Effect of neuromuscular blockade and reversal by sugammadex versus neostigmine on breathing when hypoxic or hypercapnic in volunteers

The carotid bodies, located at the bifurcation of the common carotid artery,
play a crucial and life-saving role in the control of breathing in humans. The
carotid bodies contain type 1 cells that are primarily sensitive to low oxygen
concentrations in arterial blood. In response to low oxygen the carotid bodies
send information to the brainstem respiratory centers and a brisk
hyperventilatory response will be initiated ensuring an increase in uptake of
oxygen via the lungs. Following surgery, a rapid return of the carotid body
function is vital and persistent loss of carotid body function may result in
respiratory complications that occur independent of the effects of anesthetics
(incl. muscle relaxants) on respiratory muscles. Respiratory complications that
are related to the loss of carotid body function include the inability to
respond properly to hypoxia as well the inability to overcome upper airway
obstruction. The latter is especially important in patients with sleep
disordered-breathing and obese patients. These patients rely on the optimal
function of their carotid bodies in response to hypoxia or upper airway
closure.
Important neurotransmitters involved in the carotid body response to hypoxia
include acetylcholine, which acts through local nicotinergic acetylcholine
receptors. Apart from the observation that muscle relaxants (which are blockers
of the acetylcholine receptors) affect the proper functioning of the carotid
bodies (see Eriksson et al. Anesthesiology 1993; 78: 693-9), we have no
knowledge on the dynamic effects of muscle relaxants on carotid body function
over time or on the relationship between carotid body function and
Train-of-Four (TOF) ratio over time. Additionally, there is no data on the
link between the use of NMB antagonists and return of carotid body function.
Linking TOF ratio to carotid body function is of clinical importance as a
possible relationship will allow clinicians to predict carotid body function
from the TOF ratio. The latter is highly relevant as we show in the Neuropa
trial that a large proportion of patients is extubated at TOF ratio*s < 0.7.
Apart from the carotid bodies, chemoreceptors in the brainstem exist that are
sensitive to hypercapnia. This response system is not under control of
cholinergic neurotransmission. Since we may assume that the hypercpanic
ventilatory response is not influenced by muscle relaxants we can use this
response to calibrate the hypoxic ventilatory response as both responses are
equally affected by the effect of muscle relaxants on muscle function (Eriksson
et al. Anesthesiology 1993; 78: 693-9).
As stated there are data on the effect of muscle relaxants on carotid body
function at one fixed TOF ratio (TOF ratio fixed at 0.7; Eriksson et al. 1993).
No data are available on:
1. Dynamic effect of carotid body function as measured by the hypoxic
ventilatory response at TOF ratio*s changing from 0.7 to 1.0;
2. Dynamic effect of reversal of NMB by sugammadex versus neostigmine.
Sugammadex and neostigmine are both reversal agents of neuromuscular blockade.
At LUMC we use both agents in clinical practice but remain without knowledge on
their effects on carotid body function. Our current proposal is designed to
study items 1 and 2 in healthy awake volunteers.

To assess (i) the effect of partial neuromuscular blockade (NMB; TOF ratio 0.7)
induced by low-dose rocuronium on the ventilatory response to isocapnic hypoxia
and (ii) the effect of the reversal by sugammadex, neostigmine or placebo in
healthy volunteers.
To assess the effect of partial NMB (TOF ratio 0.7) induced by low-dose
rocuronium on the ventilatory response to hypercapnia and effect of the
reversal by sugammadex, neostigmine or placebo in healthy volunteers.

Double blind, placebo-controlled and randomized

1) low dose rocuronium administration;
2) administration of either sugammadex, neostigmine or placebo
3) exposure to mild hypercapnia and mild hypoxia.

Due to the mild level of relaxation some subjects may experience some muscle
weakness and dysarthria. This is frequently seen in postoperative patients and
is well accepted, especially when subjects are well coached during the period
of mild muscle relaxation. In case the subject indicates that his discomfort is
unacceptable the level of relaxation will be reduced, as discussed in paragraph
6 of the protocol. In case the subjects demands termination of the study the
reversal agent Sugammadex will be administered.