ASSOCIATION OF INTRAOP HYPOTENSION AND CUMULATIVE NOREPINEPHRINE DOSE.pptx

ASSOCIATION OF INTRAOP HYPOTENSION AND CUMULATIVE
NOREPINEPHRINE DOSE WITH POSTOPERATIVE AKI IN PATIENT
HAVING CARDIAC SURGERY
MODERATOR – DR.AK SINHA(HOD)
DR. PRIYANKA CHOURASIA(AP)
DR. DIKSHA(SR)
PRESENTOR – DR.ANJALI (PG3)

AIM
• TO AVOID INTRAOPERATIVE HYPOTENSION AND THE NEED FOR
TREATMENT AS WELL AS LIMIT THE DURATION OF HYPOTENSION AND
THE DOSE OF VASOPRESSORS USED FOR TREATMENT.
• Hypotension harm threshold for AKI ,MAP around 65mmof g
maintaining MAP above this level during surgery is therefore
recommended .
• To maintain MAP and avoid intraop hypotension –VASOPRESSORS eg
Norepinephrine are effective but they cause AKI as –Norepinephrine
bind with alpha receptor on renal afferent arteriole

• Which cause RENAL MEDULLARY HYPOXIA
• We conclude both intraop hypotension and intraop cumulative
norepinephrine dose are independent and with postop AKI in male
and female adult having noncardiac surgery
• Intaop hypotension and wit post op AKI in high risk patient are
compared to low risk patient as per ASA status

INCLUSION CRITERIA
• Male and female adults who have non cardiac surgery with general
anaesthesia more than 60 min.
• EXCLUSION CRITERIA ;
1 CKD ,GFR<15ml/min
2 BMI>100kg/m2
3 Missing preop S.creatinine within 30 day of sx
4 Need for RRT
5 H/O of kidney transplant
6 Less than 10 MAP value per sx or MAP <0.3

7 Major sx like genitourinary sx eg Nephrectomy
8 ASA 6
9 First sx patient considered else repeated sx during study period is
excluded.
TARGET;
To keep MAP >60-70 mm of hg
Norepinephrine used as continuous infusion because of short lasting
hemodynamic effects

ACUTE HYPOTENSIVE STABS
• Initial dose – 0.05-0.15 mcg/kg/min
• Maintainance dose-2-80 mcg /min
• NOREPINEPHRINE – cumulative intraop norepinephrine dose between
beginning of GA and end of sx considering both bolu and continuous
adminstration

KDIGO –AKI ( Within first and postoperative
days)
1 Increase inS.creatinine >0.3 mg/dl witin any 48 hour period within 7
post op days
2 Increase in S.creatinine >50%from baseline within first 7
postoperative days
3 Need for Renal replacement within first 7 n postop days
(Urine output not considered in this criteria)

RESULT- study (N-38338)
• All patient both area under MAP >65 mm of hg and cumulative
intraop norepinephrine were independently an with AKI as were
baeline patient risk factor including age,BMI,DM and procedural
factors like DOS and total amount of crystalloid and colloid fluids.
• DISCUSSION;
• N-36338,Retrospective analysis suggest both intraop hypotension and
intraop cumulative norepinephrine dose are independently an with
post op AKI

ACCORDING TO RESEARCH
1 Chance of developing postop AKI increase by >50% per 1mm of hg x
days increase in the area under MAP of 65 mm of hg
2 A 1 mm of hg increase per day increase in area under MAP of 65 mm of
hg translate into an increase of 24 mm of hg x hour
For eg ,would result when intraop is 41 mm of hg for 1 hour or 53 mm of
hg for 2 hour
3 In ASA 3,4 status intraop hypotension was independently an with post
op AKI
While in ASA1,2 not so suggestive of intraop hypotension is an with post
op AKI in high risk patient but not in low risk patient.

• Intraop cumulative Norepineprine dose independently an with post op
AKI in all 3 multivariable modes
1 Model including all patient
2 Model including either or by patient ASA1,2,3 or 4
Considering all patient ,the risk of developing pot op AKI increase by 1.6%
per 1 mcg/kg increase in cumulative intraop norepinephrine dose
Eg.when a patient given nor epinephrine at a rate of 0.05mcg/kg/min fr 20
min.
The risk of developing pot op AKI would thus increae by 16% if
norepinephrine was given at 0.076mcg/kg/min for 132 min.

Background: Intraoperative hypotension is associated with acute kidney injury (AKI). Clinicians
thus frequently use vasopressors, such as norepinephrine, to maintain blood pressure. However,
vasopressors themselves might promote AKI. We sought to determine whether both
intraoperative hypotension and cumulative intraoperative norepinephrine dose are
independently associated with postoperative AKI in patients undergoing noncardiac surgery.
Methods: This was a retrospective cohort analysis of 38 338 adult male and female patients who
had noncardiac surgery. The primary outcome was AKI within the first 7 postoperative days. We
performed adjusted multivariable logistic regression analysis to determine whether
intraoperative hypotension (quantified as area under a mean arterial pressure [MAP] of 65 mm
Hg) and cumulative intraoperative norepinephrine dose were independently associated with AKI.

Results: The median (25th percentile, 75th percentile) area under a MAP of 65 mm Hg was 0.09
(0.02, 0.22) mm Hg*day in
patients with AKI and 0.05 (0.01, 0.14) mm Hg*day in patients without AKI (P<0.001). The
cumulative intraoperative
norepinephrine dose was 1.92 (0.00, 13.09) mgkg 1 in patients with AKI and 0.00 (0.00, 0.00) mgkg
1 in patients without AKI
(P<0.001). Both the area under a MAP of 65 mm Hg (odds ratio 1.55 [95% confidence interval
1.17e2.02] per mm Hg*day;
P¼0.002) and the cumulative intraoperative norepinephrine dose (odds ratio 1.02 [95% confidence
interval 1.01e1.02] per
mgkg 1; P<0.001) were independently associated with AKI.
Conclusions: Both intraoperative hypotension and cumulative intraoperative norepinephrine dose
were independently
associated with postoperative AKI in patients undergoing noncardiac surgery. Pending results of
trials testing whether
these relationships are causal, it seems prudent to avoid both profound hypotension and high
norepinephrine doses in
adults undergoing noncardiac surgery.

Intraoperative hypotension is common in patients having noncardiac surgery with general
anaesthesia and is associated with organ injury, including acute kidney injury (AKI).3e6 On a
population basis, the hypotensive harm threshold for AKI is a mean arterial pressure (MAP) of
around 65mmHg.7MaintainingMAPabovethislevelduringsurgeryis therefore recommended. To
maintain MAP and avoid intraoperative hypotension, clinicians frequently use vasopressors
such as norepinephrine.10 While vasopressors are effective against hypotension,
theythemselvesareassociatedwithAKI.10e12Norepinephrine, for example, may reduce renal
perfusion by preferentially binding to a-receptors on renal afferent arterioles, resulting in renal
medullary hypoxia. We assumed that not only intraoperative hypotension but also
norepinephrine administered during surgery may be independently associated with
postoperative AKI

. We thus primarily sought to determine whether both intraoperative hypotension and
the intraoperative cumulative norepinephrine dose are independently associated with
post operative AKI in male and female adults having noncardiac surgery. A previous
analysis reported that intraoperative hypotension was associated with postoperative
AKI in high-risk patients but not in low-risk patients.14 As a secondary analysis, we
therefore repeated our primary analysis separately for patients with low vs high
baseline risk according to the American Society of Anesthesiologists (ASA) physical
status

Methods
Study design, patients, and data sources
This was a retrospective cohort analysis of patients who had noncardiac surgery with general anaesthesia at the
University Hospital Giessen (UKGM Giessen GmbH, Giessen, Germany)
affiliated with the Justus-Liebig University Giessen between
September1,2010andSeptember7,2020.Theethicscommittee of the Justus-Liebig University Giessen initially approved
this study on October 10, 2019 (Az 194/19) and approved an amend
menttoextendthestudyperioduntilSeptember7,2020onMay 18, 2021. The sampling frame was based on the availability
of suitable data. The need for informed consent was waived. The statistical analysis plan was written and approved by
the prin cipal investigators and study statisticians before data analysis.

We included male and female adults who had noncardiac surgery with general anaesthesia
lasting >60 min (from the beginning of general anaesthesia until the end of surgery). We
excluded patients with chronic kidney disease stage 5 (preoper
ativeestimatedglomerularfiltrationrate100kgm2, missing preoperative baseline serum
creatinine values within 30 days of surgery, need for renal replacement therapy, history of
kidney transplantation, less than 10 MAP values per surgery, or MAP values min 1

Clinical management
Patientsweremonitoredandmanagedperinstitutionalroutine, which included that clinicians
generally strove to keep MAP >60e70 mm Hg. Vasopressors routinely used to treat hypoten sion
in our institution are a 20:1 mixture of cafedrine/theo
drenaline(approvedinGermanyasAkrinor®;Ratiopharm,Ulm, Germany) or norepinephrine
(Arterenol®; S anofi-Av enti s Deutschland GmbH, Frankfurt am Main, Germany). Cafedrine/
theodrenaline mediates its effects by stimulation of a-andb receptors and nonspecific inhibition
of phosphodiesterases, thereby increasing MAP by combined effects on preload, contractility,
and afterload. Cafedrine/theodrenaline isused to treat intraoperative hypotension. It is
administered as bo luses and has long-lasting haemodynamic effects. Norepi nephrine also can
be administered as a bolus, but is usually given as continuous infusion because of its short-lasting
hae modynamic effects. We routinely give norepinephrine via pe ripheral venous access.

Blood pressure was measured either intermittently using oscillometry at 3-min
intervals or continuously using an arterial catheter, and was recorded by the
anaesthesia infor mation management system at 3-min (oscillometry) or 1-min
(arterial catheter) intervals.

Hypotension exposure
We defined intraoperative hypotension as a MAP<65 mmHg.7
Considering all blood pressure measurements recorded be
tween the beginning of general anaesthesia and the end of
surgery, we calculated the cumulative duration patients had a
MAP <65 mm Hg (unit: min) and the area under a MAP of 65
mmHg(unit: mm Hg*day).2
Norepinephrine exposure
We calculated the cumulative intraoperative norepinephrine
dose, that is, the cumulative amount of norepinephrine
administered to patients between the beginning of general
anaesthesia and the end of surgery, considering both bolus and
continuous administration. We normalised the cumula tive
norepinephrine dose to body weight (unit: mgkg 1)

Outcomes
The primary outcome was AKI within the first 7 postoperative days. Postoperative AKI was defined
based on the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Acute
Kidney Injury22 as (a) an increase in serum creatinine concentration of 0.3 mg dl 1 within any 48 h
period within 7 postoperative days, or (b) an increase in serum creatinine of 50% from baseline within
the first 7 post operative days, or (c) need for renal replacement therapy
withinthefirst7postoperativedays.Wedidnotconsiderurine output criteria as urine output was not
systematically assessed and documented in our patients. The preoperative baseline serum creatinine
concentration was defined as the most recent recorded value within 30 days before surgery. We
considered AKI as a binary outcome (no AKI vs AKI of any stage).

Statistical analysis
Variables are described using absolute numbers (percentages) for categorical variables, means (standard
deviations) for normally distributed metric variables, and medians (25th percentile, 75th percentile) or
ranges for non-normally distributed metric variables. Metric variables were assumed to be non-normally
distributed if the kurtosis of the distribu tion exceeded 5. We computed bar charts to illustrate the
incidence of AKI stratified by both quartiles of intraoperative cumulative norepinephrine dose and
quartiles of intraoperative hypo tension inall patients irrespective of their ASA physical status, and
separately in patients assigned ASA physical status 1 or 2 vs 3 and 4 (the few patients assigned ASA
physical status 5 were analysed together with those assigned ASA physical status 4).

We compared patients with and without AKI within the first 7 postoperative days using
two-sided t-tests for normally distributed variables, two-sided Wilcoxon-rank sum tests
for non-normally distributed variables, or Х2 tests for categorical outcomes. We
performed univariable and multivariable logistic regression analyses to determine
whether the area un der a MAP of 65 mm Hg and the cumulative intraoperative
norepinephrine dose were associated with AKI within the first 7 postoperative days. We
adjusted multivariable logistic regression analysis for potentially confounding and
mediating factors, which were selected by clinical rationale. Additionally, we
constructed two directed acyclic graphs to conceptualise the relationships between the
exposures (area under a MAP of 65 mm Hg and cumulative intraoperative
norepinephrine dose) and the outcome (AKI within the first 7 postoperative days),
while accounting for potential confounding and mediating variables (Supplementary
Figs S1 and S2).

The selection of confounders and mediators in the two directed acyclic graphs resulted in
an identical adjustment set for both exposure outcome models. Therefore, we could
estimate the direct effect of the area under aMAPof65mmHgandthetotal effect of
cumulative intraoperative norepinephrine dose on AKI within the first 7 postoperative days
in one model. How ever, we acknowledge the presence of unmeasured con founding
factors; our analyses thus cannot confirm causal relationships and should be considered
descriptive and exploratory. We primarily performed multivariable logistic regression
analysis including all patients irrespective of their ASA physical status. To investigate
whether ASA physical status is also an effect modifier, we separately performed two
multivariable logistic regression analyses: one including only patients assigned ASA physical
status 1 or 2, and one including only patients assigned ASA physical status 3and4(the few
patients assigned ASA physical status 5 were analysed together with those assigned ASA
physical status 4).

The significance level was set to P<0.05, and no adjustment
for multiplicity was applied because of the exploratory nature
of the study. Hence, we focused on effect sizes (i.e. odds ratios
with 95% confidence intervals [95% CI]) and interpreted them in an exploratory
manner.
We performed statistical analyses in R, Version 4.2.1 (R
Foundation for Statistical Computing, Vienna, Austria) and
used the following packages: MASS, readxl, plyr, magrittr,
knitr, haven, mosaic, kableExtra, grid, gridExtra, tidyverse,
tableone, broom

Results
We included 38 338patients with a mean [SD] age of 54.8 [18.6)] yr (Fig. 1, Table 1).
Patients predominantly had general surgery (10 514 patients, 27.4%), trauma surgery
(6177 patients, 16.1%), otolaryngology surgery (5853 patients, 15.3%), neurosurgery
(5213 patients, 13.6%), orthopaedic surgery (3416 patients, 8.9%), and gynaecological
surgery (1750 patients, 4.6%). The median (25th percentile, 75th percentile) duration of
surgery was 132 (94, 194) min. The median total volume of crystalloid f luid
administration was 760 (514, 1281) ml. Of the patients, 20 452 (53.3%) were given
cafedrine/theo drenaline and 6028 (15.7%) were given norepinephrine; 4033 patients
(10.5%) were given both cafedrine/theodrenaline and norepinephrine, 16 419 patients
(42.8%) were given only cafe drine/theodrenaline, and 1995 patients (5.2%) were given
only norepinephrine. Vasopressor therapy stratified by ASA phys ical status is shown in
Supplementary Table S1.

1457 patients (3.8%) developed AKI within the first 7 post
operative days, and 724 (2.0%) died during the hospital stay.
Figure 2 shows the incidence of AKI stratified by both quartiles
of intraoperative cumulative norepinephrine dose and quar tiles of intraoperative
hypotension.
The median cumulative duration patients had a MAP <65 mm Hgwas 25 (8, 53) min
in patients with AKI and 17 (4, 39) min in patients without AKI (P<0.001) (Table 2)
The median area under a MAP of 65mm Hg was 0.09(0.02,0.22)mmHg*day in
patientswithAKIand0.05(0.01,0.14)mmHg*dayinpatients without AKI (P<0.001)
(Table 2).
The median cumulative intraoperative norepinephrine dose was 1.92 (range:
0.00e575.62) mgkg 1 in patients with AKI and 0.00 (range:

The results of univariable logistic regression analyses are
showninSupplementaryTableS2.Inmultivariable regression
analysis including all patients, both the area underaMAPof65
mm Hg (odds ratio 1.55 [95% CI 1.17e2.02] per mm Hg*day;
P¼0.002) and the cumulative intraoperative norepinephrine
dose (odds ratio 1.02 [95% CI 1.01e1.02] per mgkg 1; P<0.001)
were independently associated with AKI, as were baseline
patient risk factors including age, body mass index, diabetes
mellitus, and procedural factors (including duration of surgery
and total amounts of crystalloid and colloid fluids) (Table 3,
Supplementary Table S3).

In multivariable regression analysis including only patients
assigned ASA physical status 3or4, both the area under a MAP
of 65 mm Hg (odds ratio 1.91 [95% CI 1.36e2.67] per mm
Hg*day; P<0.001) and the cumulative intraoperative norepi
nephrine dose (odds ratio 1.02 [95% CI 1.01e1.03] per mgkg 1;
P<0.001) were independently associated with AKI (Table 4). In
multivariable regression analysis including only patients
assigned ASA physical status 1 or 2, the cumulative intra
operative norepinephrine dose was independently associated
with AKI (odds ratio 1.02 [95% CI 1.00e1.03] per mg kg 1;
P¼0.006), but the area under a MAP of 65mmHgwasnot(odds
ratio 1.00 [95% CI 0.56e1.66] per mm Hg*day; P>0.9) (Table 4,
Supplementary Table S4)

ASSOCIATION OF INTRAOP HYPOTENSION AND CUMULATIVE NOREPINEPHRINE DOSE.pptx

Discussion
Our retrospective analysis of 38 338 adult male and female
noncardiac surgery patients suggests that both intraoperative
hypotension and the intraoperative cumulative norepineph
rine dose are independently associated with postoperative
AKI.
Consistent with previous observational research5e7,14,23 we
found an association between intraoperative hypotension and
AKI. Compared with patients who did not develop post
operative AKI, those who did had about one-third more
intraoperative hypotension, as quantified by the area under a
MAPof65mmHg.Inresearch,theareaunderaMAPthreshold
is an established marker of hypotension severity and dura
tion,21 but it does not intuitively translate into measures
clinically used to quantify hypotension. According to our re
sults, the chance for developing postoperative AKI increased
by morethan50%per1mmHg*day increase in the area under
a MAPof65mmHg.A1mmHg*day increase in the area under
a MAPof65mmHgtranslatesinto an increase of 24 mm Hg*h
and, for example, would result when the intraoperative MAP is
41 mm Hg for 1hor53 mm Hg for2h.

Interestingly, intraoperative hypotension was independently associated with
postoperative AKI in our multivariable regression models including all patients and
including only patients assigned ASA physical status 3 or 4, but not in the model
including only patients assigned ASA physical status 1 or 2. This finding confirms a
previous analysis suggesting that intraoperative hypotension is associated with
postoperative AKI only in high-risk e but not in low-risk e patients.14 In general,
baseline patient risk factors are more strongly associated with AKI than
intraoperative hypotension.7,14 Our analysis, for example, suggests that the
chance of developing postoperative AKI increases when patients are older or have
diabetes mellitus. Most baseline patient risk factors are not modifiable before
surgery. In contrast, intraoperative hypo tension is amenable to interventions and
can effectively be treated byclinicians,24 usually by giving vasopressorsor fluids.

We found that the intraoperative cumulative norepinephrine dose was also
independently associated with post operative AKI in all three multivariable models
(i.e. the model including all patients and the models including either only patients
assigned ASA physical status 1 or 2 or only patients assigned ASA physical status 3
or 4). Considering all patients, the risk of developing postoperative AKI increased
by 1.6% per 1 mgkg 1 increase in the cumulative intraoperative norepinephrine
dose which would, for example, result when a patient is given norepinephrine at a
rate of 0.05 mgkg 1 min 1for 20 min. The risk of developing postoperative AKI
would thus increase by 16% if norepinephrine was given at 0.076 mgkg 1 min 1 for
132 min (the median duration of surgery in our study).

Most previous analyses on the relationship between intra operative hypotension and
postoperative AKI did not consider intraoperative vasopressor requirements as a potential
independent risk factor for AKI.4,5,7,14,25 A retrospective cohort
studyof830electivenoncardiacsurgerypatientswhowereat
least65yrofagereportedanassociationbetweenthecumu lative intraoperative vasopressor dose
and postoperative AKI.11Specifically, the cumulative intraoperative dose of any
vasopressor>20mgwas independently associated with AKI
(oddsratio2.47[95%CI1.34e4.58];P¼0.004),withevery5mg increase in the cumulative
intraoperative vasopressor dose increasing the AKI risk by 11% (95%CI 3e19%; P¼0.06).11
Similarly,aretrospectiveanalysisof32250patientswhohad major abdominal surgery suggests that
increasing the vasopressor dose from 0 to 0.04 mg kg 1min 1 of norepinephrine equivalents
would increase the risk of AKI 1.8-fold.10 Inan
internationalobservationalstudyofmorethan10000major surgery patients requiring
postoperative treatment in an intensive care or high-dependency unit, the use of vasopressors
was associated with an increased risk of developing postoperativeAKI.12

InpatientsassignedASAphysicalstatus1or2(butnot3 and4), the
cumulative intraoperative dose of cafedrine/theo drenaline
was associated with post operative AKI . One may speculate
that cliniciansusecafedrine/theodrenaline in low risk patients
and norepinephrine in high-risk patients who are more likely to
develop profound intraoperative hypotension. More
observational studies and robust interventional trials are
needed to investigate the relationship between different
vasopressors and post operative AKI.A large multi centre pilot
trial of 3626 adults having non cardiac surgery showed that
such trials are warranted and feasible.

The optimal haemodynamic treatment strategy to avoid AKI in
patients having surgery remains unknown. During the past
decade, clinicians seem to increasingly focus on avoiding
profound hypotension , often by the liberal use of vasopres sors
.A retrospective analysis of fluid and vasopressor therapy in US
hospitalsreportedthatbetween2015and2019major abdominal
surgery patients were given less fluids but more
vasopressors.10 Although the duration of hypotension
decreased during the study period, the incidence of post
operative AKI slightly increased (from11.4%in2016to13%in
2019).10

Although our retrospective observational analysis suggests that both intraoperative
hypotension and the intraoperative cumulative norepinephrine dose were
independently associated with post operative AKI, it does not allow a formal analysis
of a causal relationship between intraoperative hypotension, the administration of
vasopressors, and AKI. Norepinephrine, cafedrine/theodrenaline, and intravenous f
luids (crystalloids and colloids) have a direct effect on blood pressure and are given to
prevent or treat hypotension, and may be linked to the development of AKI. We thus
treated norepinephrine, cafedrine/theodrenaline, and intravenous f luids (crystalloids
and colloids) as mediators in our analyses. Although we adjusted our regression
models for known risk factors for AKI and potential clinical confounders, our findings
may be influenced by residual confounding.

That there was no standardised treatment protocol for intraoperative
hypotension may reflect routine care in most institutions. However,
clinicians’ personal preferences likely influenced decisions regarding fluid
and vasopressor therapy. Finally, we excluded patients in whom
preoperative baseline serum creatinine values were missing. We cannot
quantify whether and how these patients differed from patients included
in the analysis. However, it is likely that patients in whom serum
creatinine was not measured before surgery were relatively young and
healthy and had minor surgery.

Conclusions
Both intraoperative hypotension and the intraoperative
cumulative norepinephrine dose were independently
associated with postoperative acute kidney injury in female and
male adults having non cardiac surgery. Pending results of trials
testing whether these relationships are causal, it seems
prudent to avoid both pro found hypotension and high
norepinephrine doses

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