blunt the haemodynamic respon from laryngoscopy and endotracheal intubation
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17 January 2014 No. 02BLUNTING THE INTUBATION RESPONSE: FACT OR FICTION
K PurchaseModerator: C Evans
Discipline of AnaestheticsCONTENTS4MECHANISM OF THE INTUBATION RESPONSE
7BLUNTING THE HAEMODYNAMIC RESPONSE
10 2 AGONISTS
12MAGNESIUM SULPHATE (MGSO4)
15SUMMARY OF EVIDENCE
17BENEFITS OF ATTENUATING THE RESPONSE
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 responseBLUNTING THE INTUBATION RESPONSE: FACT OR FICTION
INTRODUCTIONLaryngoscopy 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
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 bers.Motor innervation- the pharynx receives efferent supply from the vagus nerve through its pharyngeal branch.(6)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 cardio-accelerator fibres and release of adrenergic mediators including norepinephrine, epinephrine and vasopressin. 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)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.
MgSO4 Gabapentin, pregabalin
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 2-4 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.
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 30g/kg given between 1.5 and 2 minutes prior to intubation provides complete attenuation of the haemodynamic response.(23)(24)(25)(26)Lower dosages, 15g/kg, seem to attenuate the BP response but not the HR response.(26)In the elderly 10g/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 10g/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 1g/kg followed by and infusion of 0.5g/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 0.5g/kg followed by an infusion of 0.25g/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 200g, decreases the incidence of side effects.
Maguire et al (28)demonstrated that a bolus dose of 0.5g/kg followed by infusion at 0.1g/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 g. 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 2g/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 ( 0.5g/kg followed by an infusion of 0.1g/kg/min) and Alfentanil ( 10g/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.
Numerous studies have looked at various doses and timing to administer Fentanyl and its effect on the intubation response. Unsurprisingly, high doses of 50-75g/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 2g/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 5-8g/kg given between 3,5-5 min pre LETI completely blunts the response. (34)(35)(36)In elderly patients a dose of 3/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 5-6g/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)
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 0,5-1g/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 1g/kg sufficiently blocked the BP and HR response. A dose of 1.5g/kg was associated with significant bradycardia requiring Atropine administration in 27% of cases.
In two comparable studies in normotensive ASA I-III patients, a bolus dose of 0.1g/kg followed by an infusion of 0.01g/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 0.2-0.3g/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.
Stimulation of the presynaptic receptors leads to reduced secretion of nor-adrenaline 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 4-5g/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 2 agonist. A biphasic cardiovascular response has been described. After a bolus of 1g/kg, a transient increase in BP and decrease in HR is seen. This is thought to be due to stimulation of 2 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 0.12g/kg over 10 min followed by an infusion of 0.006g/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 0.6g/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 1g/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.
Menda et al investigated patients undergoing fast track CABG surgery. An infusion of 1g/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 0.5g/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 -blockers pre-operatively.
In summary, from the above studies, it appears that doses between 0.5-1g/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, peri-operative Dexmedetomidine significantly increased the incidence of hypotension and bradycardia. (55) BLOCKERS
Labetolol has a combination of and blockade. The blockade is specific for 1 and non-specific for blockade. The ratio of 1 to 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 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)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 500g/kg over 4 minutes followed by an infusion of 200-300g/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).
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 (10g/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 7.5g/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.
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 pre-operatively. 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.
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.
SUMMARY OF EVIDENCEDrugDoseRouteBlunted BPBlunted HRNo effectReference
Lignocaine4ml of 4% solution Topi-
3-5 min pre LETIivimoderatemoderate32
Remifentanil0.5g/kg bolus then 0.25g/kg/miniviXX30
0.5g/kg then 0.1/kg/min in HT/ elderlyiviXX28,31
Sufentanil1g/kg 2min prior to LETIiviXX38-39
0.1g/kg then 0.01g/kg/min for 5 miniviXX40,41
60-90 pre LETIpomoderatemoderate45-48
Dexmedetomidine0.12g/kg over 10min then 0.006g/kg/
0.6g/kg/min over 10 miniviXX51
1g/kg over 20 minivimoderatemoderate52
0.5g/kg over 10 minutes, in cardiac ptivimoderatemoderate54
Esmolol500g/kg over 4min then 200-300g/kg/minivimoderateX5
Pregabalin75mg,1 hour pre LETIpox65
150mg,1 hour pre oppoX65,73
900mg,2hours pre LETIpoX62
1g, 1 hour pre LETIpoXX63
400mg 1 hour pre LETIpoX
800mg,1 hour pre oppomoderatemoderate64
X= effect on parameter
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.
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 non-cardiac 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, MAP100mmHg and SBP160mmHg or any duration of time.
The primary end-point was negative surgical outcome (NSO) including post-operative 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