Ketanest In Septic Shock

Ketamine is a NMDA receptor antagonist causing dissociative anesthesia,
introduced in the 1970s. Advantages like spontaneous breathing, hemodynamic
stability, and the combination of anesthesia and analgesia were offset by
adverse psychological reactions, like hallucinations. Besides, it is also a
cheap anesthetic, and therefore frequently used in developing countries
nowadays.
However, since the introduction of its S(+) enantiomer, ketanest, in 1990,
there has been a renewed interest in the clinical applicability of this drug.
Ketanest is associated with fewer side effects (1). One particular interesting
area may be its use during early sepsis if it is decided that the patient
should be intubated and ventilated. Patients presenting with sepsis or septic
shock receive early goal-directed therapy, according to the surviving sepsis
campaign guidelines (2,3), in an attempt to restore normal physiology. The use
of ketanest during sepsis may have some striking advantages contributing to the
restoration of normal physiology.
The first advantage may be cardiovascular stability. All induction agents,
including ketanest, are cardiodepressive. However, ketamine may be the least
cardiodepressive induction agent (4). Ketanest causes an, central nervous
system mediated, increased sympathetic nervous system activity overruling the
direct cardiodepressive effects. Consequently, and in contrast to other
induction agents, cardiac output and blood pressure usually rise during the
induction phase. Some concern may be justified about the use of ketanest in
critically ill, catecholamine depleted, patients (5), since they cannot
increase their sympathetic nervous system activity. However, a randomised
clinical trial on this matter is lacking.
During sedation with ketamine, van der Linden and co-workers ((7) found
ketamine to preserve cardiovascular stability better than other anesthetic
agents in dogs with induced septic shock. Notably, in the same study, the
authors noted that ketamine appeared to have the least deleterious effects on
the hypoxic tissues, as lactate levels fell only in the ketamine group.
Finally, it is conceivable that stimulating the sympathetic nervous system,
instead of infusing exogeneous catecholamines, contributes to the restoration
of normal physiology.
The second advantage may be the preservation of spontaneous ventilation and
bronchodilation. The former will preserve diaphragm tone, thus contributing to
the prevention of atelectasis. The latter is probably caused by both, direct
effects on the smooth muscles of the airway, and indirect effects through the
increased sympathetic nervous system activity. The bronchodilation caused will
reduce airway resistance. The preservation of spontaneous ventilation and
brochodilation together will maintain, or possibly improve, compliance. It
remains to be seen whether this effect is of enough importance to be detected
in septic patients.
The third advantage may be the antiinflammatory effect of ketanest. Mazar and
collegeas (8) found that in mice with sepsis ketamin reduced mortality,
leucocyte recruitment, as well as tumor necrosis factor a (TNFa) and
interleukin (IL) 6 levels. Roytblat and co-workers (9) found that a single dose
of ketamine (0.25 mg/kg) before cardiopulmonary bypass (CPB) suppressed the
increase in serum IL6 during and after coronary bypass grafting (CABG) in man.
Likewise, Bartoc and co-workers (10) found ketamine (0.5 mg/kg) to attenuate
increases in C-reactive protein (CRP), IL6 and IL10 while decreasing
vasodilation after CPB in man.
These advantages suggest ketanest to be a potentially beneficial induction and
sedation agent in patients with sepsis in need of ventilatory support. However,
to the best of our knowledge, randomised clinical trials into this matter are
non-existent, as has been noted before (11).
Most physicians may be inclined to induce anesthesia with etomidate in patients
with septic shock, regarding its favourable effect on cardiovascular stability.
However, in recent years increasing evidence points out that even a single shot
of etomidate may cause adrenal insufficiency (12,13). This growing awareness on
the adverse effects of etomidate and the growing evidence on the potential
advantages of ketanest induction in critically ill septic patients urges a
study on the comparison of both agents.

Primary Objective: To compare ketanest induction and maintenance to etomidate
induction and maintenance with midazolam and fentanyl on hemodynamic,
ventilatory and endocrine parameters during the first 2h after the diagnosis of
sepsis and in need of mechanical ventilation.
We hypothesise that (restoration of) a adequate circulation are reached sooner
and with less inotropic support, fluids and RBC transfusions using ketanest.

Secondary Objective(s): Furthermore, we hypothesise that adrenal gland is not
suppressed following induction of anesthesia with ketanest, in contrast to
induction with etomidate.

prospective single center randomized not-blinded clinical trial

Patients accepted for this study are randomised to either the ketanest (K) or
etomidate (E) group. The primary objective in patients with septic shock is
restoration of adequate tissue perfusion. The only a priori difference in
treatment will be the induction and maintenance agent.
The K protocol demands induction with ketanest (1.0 mg/kg) and rocuronium 1.2
mg/kg, followed by maintenance with ketanest (1-3mg/kg/h). The E group is
induced with etomidate 0.2 mg/kg and rocuronium 1.2 mg/kg, followed by
maintenance with midazolam (4-10 mg/h) and fentanyl (100ug/h). Maintenance
doses must be titrated to effect.
Two hours after induction of anesthesia (i.e. start of the intervention)
maintenance with ketanest will be switched to midazolam and fentanyl. Sedation
with midazolam and fentanyl must be continued for at least 22 hours in order to
prevent adverse psychological effects.

Ketamine is well known for its psychological side effects. Ketanest is
associated with less side-effects (1). It has been hypothesised that adverse
psychological reactions are only associated with recovery from ketanest
anesthesia. These adverse psychological reactions (incidence ranges from
3-100%) consist of hallucinations, illusions, confusion and vivid dreaming, are
normally short lived, and (partially) prevented by midazolam. There is no data
on the appropriate rate or duration of midazolam infusion.
In this study ketanest infusion will be stopped 2 hours after induction of
anesthesia, and replaced by fentanyl infusion. Midazolam and fentanyl will be
infused continuously for at least another 23 hours, in order to prevent
possible adverse psychological reactions associated with recovery from ketanest
anesthesia.