Download blunting the intubation response: fact or fiction

17 January 2014
No. 02
BLUNTING THE INTUBATION
RESPONSE: FACT OR FICTION
K Purchase
Moderator: C Evans
Discipline of Anaesthetics
CONTENTS
MECHANISM OF THE INTUBATION RESPONSE............................................... 4
BLUNTING THE HAEMODYNAMIC RESPONSE ................................................ 7
LIGNOCAINE........................................................................................................ 7
OPIOIDS ............................................................................................................... 8
α 2 AGONISTS ................................................................................................... 10
β BLOCKERS ..................................................................................................... 11
MAGNESIUM SULPHATE (MGSO4) .................................................................. 12
NOVEL IDEAS .................................................................................................... 13
SUMMARY OF EVIDENCE................................................................................. 15
BENEFITS OF ATTENUATING THE RESPONSE ............................................. 17
CONCLUSION .................................................................................................... 20
REFERENCES.................................................................................................... 21
Page 2 of 26
OBJECTIVES
 Discuss the mechanism of the intubation response
 Explore the various pharmacological methods to attenuate the intubation the
response
 Attempt to determine the benefits of blunting the intubation response
Page 3 of 26
BLUNTING THE INTUBATION RESPONSE: FACT OR FICTION
INTRODUCTION
Laryngoscopy and tracheal intubation are noxious stimuli associated with a
transient increase in autonomic response. King et al described this response more
than 60 years ago.(1)
It is most often associated with an increase in heart rate and blood pressure and
is thought to be of little consequence in the healthy individual but could be
deleterious in the vulnerable patient.(2) This response varies with depth of
anaesthesia, duration and difficulties during laryngoscopy and intubation, and
certain patient factors including history of diabetes(3) and cardiovascular
disease(4)(5)
MECHANISM OF THE INTUBATION RESPONSE
Basic anatomy:
Figure 1: the sensory innervation of the airways(6)
The pharynx: sensory innervation – Glossopharyngeal nerve supplies the
posterior third of the tongue, the fauces and tonsillae, anterior epiglottis and all
parts of the pharynx with visceral sensory fibers.Motor innervation- the pharynx
receives efferent supply from the vagus nerve through its pharyngeal branch.(6)
Page 4 of 26
The larynx: sensory innervation – the internal laryngeal nerve, branch of the
superior laryngeal nerve, provides sensory supply from the posterior epiglottis to
the vocal cords. The recurrent laryngeal nerve supplies the larynx below the vocal
cords and the trachea.
Motor innervation: the recurrent laryngeal nerve supplies all intrinsic muscles of
the larynx except the cricothyroid muscles. (6)
Figure 2: innervation of the larynx (7)
Simply put, with regards to sensory innervation, the oropharynx, posterior third of
the tongue and anterior part of the epiglottis are supplied by glossopharyngeal.
The posterior epiglottis and distal airway structures are supplied by branches of
the vagus nerve.
Mechanism of the intubation response
The precise mechanism of the intubation response (IR) is elusive but it has been
established that it has both a sympathetic and parasympathetic element. The
effect is transient occurring 30 seconds after intubation and lasting for less than
10 minutes thereafter.(8) The sympathetic response is a polysynaptic pathway with
the glossopharyngeal and vagus nerve forming the afferent arc to the sympathetic
nervous system via the brain stem and spinal cord. This ensures a diffuse
autonomic response at the efferent side including increased firing of the cardioaccelerator fibres and release of adrenergic mediators including norepinephrine,
epinephrine and vasopressin.
Page 5 of 26
The net effect of this autonomic surge is an increased Blood pressure (BP), heart
rate (HR), pulmonary artery wedge pressure and decreased ejection fraction.
The parasympathetic reflex is monosynaptic and more common in children but
can occur in some adults. The reflex is mediated by increased vagal tone at the
SA node. (2)
The haemodynamic response to laryngeal and endo- tracheal intubation (LETI) is
transient and in most patients thought to be of little consequence. In patients with
coronary artery disease (CAD), hypertension, raised intra cranial or intra ocular
pressure it may be associated with myocardial ischaemia, infarction, arrhythmias,
cardiac failure, pulmonary oedema and cerebral haemorrhage. (5)
The process of intubation comprises of different phases and these affect the
haemodynamic response differently. Orotracheal intubation consists of 2 phases:
direct laryngoscopy and passing of endotracheal tube through the vocal cords and
trachea. (9)
Four studies looked at this differential effect. Sing(9), Shinji(10) and Hassan(11)
concur that tracheal intubation and cuff inflation produce a substantial
haemodynamic effect, significantly greater than laryngoscopy alone. Shribman(12)
however found that orotracheal intubation did not significantly contribute to the
haemodynamic effect. These studies give the impression that greatest increase in
HR occurs during LETI and greatest increase in BP occurs during laryngoscopy.
With no active attempt at blunting this haemodynamic response, increases in SBP
of 41-53 mmHg, HR 20-23 and MAP of up to 100% above baseline have been
documented.(1)(13)
Page 6 of 26
BLUNTING THE HAEMODYNAMIC RESPONSE
The possibilities to offset or blunt the intubation response are numerous. Options
include pharmacological, peripheral blocks and variations in techniques including
various blades and conduits for intubations.
This booklet will only focus on pharmacological techniques.
Pharmacological options:
 Local anaesthetics
 Opioids
 α 2 agonists
 β 2 blockers
 MgSO4
 Gabapentin, pregabalin
LIGNOCAINE:
The effectiveness of lignocaine to blunt the intubation response (IR) is
contentious. Numerous studies dating from 1960 have looked at different doses,
timing and routes of administering Lignocaine. From the discussion above on the
nerve supply of the larynx and the effect that tracheal intubation has on the IR it is
apparent why laryngeal tracheal routes will not entirely blunt the response.(14)(15)
Hamill et al and Laurito et al both looked at the IV route of Lignocaine to blunt the
response to LETI.
Hamill (14) used a dose of 1.5mg/kg, ivi 1minute prior to LETI and compared this to
4ml of a 4% solution sprayed laryngealtracheally. The group that received topical
lignocaine sustained significant increase in HR and BP after LETI that lasted for
more than 2 minutes. The authors note that the IV route did not completely
attenuate the response as there was still significant increase in BP and HR
although only sustained for 1 minute or less. Laurito et al(16) compared IV
Lignocaine (2mg/kg) 1 minute pre LETI to nebulized lignocaine 4mg/kg 15
minutes prior to LETI. Within each group all haemodynamic variables increased
significantly. With mean arterial pressures of 140mmHg recorded.
Miller et al(17) also failed to demonstrate that Lignocaine attenuates the
haemodynamic response to LETI. They studied Lignocaine 1.5mg ivi given 1,2
and 3 minutes prior to LETI. Sklar et al (18)found that aerosol application of
lignocaine 120mg was effective in attenuating the both the BP and HR response
in adults. This was applied for 5 minutes duration and 8.5 min prior to induction.
Various other studies support the use of Lignocaine 1,5mg/kg ivi given between 24 minutes to attenuate the response. Tam et al(19) and Splinter et al(20) could only
demonstrate benefit with regards to the BP response, however Helfman(21) found a
dose of 1,5 mg/kg, given 2 minutes prior to LETI, to blunt both the BP and HR
response.
The principal limitation when comparing studies is heterogeneity of the studies.
Various doses, timings, pre medications and induction agents are used.
Page 7 of 26
At best, intra venous Lignocaine will occasionally blunt the BP response and
almost never the HR response. If administered it should be at a dose of 1,5mg/kg,
3 minutes prior to intubation.(2)
Topical routes are not effective in blunting the intubation response and few studies
have shown convincing benefit of the aerosol route.(22)
OPIOIDS
The addition of opioids deepens the level of anaesthesia and therefor decreases
the sympathetic outflow.
Alfentanil: numerous studies show that a dose of 30µg/kg given between 1.5 and
2 minutes prior to intubation provides complete attenuation of the haemodynamic
response.(23)(24)(25)(26)
Lower dosages, 15µg/kg, seem to attenuate the BP response but not the HR
response.(26)
In the elderly 10µg/kg given 3-4 minutes pre induction has also been shown to
completely blunt the haemodynamic response.(27)
Higher dosages have been associated with bradycardia and hypotension.(23)
Few studies distinguish between hypertensive and non-hypertensive patients.
Only Miller(25) et al used patients from ASA 1-3 stages but did not specify the
reason for the staging.
A dose of Alfentanil 10µg/kg given over 30 seconds has been suggested to be
effective in blunting the cardiovascular effect in hypertensive patients on long term
treatment. In this study 3/20 patients developed hypotension requiring
Ephedrine.(28)
Remifentanil:
The rapid onset and short duration of Remifentanil makes it an attractive drug for
attenuating the IR.
Thompson et al(29) initially found that a dose of 1µg/kg followed by and infusion of
0.5µg/kg/min attenuated the haemodynamic response in healthy adults. This dose
was associated with profound bradycardia and hypotension in half the patients.
A subsequent study(30) indicated that 0.5µg/kg followed by an infusion of
0.25µg/kg/min was as effective in blunting the response with no incidence of
bradycardia or hypotension requiring treatment. They also indicate that at the
higher doses, pre-treatment with glycopyrrolate 200µg, decreases the incidence of
side effects.
Page 8 of 26
Maguire et al (28)demonstrated that a bolus dose of 0.5µg/kg followed by infusion
at 0.1µg/kg/min effectively reduces the response to LETI in hypertensive patients
on treatment. Of note is that all patients were pre-treated with glycopyrrolate 200
µg. None of the patients developed a bradycardia but 7/20 patients required
rescue medication for hypotension. (SBP 80-100 mmHG).
Most studies agree that a dose of 2µg/kg significantly reduces the BP and HR and
that this dose is not recommended for the elderly or compromised patient.(22)
Hart et al(31) compared Remifentanil ( 0.5µg/kg followed by an infusion of
0.1µg/kg/min) and Alfentanil ( 10µg/kg) in elderly patients. The study included
patients of ASA I-III but excluded patients with evidence of cardiovascular
disease.
They concluded that both drugs similarly attenuated the haemodynamic response
but that the incidence of hypotension in both groups justifies caution in the elderly.
Fentanyl:
Numerous studies have looked at various doses and timing to administer Fentanyl
and its effect on the intubation response. Unsurprisingly, high doses of 50-75µg/kg
completely blunt the response but are associated with significant side effects. (2)
In normotensive ASA I/II patients various authors indicate that a dose of 2µg/kg
given between 3,5-5 min pre LETI suppress the response. (32)(33)
Kautto et al (34) and Feng at al (33) indicated that although the BP response was
attenuated at this dose, the HR response was not sufficiently obtunded.
Others indicate that a dose of 5-8µg/kg given between 3,5-5 min pre LETI
completely blunts the response. (34)(35)(36)
In elderly patients a dose of 3µ/kg has been indicated to prevent a haemodynamic
response.(37)
Again, most studies are heterogenic and difficult to compare. Dosages that seem
to be most effective are between 5-6µg/kg given 3-5 minutes prior to LETI. Dose
reduction is prudent in the elderly. With these doses there is a risk for
complications including respiratory depression and delayed awakening in short
cases.(2)
Sufentanil:
The use of Sufentanil has been researched extensively in the paediatric
population but research in the adult population appears scanty.
Kay et al reported a dose of 0,5-1µg/kg given 2 minutes pre LETI sufficiently
blocked the response in adults.(38)
Zhang et al(39) reported that in patients for heart valve replacement, a dose of
1µg/kg sufficiently blocked the BP and HR response. A dose of 1.5µg/kg was
associated with significant bradycardia requiring Atropine administration in 27% of
cases.
Page 9 of 26
In two comparable studies in normotensive ASA I-III patients, a bolus dose of
0.1µg/kg followed by an infusion of 0.01µg/kg/min for 5 minutes prior to LETI was
effective in blunting both the BP and HR response.(40)(41)
In children, a dose between 0.2-0.3µg/kg administered 2 min prior to LETI has
been found to significantly attenuate the haemodynamic response to
intubation.(42)(43) None of the children in the higher range group experienced
significant side effects requiring treatment.
α 2 AGONISTS
Stimulation of the presynaptic α receptors leads to reduced secretion of noradrenaline and renin. Vagotonic effects that decrease the HR are also present.
Most of the studies compare Clonidine as a premedication to various methods of
anaesthesia that included variable doses of Fentanyl and Alfentanil.
Studies indicate that, used in addition to a standard general anaesthetic, Clonidine
4-5µg/kg po given between 60-90 minutes prior to surgery can be beneficial.
Benefits include reduced doses of opioids and induction agents, decreased
haemodynamic response to LETI and improved intraoperative haemodynamics.
The risk of bradycardia is always present and was treated with Atropine in some
of the studies.(44)(45)(46)(47)(48)
Drawbacks of Clonidine include long duration of onset, prolonged duration of
action and therefore the risk of post-operative sedation in short procedures as well
as the risk of hypotension and bradycardia.(2)(44)
Dexmedetomidine is a highly selective α2 agonist. A biphasic cardiovascular
response has been described. After a bolus of 1µg/kg, a transient increase in BP
and decrease in HR is seen. This is thought to be due to stimulation of α2
receptors in vascular smooth muscle. The vasoconstriction effect thus appears
before the central effects. This response can be decreased but not completely
avoided by giving the bolus dose as an infusion over 10 minutes.(49)
Aho et al (50) showed in healthy patients a bolus infusion of 0.12µg/kg over 10 min
followed by an infusion of 0.006µg/kg significantly reduced the HR but not the BP
response to LETI. Of note is that 40% of the patients in the Dexmedetomidine
group required Atropine to treat bradycardia.
Jaakola et al (51) found an infusion of 0.6µg/kg/min 10 minutes prior to LETI
reduced the BP and HR response in patients presenting for ophthalmic surgery.
Bajwa et al(52) indicated that an infusion of 1µg/kg over 20 minutes attenuated but
did not completely obtund the response to LETI. None of the patients in this study
had a significant bradycardiac or hypotensive episode however only healthy ASA I
patients were included.
Page 10 of 26
Menda et al investigated patients undergoing fast track CABG surgery. An
infusion of 1µg/kg was given over 15 minutes. This was compared to a placebo
group. Their conclusion was that Dexmedetomidine can safely be used to
attenuate the haemodynamic response. The incidence of hypertension post
intubation in the placebo group was statistically significant. The incidence of
hypotension was not statistically significantly between the 2 groups. (53)
Sulaiman et al(54) confirm these results but at much lower doses. 60 patients for off
pump CABG were randomly allocated to a Dexmedetomidine group or placebo
group. An infusion of 0.5µg/kg over 10 minutes found better haemodynamic
control post LETI in the Dexmedetomidine group. No adverse effects needing
treatment were observed. Significantly, almost 50% of the patients in each group
were on β-blockers pre-operatively.
In summary, from the above studies, it appears that doses between 0.5-1µg/kg as
an infusion over 10-20 minutes prior to LETI, in addition to low dose opioids,
decrease the response to LETI and improve haemodynamics.
The risk of hypotension and bradycardia should always be considered. A recent
meta-analysis confirmed, in cardiac patients for non-cardiac surgery, perioperative Dexmedetomidine significantly increased the incidence of hypotension
and bradycardia. (55)
β BLOCKERS
Labetolol has a combination of α and β blockade. The α blockade is specific for α 1
and non-specific for β blockade. The ratio of α1 to β blocking effect is 1:7. It has an
onset of 1-5 minutes and a half-life of up to 5.5 hours. (72)
Inanda et al(61) compared Labetolol (5mg and 10mg) to Lignocaine (100mg) and a
placebo group in healthy patients presenting for general surgery.
Labetolol 10mg ivi (+/- 0.14mg/kg) 2 minutes prior to LETI blocked the HR
response better than the other 2 groups but the BP response was the same in all
four groups.
Chung et al (62) confirmed these findings with a larger dose of 0.4mg/kg
administered 5 minutes prior to LETI.
Leslie et al(63) compared doses between 0.25mg/kg to 1mg/kg. It was found that
Labetalol effectively attenuated the HR and BP response in a dose dependant
manner. But they also state that although the higher doses block the BP
response, they are at the expense of significant post intubation hypotension.
One of the main concerns of Labetalol is the prolonged duration of action.
Esmolol is a cardio selective β blocker with rapid onset and offset. (72)It reaches
peak blood levels in about 2 minutes and has an approximated half-life of 9
minutes.(2)
Page 11 of 26
Several studies have assessed the effectiveness of Esmolol in blunting the
response to LETI. As with many of the other drugs mentioned, little consensus
has been reached with regards to optimal dose, time and risk of side effects in the
different population groups.
A recent meta-analysis(5) attempts to determine the optimal dose of Esmolol
needed to minimize the response to LETI and decrease post intubation
hypotension. The analysis includes 38 studies and concludes that a loading dose
of 500µg/kg over 4 minutes followed by an infusion of 200-300µg/kg/min is the
best approach. It also states that a dose dependant risk of hypotension is entailed
during induction and its routine use is not recommended.
A comment on this meta-analysis is that of the 38 studies evaluated, only 6
studies evaluated the use of Esmolol in patients with hypertension or coronary
artery disease. A sub analysis could not be done as the numbers were insufficient.
Nevertheless these 6 studies indicated that neither the effectiveness of the drug
nor the magnitude of adverse effects were seemingly different from the studies in
healthy patients.
Of note is that 19 of the included studies included the use of different opioids as
premedication or as part of induction.
MAGNESIUM SULPHATE (MGSO4)
MgSO4 is involved in several physiological processes including control of
vasomotor tone, cardiac excitability and release of neurotransmitters. Through
various methods it causes vasodilation and decreases release of catecholamines
from the nerve terminals and adrenal gland.(56)
A small but eloquent study by James et al(57) studied the effect of 60mg/kg MgSO4
pre-treatment on the cardiovascular response to LETI and catecholamine release.
16 healthy male patients were randomly allocated to a placebo group or the
MgSO4 group. All patients were pre-medicated with Diazepam 10mg po 1 hour pre
surgery. No opioids were used during induction. Although MgSO4 caused a slight
increase in HR after injection, the increase post intubation was still less when
compared to the placebo group.
BP readings were significantly lower in the MgSO4 group post LETI. The study
also indicated that MgSO4 can significantly attenuate catecholamine output at the
time of LETI.
Puri et al(58) studied the use of MgSO4 in patients with coronary artery disease
presenting for CABG. A dose of 50mg/kg(n=19) was compared to Lignocaine
1mg\kg (n=17).
Page 12 of 26
They concluded that MgSO4 attenuated the haemodynamic response to LETI
more effectively than Lignocaine. None of the patients in the MgSO4 had
significant ST changes, compared with three patients in the Lignocaine group.
Panda et al(56) determined that the minimal effective dose of MgSO4 needed to
attenuate the intubation response in controlled hypertensive patients was
30mg/kg.
Higher dosages were associated with significant hypotension.
James et al(59) compared Lignocaine (1,5mg/kg), Alfentanil (10µg/kg) and MgSO4
(40mg/kg) in hypertensive, proteinuric pregnant patients. Systolic blood pressure
exceeded baseline values the first 5 min after tracheal intubation in the lignocaine
group, but no mean increase in pressure occurred in the two other groups.
Alfentanil caused the least change in heart rate, but resulted in significant fetal
depression.
In a subsequent study(60), MgSO4 40mg/kg was compared to MgSO4 30mg/kg with
Alfentanil 7.5µg/kg. The conclusion was that both methods controlled the
haemodynamic response satisfactorily but that the combination was superior in
controlling both the BP and HR response. There was no difference in fetal
outcome between the two groups.
NOVEL IDEAS
Gabapentin inhibits membrane voltage gated calcium channels. It is being used
more frequently as an adjunct for treatment of acute post-operative pain in the
setting of chronic pain. (61)(72)
Fassoulaki et al(61) studied the impact of their standard analgesic regime of
Gabapentin, on the haemodynamic changes during LETI. 46 ASA I-II patients
scheduled for elective hysterectomy were randomly allocated to receive
Gabapentin 400mg or placebo 6 hourly, starting at noon the day prior to theatre
(total dose 1600mg). No other premedication was given and a standard induction
was done with Propofol and Cisatracuruim. No opioids were given prior to
intubation. They found that this regime attenuated the BP response but not the HR
response.
Kumari et al(62) studied the effect of a single dose of 900mg given 2 hours preoperatively. The only statistically significant effect was noted at the 10 minute post
LETI interval. Although this study came to the conclusion that a single dose is
effective in reducing the response to LETI, it is questionable since most authors
agree that the response to LETI lasts a maximum of 10 minutes with the peak
effect in the first few minutes. No mention is made of an anxiolytic or opioid given
pre induction with Propofol 2.5mg/kg.
In a similar study Bafna et al(63) found that a single dose of 1g, 1hour pre op had a
statistically significant effect in controlling the BP and HR. Once again this study
was conducted in healthy patients for elective surgery.
Page 13 of 26
The significant difference is that the patients were pre-medicated with Midazolam
and Fentanyl and induced with Thiopentone 5mg/kg. The most convincing study
of a single dose of Gabapentin is Memis et al (64). 90 healthy patients were
randomised to either a placebo, Gabapentin 400mg or 800mg group administered
1 hour before surgery. No other pre medications were given and no opioids were
used during induction. Patients were induced with Propofol 2mg/kg. They showed
a statistically significant decrease in HR and BP, in the 800mg group, at all
intervals recorded when compared to the other groups.
Pregabalin is structurally but not functionally related to gamma-aminobutyric acid
(GABA). It acts by inhibiting the synthesis of the neurotransmitter glutamate.(72) In
a prospective study Bhawna et al(65) randomly allocated 90 healthy patients to
either a placebo (group I), Pregabalin 75mg (group II) or Pregabalin 150mg (group
III) group administered 1 hour pre induction. Statistically significant increases in
BP post LETI were seen in group I and II while a significant decrease was seen in
group III. There was no significant decrease in HR in any group. These results
are confirmed by another study. Sunder et al (73) found that a single dose of
Pregabalin 150mg attenuated the response to LETI in patients presenting for
cardiac surgery. In contrast to Bhawna et al this study showed a statistically
significant reduction in HR response to LETI. Possible reasons for this include that
the Sunder trial was done in cardiac patients and a therefor a significant
proportion of patients were on rate modulating medication. Another contributing
factor is that the Sunder study used opioids a part of the induction.
Page 14 of 26
SUMMARY OF EVIDENCE
Dose
Drug
Lignocaine
4ml of 4% Topisolution
cal
1.5mg/kg
ivi
4mg/kg
2mg/kg
1.5mg/kg
120mg
Alfentanil
Rout
e
1.5mg/kg
1.5mg/kg
30µg/kg
15µ/kg
elderly
Nebulised
ivi
ivi
Aerosol
ivi
ivi
ivi
ivi
Blunte Blunte
d BP
d HR
moder
ate
X
X
X
X
X
Page 15 of 26
No
Reference
effec
t
X
14
modera
te
14
X
16
X
X
X
16
17
18
X
X
X
19,20
21
23-26
27
10µg/kg
Longstandin
g
Treated HT
Fentanyl
2µg/kg
3-5 min pre
LETI
2µg/kg
5-8µg/kg
Remifentanil 0.5µg/kg
bolus
then
0.25µg/kg/min
0.5µg/kg then
0.1µ/kg/min in
HT/ elderly
Sufentanil
1µg/kg 2min
prior to LETI
0.1µg/kg then
0.01µg/kg/min
for 5 min
Clonidine
5µg/kg
60-90
pre
LETI
Dexmedeto
0.12µg/kg
midine
over
10min
then
0.006µg/kg/
min
0.6µg/kg/min
over 10 min
1µg/kg over
20 min
0.5µg/kg over
10 minutes, in
cardiac pt
Labetolol
10mg
0.4mg/kg
Esmolol
500µg/kg
over
4min
then
200300µg/kg/min
Pregabalin
ivi
X
ivi
moderate moderate
32
ivi
ivi
ivi
X
X
X
none
X
X
33,34
34-36
30
ivi
X
X
28,31
ivi
X
X
38-39
ivi
X
X
40,41
po
moderate moderate
ivi
X
28
45-48
X
50
X
51
ivi
X
ivi
moderate moderate
52
ivi
moderate moderate
54
ivi
ivi
ivi
X
X
moderate X
61
62
5
75mg,1 hour po
pre LETI
Page 16 of 26
x
65
150mg,1 hour
pre op
Gabapentin 400mg/6
hourly
900mg,2hour
s pre LETI
1g, 1 hour pre
LETI
400mg 1 hour
pre LETI
800mg,1 hour
pre op
Magnesium 60mg/kg
30mg/kg
40mg\kg
50mg\kg
X= effect on parameter
po
X
65,73
po
X
61
po
po
X
X
X
po
62
63
X
po
moderate moderate
64
ivi
ivi
ivi
ivi
X
X
X
X
57
56
59-60
58
moderate
moderate
moderate
moderate
BENEFITS OF ATTENUATING THE RESPONSE
Central to the question regarding the benefit of blunting the IR is the differentiation
between final outcomes (death, peri-operative MI) and process outcome
(ischemia,hypotension,tachycardia,arrhythmias).(2)
As seen, numerous studies have been done to modify the response to LETI. They
invariably report on variables such as HR, BP, rate- pressure ratio and ST
changes.
Most studies record this for approximately 10 minutes post LETI. Very few report
on the influence these have on final outcomes. (66)
Therefore, benefits of the techniques described are presumptive and we assume
that by altering the haemodynamic response to LETI, we will improve or alter
outcome.
Both HR and BP are determinants of delivery and demand of oxygen. An increase
in heart rate deleteriously affects both supply and demand of oxygen. BP is
related to cardiac output (CO) and systemic vascular resistance (SVR). A change
in either CO or SVR will result in a compensatory change in the other.
Hypertension can therefore affect both supply and demand(66). All other organs but
most important to this discussion, the brain, heart and kidneys depend on
systemic pressure to maintain perfusion pressure.
Therefore it is inferred that certain patients cannot tolerate the consequences of
the haemodynamic response to LETI.
Page 17 of 26
These would unarguably include eclamptic patients due to the risk of cerebral
haemorrhage and pulmonary oedema. Other such populations would include
patients with raised intra cranial pressure, patients presenting for cardiac surgery
or patients with acute hypertensive urgencies/emergencies.
The grey area appears when researching the benefit in patients with risk factors
for cardiovascular disease but with no target organ damage presenting for noncardiac surgery.
Reich et al(67)performed a retrospective sub analysis (n=797). The aim was to see
if intra-operative deviations of HR and BP were associated with peri-operative
mortality and morbidity. All patients were undergoing complex non cardiac surgery
and controlled for the influence or pre-operative medical conditions.
Deviations were defined as HR< 45 />110, MAP<55/>100mmHg and
SBP<80/>160mmHg or any duration of time.
The primary end-point was negative surgical outcome (NSO) including postoperative hospital stay > 10days with a morbid condition or death during the same
hospitalization.
There was no strong association between NSO and variations in haemodynamics
in surgeries lasting less than 220 min.
For surgeries lasting more than 220min there was a strong association with low
MAP and increased HR. Increased HR was the stronger predictor.
Increased HR and increased SBP were both strong, independent predictors of
adverse outcomes in surgeries lasting more than 220 minutes.
Bijker et al (68) studied the association between 1 year mortality and intra operative
hypotension (IOH). This retrospective review (n=1705) included patients
undergoing general and vascular surgery. Among others, the study examines the
effect of hypotension, defined in 48 different ways, on mortality.
After adjusting for confounding variables, the regression analysis failed to show
any association between IOH and 1 year mortality.
The only positive associations were between advanced age, history of
hypertension, prolonged surgery and IOH. This study failed to indicate what
degree and what duration of IOH can be tolerated during surgery.
Monk et al (69)studied the association between anaesthetic management and one
year mortality after non cardiac surgery. This study included 880 patients.
Multivariate analysis indicated 3 significant predictors of 1 year mortality. One of
these predictors included IOH. Systolic hypotension increased mortality risk by
1.036(RR) per minute below <80mmHg. (95 % CI 1.006-1.066)
Page 18 of 26
Walsh et al(70) analysed prospectively gathered data from over 33 000 patients
undergoing non cardiac surgery. They found that a MAP <55mmHg was
independently associated with the development of acute kidney injury, myocardial
injury and cardiac complications. This risk escalates with time spent under
MAP<55mmHg but there does not appear to be any safe amount of time to spend
under a MAP<55mmHg.
A Cochrane review from 2013(71) had the primary objective to determine the
effectiveness of pharmacological agents in preventing the morbidity and mortality
resulting from the haemodynamic changes during LETI. Secondary objectives
included the effect on arrhythmias and on ECG changes associated with
ischemia. The review included 72 randomised controls trials that studied the effect
of 32 different drugs belonging to different pharmacological classes.
Only 2 trials mentioned the primary outcome of morbidity and mortality and both
these trials reported no major morbidity or mortality. From this review there is no
observed evidence that pharmacological agents influence morbidity or mortality.
This review also suggests that the pre-treatment with pharmacological
interventions is associated with a decreased risk of arrhythmias. None of the
studies commented on the percentage of patients requiring treatment for the
observed arrhythmias or any further consequences related to the rhythm
disturbances.
31 studies included myocardial ischaemia. None of the studies examined the final
outcome of intra operative evidence of ischaemia in the post-operative period.
Over all, pharmacological intervention reduced the risk of myocardial ischaemia.
But all the evidence came from 9 trials and therefor it should be treated with
caution. Further, Local anaesthetic was the only contributor in this sub group but
the analysis was dominated by a single study. β blockers were the largest
contributor in this sub group analysis and showed no advantage. Once again this
should be treated with caution as the studies were mostly underpowered to look
for this complication.
In the sub group analysis comparing high risk (17 studies) to low risk patients,
treatment was effective in low risk patients but not in high risk patients. This could
be due to underpowering of the studies or due to other medications not accounted
for in the high risk group. Overall all the studies were underpowered to detect a
reduction in the risk of ECG abnormalities.
In summary, in low risk patients, pre-induction use of pharmacological agents
reduces the risk of arrhythmias from 13% to 4% and appears effective in reducing
the risk of myocardial ischaemia.
In high risk patients pharmacological agents resulted in a reduction in the risk of
arrhythmias but not in ECG evidence of ischaemia.
The above summary must be viewed with the limitations discussed previously.
Page 19 of 26
CONCLUSION
Evidence of the hemodynamic effect to LETI has been available for more than 60
years. The precise mechanism is still being debated but the immediate
physiological consequences are well documented.
Numerous methods are available to attenuate this response and literarlly
thousands of trials have been done to this regard. The long-term consequences
and effect on morbidity and mortality of the intubation response in different
surgical population groups are not well established. Therefore the benefit of
attenuating this response in all patients is not clear cut.
The interventions applied to blunt the response are not without complications,
some of which have their own effect on morbidity and mortality.
In certain high risk groups the benefit is inferred as it would be unethical to study
the consequence of not blunting the response.
Modification of the haemodynamic response to LETI is an admirable objective and
clearly warranted in a select group of patients in whom a transient hyper-dynamic
episode can lead to catastrophe. However, extending the principle of vigilant
haemodynamic control to the entire peri-operative period holds more logic than
tunnel vision surrounding the 2 minutes around intubation.
Page 20 of 26
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