a dedicated catheter. This device measures global end-diastolic volume (volumetric marker of cardiac preload), cardiac function index, and extravascular lung water (quantitative index of pulmonary edema). Those variables are useful to conduct an adequate resuscitation with fluid, vasopressors, and inotropes. Thermodilution is coupled to a pulse contour analysis system. Hence, a real-time calculation of cardiac output is feasible. Potential drift over time makes regular calibration mandatory.

Echocardiography cannot provide continuous hemodynamic data. Performing transthoracic echocardiography in the operating room is challenging due to surgical field. However, it can help physician to characterize the hemodynamic state, to choose the best treatment options, and finally to assess the therapy response. Nevertheless, transesophageal echocardiography (TEE) provides reliable data, as cardiac output, left ventricular ejection fraction (mainly depending of contractility and afterload), left ventricular filing pressure (by analysis of transmitral flow), and preload responsiveness (respiratory variation of VTI or after fluid challenge, superior vena cava variation). All measurements are described in guidelines and require an adequate training [39]. Lung ultrasound also provides interesting variables. For instance, the observation of B-lines may suggest pulmonary edema.

Biological monitoring is critical to assess microcirculation during shock. It helps for shock diagnosis, therapeutic adjustment, and outcome determination. Plasma lactate levels increase in the cases of inadequate oxygen delivery, with 2 mmol/L as a cut-off. This is now part of the definition of septic shock [36]. A decrease in plasma lactate levels (10%/h) is associated with decreased mortality rate. Serial measurements of plasma lactate level are recommended to guide therapy in the critically ill patient [40].

In the septic shock patient, ScvO₂ (measured from superior venous cava catheter) provides information on the adequacy of oxygen transport. It reflects hemoglobin, oxygen consumption, arterial oxygen saturation, and cardiac output. A low level of ScvO₂ values (<70%) in the context of circulatory failure is a relevant marker for the need of fluid (if fluid responsiveness is found) or positive inotrope (if fluid responsiveness is not found). A supranormal ScvO₂ value is associated with impaired outcome in the patient with septic shock [41]. It probably reflects a deep microcirculatory failure. Venoarterial carbon dioxide difference (pCO₂ gap) (measurement of the difference in carbon dioxide between central venous blood and arterial blood) can be used. Values >6 mmHg suggest insufficient blood flow even for ScvO₂ values >70% [42].

The management of patients with septic shock should follow the Surviving Sepsis Guidelines [36]. In the operating room, the monitoring of preload should rely on dynamic index rather than on CVP, although the level of evidence is weak. One should keep in mind that it is critical to exclude the source of infection within the 6 h after diagnosis. Then, surgery should be performed even if the patient remains hemodynamically unstable, after a short period of resuscitation.