Cardiovascular Pathophysiology And Outcomes

E   Original Clinical Research Report

Intraoperative Hypotension and Myocardial Infarction

Development Among High-Risk Patients Undergoing
Noncardiac Surgery: A Nested Case-Control Study
Linn Hallqvist, MD, PhD Student, DESA,*† Fredrik Granath, PhD,‡ Michael Fored, MD, PhD,‡
and Max Bell, MD, PhD*†
See Article, p 2

BACKGROUND: Hemodynamic instability during anesthesia and surgery is common and associ-
ated with cardiac morbidity and mortality. Information is needed regarding optimal blood pressure
(BP) threshold in the perioperative period. Therefore, the effect of intraoperative hypotension (IOH)
on risk of perioperative myocardial infarction (MI) was explored.
METHODS: A nested case-control study with patients developing MI <30 days postsurgery matched
with non–MI patients, sampled from a large surgery cohort. Study participants were adults under-
going noncardiac surgery at 3 university hospitals in Sweden, 2007–2014. Matching criteria were
age, sex, American Society of Anesthesiologists (ASA) physical status, cardiovascular disease,
hospital, year-, type-, and extent of surgery. Medical records were reviewed to validate MI diagnoses
and retrieve information on comorbid history, baseline BP, laboratory and intraoperative data. Main
exposure was IOH, defined as a decrease in systolic blood pressure (SBP), in mm Hg, from preop-
erative individual resting baseline lasting at least 5 minutes. Outcomes were acute MI, fulfilling the
universal criteria, subclassified as type 1 and 2, occurring within 30 days and mortality beyond 30
days among case and control patients. Conditional logistic regression assessed the association
between IOH, decrease in SBP from individual baseline, and perioperative MI. Mortality rates were
estimated using Cox proportional hazards. Relative risk estimates are reported as are the corre-
sponding absolute risks derived from the well-characterized source population.
RESULTS: A total of 326 cases met the inclusion criteria and were successfully matched with 326
controls. The distribution of MI type was 59 (18%) type 1 and 267 (82%) type 2. Median time to MI
diagnosis was 2 days; 75% were detected within a week of surgery. Multivariable analysis acknowl-
edged IOH as an independent risk factor of perioperative MI. IOH, with reduction of 41–50 mm Hg,
from individual baseline SBP, was associated with a more than tripled increased odds, odds ratio (OR)
= 3.42 (95% confidence interval [CI], 1.13-10.3), and a hypotensive event >50 mm Hg with consid-
erably increased odds in respect to MI risk, OR = 22.6, (95% CI, 7.69-66.2). In patients with a very
high-risk burden, the absolute risk of an MI diagnosis increased from 3.6 to 68 per 1000 surgeries.
CONCLUSIONS: In patients undergoing noncardiac surgery, IOH is a possible contributor to
clinically significant perioperative MI. The high absolute MI risk associated with IOH, among a
growing population of patients with a high-risk burden, suggests that increased vigilance of BP
control in these patients may be beneficial.  (Anesth Analg 2021;133:6–15)

KEY POINTS
• Question: Are intraoperative hypotensive events independently associated with development of
perioperative myocardial infarction (MI) in high-risk patients undergoing noncardiac surgery?
• Findings: In this nested case-control study of high-risk surgical patients, intraoperative hypo-
tensive events >50 mm Hg, decrease from individual baseline, was associated with a 20-fold
relative—and a 6% absolute—risk increase of clinically significant perioperative MI.
• Meaning: The elevated MI risk associated with intraoperative hypotension in high-risk patients
suggests that increased vigilance of intraoperative blood pressure may be beneficial.

From the *Department of Perioperative Medicine and Intensive Care (PMI),
Karolinska University Hospital, Stockholm, Sweden; †Department of
Pharmacology and Physiology, Karolinska Institutet, Stockholm, Sweden;
and ‡Clinical Epidemiology Unit, Department of Medicine, Karolinska
Institutet, Stockholm, Sweden.
Accepted for publication December 11, 2020.
Funding: The study was supported by the Swedish Heart-Lung Foundation
(no: 20180713), a charitable fundraising organization which took no part in
study design; collection, analysis and interpretation of data; in writing the
report; or in the decision to submit the article for publication. All researchers
in the group are independent from funders.
The authors declare no conflicts of interest.
Copyright © 2021 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000005391
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journal’s website (www.anesthesia-analgesia.org).
The study was registered at ClinicalTrials.Gov (identifier NCT03974321)
before data analysis.
The study protocol (2014/1306-31/3) was approved by the Regional Ethics
Committee of Stockholm, Sweden (Chairperson: Pierre Lafolie) on September
24, 2014, which also waived informed consent.
Listen to this Article of the Month podcast and more from OpenAnesthesia.org®
by visiting http://journals.lww.com/anesthesia-analgesia/pages/default.aspx.
Reprints will not be available from the authors.
Address correspondence to Linn Hallqvist, MD, PhD Student, DESA,
Department of Perioperative Medicine and Intensive Care (PMI), Karolinska
University Hospital, Solna, S-171 76, Stockholm, Sweden. Address e-mail to
linn.hallqvist@sll.se.

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 E  Original Clinical Research Report

GLOSSARY
AF = atrial fibrillation; AIC = Akaike information criterion; AKI = acute kidney injury; ASA = American
Society of Anesthesiologists; BP = blood pressure; CI = confidence interval; CHF = congestive heart
failure; DM = diabetes mellitus; ECG = electrocardiogram; ENT = ear, nose, and throat; GI = gastro-
intestinal; Hb = hemoglobin; HR = hazard ratio; ICD = International Classification of Diseases; IHD
= ischemic heart disease; IOH = intraoperative hypotension; KDIGO = Kidney Disease: Improving
Global Outcomes; MAP = mean arterial blood pressure; MI = myocardial infarction; N/A = not
applicable; NPR = National Patient Register; OR = odds ratio; Sao2 = arterial oxygen saturation;
SAP = systolic arterial pressure; SBP = systolic blood pressure; Spo2 = periferal oxygen saturation

H
ypotension is common after the anesthetic
induction,1 and may result from blood loss, fluid
shifts, and cytokine release perioperatively.
Hemodynamic instability is associated with periopera-
tive cardiac, kidney and cerebral injury, and increased
mortality in high-risk surgical patients.2–6 Consensus is
lacking regarding optimal blood pressure (BP) thresh-
olds to maintain adequate organ perfusion and oxygen-
ation during anesthesia and surgery. Various definitions
of perioperative hypotensive events exist. Multiple stud-
ies with binary cut-offs show associations with increased
risk of organ damage and mortality.2–4 Individualized
intraoperative hypotension (IOH) definitions are theo-
retically better when investigating the risk of periopera-
tive myocardial5,7 and kidney injury.8 Higher BP may be
beneficial for certain high-risk patients.2,3,7,9
Perioperative myocardial infarction (MI) diagnos-
ing is challenging since ischemic symptoms often are
disguised.6,10,11 MI is traditionally divided into different
types: MI type 1 from occlusive coronary artery disease,
plaque rupture, and thrombosis, and MI type 2, char-
acterized by a supply-demand imbalance resulting in
myocardial ischemia.12 Isolated cardiac troponin eleva-
tion, without other features of infarction, that is, ischemic
electrocardiogram (ECG) changes to the ST segment
and T-wave or symptoms, is termed myocardial injury.13
Perioperatively, hemodynamic instability is a presumed
mechanism.2,4–6 Perioperative myocardial injury and
infarction are associated with increased mortality.11,14–16
We investigated whether IOH is an independent
risk factor for acute perioperative MI, defined accord-
ing to the third universal definition,17 in a noncardiac
high-risk surgical population. Data on the frequency
of MI type 1 versus type 2, and on intraoperative
events possibly associated with the development of
MI; tachycardia, hypoxia, loss of blood, and hemoglo-
bin (Hb) were retrieved.
METHODS
Study Design
In a nested case-control study, MI case patients
matched with non–MI patients from the same source
population.
The study registered at ClinicalTrials.Gov
(NCT03974321; Intraoperative Hypotension and
Perioperative Myocardial Injury) before analysis
is provided in the Supplemental Digital Content 1,
Registry Protocol, http://links.lww.com/AA/D361.
Data Sources and Study Population
The source population was identified from a large
surgical cohort, the Orbit cohort,18 of patients under-
going noncardiac surgery in Sweden between 2007
and 2014. This was collected from 23 Swedish hospi-
tals and data were linked, using the unique Swedish
personal identification number, to several national
registries held by the National Board of Health and
Welfare; the National Patient Register (NPR)19 using
International Classification of Diseases (ICD)-10 codes,
the Swedish Cause of Death Registry,20 the Swedish
Prescribed Drug Register21 and to the National Quality
Registry: Swedeheart.22 Detailed information is found
in the previous study.18
Study Participants
Adults undergoing noncardiac surgery at 3 Swedish
hospitals, Karolinska-, Malmö-, and Lund University
hospital, were eligible for inclusion. We excluded car-
diac-, obstetric-, minor, and ambulatory care surger-
ies and if valid surgery codes or American Society
of Anesthesiologists (ASA) physical status were
unavailable.
Cases were patients developing MI <30 days post-
surgery as registered in the NPR—and/or Swedeheart.
One control was selected for each case, matched by
age (5-year intervals), sex, ASA physical status, car-
diovascular disease, surgical year, hospital, surgical
code, acute/elective surgery, and duration of surgery
(less or greater than 3 hours). The selection of matching
variables was based on risk factors of MI identified in
the Orbit cohort study.18 For 10% of the sampled cases,
an exact matched control could not be identified and
matching on calendar year and duration of surgery
was relaxed, resulting in a slight imbalance regarding
these factors. Controls were sampled among patients
alive without MI diagnosis at day 30, that is, cumula-
tive incidence sampling. Description of the source pop-
ulation and case-control selection is found in Figure 1.
Data Collection
Electronic medical records validated MI diagnoses and
comorbidities. Information retrieval was performed

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 Intraoperative Hypotension and Perioperative MI
Figure 1. Participant flowchart. ASA indicates American Society of Anesthesiologists.
blinded to case-control status. Preoperative history
of cardiovascular disease and diabetes mellitus (DM)
was registered. Baseline BP was determined as the
patient’s habitual value measured as an estimate of
all BPs, 5 on average, documented within 2 months
before surgery, obtained from the surgical ward, pre-
operative anesthetic consultation or documentations
from the primary health care. Lowest Hb and high-
est creatinine values, included in routine laboratory
testing within a week before surgery, and postopera-
tive days 1–3, were registered. Intraoperative medi-
cal information was collected from anesthetic charts,
including systolic blood pressure (SBP), heart rate,
oxygen saturation, blood loss, and fluid balance. The
predefined intraoperative events were hypotension
(decrease in SBP relative to each patient’s baseline
>5 minutes), tachycardia (increase in heart rate to
>110 beats per minute >5 minutes), blood loss (mL),
hypoxemia (periferal oxygen saturation [Spo2] <
90% >5 minutes), and cumulative fluid balance (mL).
Intraoperative information in nonelectronic anes-
thetic charts, including BP, has previously been vali-
dated, detailed in Supplemental Digital Content 2, BP
Validation, http://links.lww.com/AA/D362.
Exposure
The main exposure was IOH, defined as at least 1
event of an absolute decrease in SBP, from patient
preoperative baseline, lasting >5 minutes. IOH was
categorized into quartiles in accordance with inci-
dence among controls; ≤20, 21–40, 41–50, or >50 mm
8   
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Hg drop from individual baseline. Notably, IOH was
further analyzed as an absolute threshold and as a
relative decrease from baseline, detailed in statistics.
Outcomes
Acute MI, fulfilling the universal criteria,17 subclassi-
fied as type 1 and 2, occurring within 30 days. Mortality
beyond 30 days among case and control patients.
Statistical Analysis
Data were analyzed using STATA 14.2 (Stata Corp,
College Station, TX). Continuous data are presented
as medians with 25th–75th percentiles and categori-
cal variables as percentages. For comparison of lin-
ear and categorical variables, Mann-Whitney U test
or χ2 tests were used. Statistical tests are 2-sided, P
values <.05 considered significant. Several descrip-
tive analyses were performed; incidence of IOH at
the 3 surgical sites and frequency of IOH in different
surgical and anesthetic procedures were analyzed,
presented in Supplemental Digital Content 3, Tables
3–6, http://links.lww.com/AA/D363. Conditional
logistic regression was used to assess associations
between predefined risk covariates and perioperative
MI. Confounding was, first and foremost, handled, by
design, in the matching procedure. The controls were
carefully selected and closely matched to the corre-
sponding case, based on the strong risk factors of MI
identified in the Orbit cohort study,18 thus maximizing
the possibility—power—to study potential confound-
ing effect of intraoperative risk factors. In the analysis
ANESTHESIA & ANALGESIA
 E  Original Clinical Research Report
phase, confounding was further assessed using multi-
variable conditional logistic regression; preoperative,
unmatched, risk factors; preoperative BP, DM, isch-
emic heart disease (IHD), and intraoperative risk fac-
tors; blood loss, low Hb value and fluid balance, were
evaluated as potential confounders. Three definitions
of the main exposure, IOH, were explored; relative to
baseline (mm Hg), relative to baseline (%), and abso-
lute intraoperative thresholds. All 3 definitions were
subdivided into 4 categories, according to incidence
among controls. The multivariable models yielded
were compared using Akaike information criterion
(AIC) test.
To illustrate the overall low-absolute risks, cases
and controls were distributed to different risk strata,
according to 5 risk groups created in the original Orbit
cohort study:18
1. Very low risk: age <65, ASA physical status I,
low-risk surgery, no cardiovascular comorbid-
ity, or DM.
2. Low risk: same as group 1, but with 2 or 3 fac-
tors described in risk group 3 below.
3. Medium risk: age 65–79, ASA physical status
II, medium-risk surgery, cardiovascular comor-
bidity without previous MI, DM.
4. High risk: same as group 3 but with 2 or 3 fac-
tors described in group 5 below.
5. Very high risk: age ≥80, ASA physical status >II,
high-risk surgery, cardiovascular comorbidity
with previous MI.
The surgical risk groups, also obtained from the Orbit
study, were low (endocrine, ear, nose, and throat
[ENT], ophthalmic dental, breast, and gynecological
surgery), medium (gastrointestinal [GI], neuro, uro-
logic, orthopedic, and dermatologic surgery), and
high (vascular and thoracic surgery). Absolute risks
in these risk groups in relation to hypotensive events
were calculated using absolute risks of MI in the Orbit
study and the relative risks associated with IOH in this
study. These calculations rely on the assumption that
the estimated incidence of IOH events among our sam-
pled controls corresponds to the incidence of IOH in
the whole Orbit cohort; thus the estimated odds ratios
(ORs) in this study apply to the source population.
Mortality among cases and controls from day 31 to
90 and day 91 to 365 was compared with stratified Cox
regression, crude and adjusted hazard ratios (HRs)
with 95% confidence interval (CI) are presented. The
IOH-related risk of a fatal MI <30 days was analyzed
with logistic regression. Controls were selected using
cumulative incidence sampling; all controls were
bound to be alive at 30 days; thus 30-day mortality
difference between cases and controls could not be
analyzed.
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Sensitivity Analysis
We assessed effect modification by preoperative BP,
risk group, MI day, and tachycardia. Internal strati-
fied analyses of preoperative BP (<140 vs ≥140 mm
Hg), risk group; low (1–3) versus high (4–5), postop-
erative day of MI diagnose (day 1–2 versus >day 2),
and tachycardia (yes/no) were performed together
with interaction tests.
RESULTS
Study Participants
In total, 326 cases met the inclusion criteria and were
successfully matched with 326 controls (Figure  1).
Table  1 shows baseline and perioperative character-
istics. Cases had more DM and more frequently pre-
vious MI, even though cardiovascular disease was
a matching criterion and cases with a MI within 30
days before surgery were excluded. MI cases had
significantly higher preoperative BP (150 vs 133 mm
Hg) than controls. Preoperative laboratory status
(Hb and creatinine) were equal, as were intraopera-
tive anesthetic procedures and duration of surgery.
Intraoperative events—blood loss, low Hb levels,
excessive fluid balance—were more frequent in MI
cases than in controls (P < .001). MI cases more com-
monly developed AKI, fulfilling the Kidney Disease:
Improving Global Outcomes (KDIGO) criteria23 stage
1 within 2 postoperative days; 109 (39%) vs 34 (12%)
among controls (P < .001). The distribution of MI type
among cases was 59 (18%) type 1 and 267 (82%) type
2. Median time from surgery to MI diagnosis was 2
days; 75% were diagnosed within a week of surgery.
Outcomes
Presented in Table  2 and Figure  2, risk estimates
increased gradually with increasing intraoperative BP
drop. An intraoperative hypotensive reduction of 41–50
mm Hg, from individual baseline systolic arterial pres-
sure (SAP), was associated with more than tripled MI
risk, OR = 3.42 (95% CI, 1.13-10.3), and a hypotensive
event >50 mm Hg with considerable increased odds,
OR = 22.6 (95% CI, 7.69-66.2). These risk estimates are
derived after adjustment for preoperative covariates:
high BP (SAP ≥140 mm Hg), DM, and IHD and intraop-
erative risk events: blood loss (>1800 mL), Hb <85 g/L,
hypoxia (Sao2 <90%), and fluid balance (>2000 mL).
The right panel of Table 3 displays absolute risks
of MI in relation to IOH together with estimated inci-
dence of IOH in different risk groups. High absolute
excess risks were observed among patients with a SBP
drop >50 mm Hg as compared to patients with a SBP
drop ≤40 mm Hg; patients with very high baseline risk
increased their risk from 3.6 to 68 per 1000 operations,
patients with high risk increased from 0.5 to 10 and the
corresponding increase in lower-risk patients was 0.1
to 1.8. The incidence of high-risk hypotensive events
 Intraoperative Hypotension and Perioperative MI

Table 1. Characteristics of Cases and Controls Table 1. Continued

Cases Controls Cases Controls
Matched variables n = 326 n = 326 P Matched variables n = 326 n = 326 P
Age 78 (68–85) 78 (68–85) .995   Blood loss >1800 mL 24 (7) 9 (3) <.001
Female sex 146 (44.8) 146 (44.8) 1   Blood loss and/or low Hbc 61 (19) 22 (7) <.001
ASA physical status   Fluid balance (mL) 1000 600 <.001
 I 3 (0.92) 3 (0.92) 1 (440–1800) (300–1145)
 II 51 (15.6) 51 (15.6) 1   Fluid balance >2000 mL 69 (21) 28 (9) <.001
 III 238 (73) 238 (73) 1  AKI 109 (37) 34 (12) <.001
 IV 34 (10.4) 34 (10.4) 1 MI type
Cardiovascular disease  1 59 (18) N/A N/A
 None 39 (12) 40 (12) .914  2 267 (82)
  No previous MI 209 (64) 210 (65) Time to MI (d) 2 (1–7) N/A N/A
  Including previous MI 78 (24) 76 (23) Mortality
Surgery status   Day 31–90 17 (5) 18 (5) .862
 Elective 145 (44) 145 (44) 1   Day 91–365 39 (12) 26 (8) .065
Year of surgery Abbreviations: AF, atrial fibrillation; AKI, acute kidney injury; ASA, American
 2007–2008 37 (12) 38 (12) .983 Society of Anesthesiologists; CHF, congestive heart failure; DM, diabetes
 2009–2010 63 (19) 64 (19) mellitus; ENT, ear, nose, and throat; Hb, hemoglobin; IHD, ischemic heart
 2011–2012 113 (31) 114 (31) disease; MI, myocardial infarction; N/A, not applicable; Sao2, arterial oxygen
 2013–2014 111 (34) 112 (34) saturation; SBP, systolic blood pressure.
Hospital
a
Decrease in SBP in mm Hg, from baseline for >5 min.
b
Decrease in SBP in percent, from baseline for >5 min.
 Karolinska 133 (41) 133 (41) 1 c
Blood loss (>1800 mL) and/or Hb <85 g/L.
 Lund 53 (16) 53 (16)
 Malmö 140 (43) 140 (43)
Type of surgery
(ie, SBP drop >50 mm Hg) decreased with increasing
  Gastrointestinal surgery 55 (17) 55 (17) 1
 Urology 32 (10) 32 (10) risk factor burden (P = .005). The left panel of Table 3,
  Orthopedics surgery 122 (37) 122 (37) displaying Orbit study results,18 shows that 19% of
 Vascular 56 (17) 56 (17) surgeries are characterized as very high risk, with 76%
 Neuro 33 (10) 33 (10)
 Gynecology 6 (2) 6 (2)
of MI’s occurring in these patients. The corresponding
  ENT surgery 12 (4) 12 (4) fraction among cases in this study was 75%.
 Breast 4 (1) 4 (1) Absolute decrease in mm Hg, from individual pre-
 Ophthalmology 2 (0.5) 2 (0.5) operative BP baseline, was selected as main IOH defi-
 Dermatology 4 (1) 4 (1)
Duration of surgery >3 h 70 (21) 67 (21) .864
nition. Multivariable comparison of the 3 final models
Cases Controls based on different IOH definitions yielded similar
Not matched variables n = 326 n = 326 P odds estimates. The AIC test favored the models with
Comorbidities IOH defined as a relative to baseline measure, ahead
 IHD 152 (47) 110 (34) <.001 of the model with absolute BP thresholds (AIC value
 AF 64 (20) 76 (23) .255
 CHF 75 (23) 57 (17) .079
226), while data do not clearly support discrimina-
 DM 93 (29) 62 (19) .004 tion between the models based on absolute and rela-
Preoperative data tive change from baseline BP (AIC value 214 vs 210);
 Hb 125 126 .450 results are shown in Supplemental Digital Content 3,
(112–138) (112–139)
 Creatinine 88 83 .006 Table 2, http://links.lww.com/AA/D363.
(70–127) (67–104)
  Blood pressure (SBP, mm Hg) 150 133 <.001 Results From Sensitivity Analyses
(140–160) (125–140) There was no evidence of effect modification between
Intraoperative data
  Blood pressure (SBP, mm Hg) 80 (65–90) 90 (80–110) <.001
preoperative BP or intraoperative tachycardia and
 Hypotensiona (SBP, mm Hg) 70 (55–80) 40 (20–50) <.001 IOH. Although not significant, a more pronounced
 Hypotensionb (%) 47 (39–54) 30 (17–38) <.001 effect of IOH in higher-risk patients compared to lower-
  Tachycardia (>110 bpm) 81 (25) 23 (7) <.001 risk patients was observed, as in MI development on
  Hypoxia (Sao2 <90%) 21 (6) 2 (0.5) <.001
Anesthesia postoperative days 1–2 compared to later diagnosed
 General 166 (51) 158 (48) .168 MI cases; results are detailed in Supplemental Digital
  General and regional 43 (13) 37 (11) Content 3, Table 1, http://links.lww.com/AA/D363.
  Regional: spinal/epidural 90 (28) 113 (35)
None of the interaction tests involving these covari-
  Local anesthesia 27 (8) 18 (6)
Postoperative data ates were significant.
  Hb (g/L) 99 109 <.001
(90–111) (96–121) MORTALITY
  Hb <85 g/L 40 (12) 13 (4) <.001 In Table  4, results from mortality analyses are pre-
  Blood loss (mL) 200 100 <.001
(50–500) (0–300) sented. At 30 days postoperatively, 88 of 326 (27%)
(Continued) cases were deceased. There was no difference in IOH

10   
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 E  Original Clinical Research Report

Table 2. ORs of MI in Relation to Intraoperative Hypotension

Cases Controls OR (unadjusted) OR (adjusteda) OR (adjustedb)
Risk factor n (%) n (%) (95% CI) (95% CI) (95% CI)
Hypotensive eventc (mm Hg)
 ≤20 13 (4) 84 (26) Ref Ref Ref
 21–40 22 (7) 105 (32) 1.53 (0.60-3.94) 1.37 (0.50-3.73) 1.37 (0.48-3.92)
 41–50 31 (10) 64 (19) 5.30 (1.87-15.1) 4.58 (1.60-13.1) 3.42 (1.13-10.3)
 >50 260 (80) 73 (22) 38.8 (14.5-104) 27.0 (9.82-74.1) 22.6 (7.69-66.2)
Abbreviations: CI, confidence interval; DM, diabetes mellitus; Hb, hemoglobin; IHD, ischemic heart disease; MI, myocardial infarction; OR, odds ratio; Sao2,
­arterial oxygen saturation; SBP, systolic blood pressure.
a
Adjusted for preoperative risk factors: SBP, IHD, and DM.
b
Further adjusted for intraoperative risk factors: blood loss (>1800 mL), Hb <85 g/L, hypoxia (Sao2 <90%), and fluid balance (>2000 mL).
c
Decrease in SBP (mm Hg) from baseline for >5 min.

Figure 2. Odds ratios (log scale)

of MI in relation to intraopera-
tive hypotension. *Decrease in
SBP (mm Hg) from baseline for
>5 min. †Adjusted for preopera-
tive risk factors: SBP, IHD, and
DM. ‡Further adjusted for intra-
operative risk factors: blood
loss (>1800 mL), Hb <85 g/L,
hypoxia (Sao2 <90%), and fluid
balance (>2000 mL). DM indi-
cates diabetes mellitus; Hb,
hemoglobin; IHD, ischemic
heart disease; MI, myocardial
infarction; Sao2, arterial oxygen
saturation; SBP, systolic blood
pressure.

Table 3. MI Risk in Relation to Intraoperative Hypotensive Events and Preoperative Risk Group
Orbit studya Case-control study
No. of No. of MI No. of MI risk per 1000 operations (% with
Risk group(1–5) operations (%) MI (%) per 1000 MI (%) hypotensive event in the populationb)
Hypotensive eventc ≤40 41–50 >50
Relative risk (OR) Ref 2.81 18.6
Low(1+2) + medium(3) 230,108 (64) 121 (8) 0.8 33 (10) 0.1 (38) 0.3 (23) 1.8 (38)
High(4) 63,178 (17) 223 (16) 3.5 48 (15) 0.5 (49) 1.5 (20) 10 (31)
Very high(5) 67,404 (19) 1066 (76) 15.8 245 (75) 3.6 (64) 10 (19) 68 (17)
Risk groups: 1–2 (low risk): age <65 y, ASA physical status I, low-risk surgery, no cardiovascular comorbidity or DM, with 2 or 3 factors described in risk group 3.
3 (medium risk): age 65–79 y, ASA physical status II, medium-risk surgery, cardiovascular comorbidity, no previous MI, DM. 4 (high risk): same as risk group 3 but
with 2 or 3 factors described in risk group 5. 5 (very high risk): age ≥80 y, ASA physical status >II, high-risk surgery, cardiovascular comorbidity with previous MI.
Abbreviations: ASA, American Society of Anesthesiologists; DM, diabetes mellitus; MI, myocardial infarction; OR, odds ratio; SBP, systolic blood pressure.
a
Data from Orbit.18
b
Estimated from the controls in this study (P = .005 for difference between risk groups).
c
Decrease in SBP (mm Hg) from baseline for >5 min.

occurrence among patients with fatal (<30 days) and Crude HR was 2.12 (95% CI, 1.27-3.55), adjustment for
nonfatal MI, adjusting for age, sex, ASA physical sta- DM and IHD resulted a HR of 2.01 (95% CI, 1.19-3.38).
tus, and comorbidities in logistic regression (P = .84). During 31–90 days, there was no difference in mortal-
Day 91–365, 39 cases (20%) and 26 controls (9%) died. ity between cases and controls.

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 Intraoperative Hypotension and Perioperative MI
Table 4. Mortality Rates in Patients Developing MI Within 30 d After Surgery
Case Controls
Mortality n = 326 (%) n = 326 (%)
<30 da 88 (27) N/A
Day 31–90 17 (7) 18 (8)
Day 91–365 39 (20) 25 (9)
HR presented for mortality day 31–90 and day 91–365 after surgery.
Abbreviations: ASA, American Society of Anesthesiologists; HR, hazard ratios; MI, myocardial infarction; N/A, not applicable; OR, odds ratio.
a
Data from Orbit study. OR adjusted for 5-y age group, sex, ASA physical status, cardiovascular disease, previous MI, renal-, cerebrovascular-, and pulmonary
disease, diabetes mellitus, Charlson comorbidity index, surgical risk group, acute versus elective status, and year of surgery.
b
Adjusted for diabetes mellitus and ischemic heart disease.
DISCUSSION
In this case-control study, nested within a well-defined
cohort of high-risk noncardiac surgical patients, IOH
was identified as an important risk factor for MI
development in the perioperative period. A decrease
in systolic BP of 50 mm Hg, for at least 5 minutes,
from preoperative individual resting baseline, was
strongly associated with perioperative MI. However,
even though the relative risk of clinically manifested
MI associated with a large fall in BP was 20-fold, this
corresponds to low absolute excess risk for the major-
ity of operated patients. For patients with very high
preoperative risk burden, the associated absolute
excess risk was estimated to 6%. Long-term mortality
was increased with doubled mortality rates up to 1
year postsurgery, among patients surviving the first
3 postsurgery.
STRENGTHS
This project is unique considering the extensive source
population, enabling extraction of validated MI cases
within a prespecified period (30 days) after surgery
and selection of matched controls. Using high-reso-
lution data from a Swedish Quality Registry and the
NPR, we identified MI type 1 and the symptomatic
MI type 2, even though not referred to cardiology
clinics or subject to cardiac intervention. All cases
with MI diagnoses were validated, and the exact date
of MI development was obtained using electronic
medical records. Data included preoperative baseline
SBP and intraoperative values, enabling comparison
of different IOH definitions. A validation trial has
previously been performed to evaluate BP record-
ings (Supplemental Digital Content 2, BP Validation,
http://links.lww.com/AA/D362). An important
consideration is that our cases and controls are
sampled from a well-characterized surgery cohort.18
This allows estimation of the proportion of patients
exposed to IOH events in the population, from our
controls, and we are able to transfer the relative risk to
a corresponding absolute risk increases, even though
this is a case-control designed study. The risk-group
distribution of cases and controls were available and
information of postoperative day of MI development.
Analyses suggest additional effect of hypotension in
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OR (adjusteda) HR (unadjusted) HR (adjustedb)
5.49 (4.76–6.32)
1.14 (0.57–2.29) 1.02 (0.47–2.19)
2.12 (1.27–3.55) 2.01 (1.19–3.38)
patients belonging to higher risk groups and in MI
cases diagnosed within 2 days of surgery.
LIMITATIONS
The source population is collected from large regis-
tries and databases, with possible reporting bias, cod-
ing errors, and risk of misclassification. Furthermore,
it cannot be ensured that all physicians across Sweden
used the universal definition when the MI diagnosis
was made in the source population, which may result
in that MI cases are missed. Another major limitation
is the lack of cardiac biomarkers in all patients in the
source population; cardiac troponins measured rou-
tinely would have captured a larger proportion of
MI developed in the perioperative period (including
myocardial injuries), since many of these incidents
are clinically silent.14 Troponins may more readily
be analyzed in elderly/high-risk patients, possibly
leading to an overrepresentation of more severe and
frail patients among cases. Reverse causality must
be considered; we are unable to exclude the possibil-
ity that the hypotensive event is a consequence of a
major MI occurring on the operating table. However,
from a clinical perspective, MI following a fall in BP
is more probable. Moreover, all cases with a major
hypotensive episode, leading to cardiac biomarker-
analysis postsurgery despite the absence of other clin-
ical signs and ischemic symptoms were excluded to
minimize the risk of reversed causation. Additionally,
an observed episode of IOH may increase the likeli-
hood of MI diagnosis, leading to overestimation of
risk. Intraoperative data were extracted manually
from anesthetic charts, with inherent risk of errors.
Mean arterial blood pressure (MAP) data are lacking,
since this information is inadequately registered, and
the SBP-based IOH definition may affect the ability to
contextualize the results. The MI data were not avail-
able in the registry data; controls were sampled among
patients alive and MI-free at day 30. This cumula-
tive density sampling will overestimate relative risk;
however, since MI is a rare event, the overestimation
is small.24 Furthermore, this sampling scheme pre-
cludes estimation of 30-day mortality related to MI.
A previous study of our source population showed
perioperative MI increasing 30-day mortality 5-fold.
ANESTHESIA & ANALGESIA
 E  Original Clinical Research Report
In this study, MI cases had a 27% 30-day mortality,
compared to 26% in the source population.18 The
majority of cases are patients with elevated risk factor
burden, and our ability to estimate IOH-associated MI
risk among patients with low underlying risk is lim-
ited. The sensitivity analysis suggests lower relative
impact of IOH in low-risk patients and higher impact
among high-risk patients. Absolute excess among
high-risk patients may thus be under-estimated and,
correspondingly, in lower-risk patients, risks may be
overestimated.
Our results are in line with previous stud-
ies,2,4,5,7,9,25,26 but with a more pronounced effect of
hypotension. The nested case-control design and
the use of a well-defined population of high-risk
surgical patients give reliable estimates of asso-
ciations even in rare outcomes, reducing risk of
residual confounding. Further plausible reasons
for the strong association are our outcome—and
exposure—definitions. Only symptomatic MIs, ful-
filling the universal definition, are included, myo-
cardial injuries are not. Regarding exposure, since
we had access to pre- and intraoperative BP values,
we could compare different definitions, relative
to baseline (mm Hg), relative to baseline (%), and
absolute intraoperative thresholds. All resulted
in similar risk estimates with a gradual elevation
of MI risk in relation to an increasing fall in BP.
Statistically, relative drop in mm Hg from indi-
vidual baseline was favored. Little is known about
optimal BP thresholds perioperatively. A review
of IOH identified 140 definitions in 130 studies.27
Previous investigations are limited by use of spe-
cific systolic- or mean BP and may underestimate
IOH as a risk factor. Many studies use binary cut-
offs, MAP <55 mm Hg or systolic BP <80 mm Hg,
showing associations with organ damage and mor-
tality.2–4 Individual IOH definitions being beneficial
was strengthened by a randomized trial evaluating
BP in septic shock, where outcomes were improved
by high BP targets only in patients with hyperten-
sion.28 In patients with preexisting hypertension,
the autoregulatory capacity in the kidney and
brain, an essential mechanism to preserve optimal
blood perfusion when systemic BP fluctuates, is
affected.29,30 However, there are studies showing
that absolute and relative thresholds are compa-
rable in their ability to discriminate patients with
myocardial injury from those without.9 A random-
ized study showed that targeting an individual-
ized SBP, compared with standard management,
reduced postoperative organ dysfunction.26
Clinical Significance
MI in the perioperative period has a significant
impact on postoperative morbidity and mortality.
July 2021 • Volume 133 • Number 1 www.anesthesia-analgesia.org 13
Copyright © 2021 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
Thirty-day mortality is increased 5-fold,18 and the
risk increase remains; nonfatal perioperative MI
patients have a doubled risk of death at 1 year post-
surgery. Perioperative MI is an overall rare condi-
tion explaining why these striking findings have
not been identified previously. Patients developing
MI postsurgery are at increased risk of other com-
plications, such as respiratory failure, pneumonia,
wound infection, deep venous thrombosis, and con-
fusion. They also have a prolonged postoperative
length of stay and more commonly need treatment
at the intensive care unit.6,14,31–33 Our study identified
IOH as a potential major contributor to MI, irrespec-
tive of MI type. IOH was equally common among
patients with fatal and nonfatal MI, suggesting that
IOH is merely a trigger and that the mortality is a
result of other risk factors. Notably, IOH was signifi-
cantly more frequent in lower-risk than in higher-
risk groups, implying more vigilant anesthesia in
comorbid and fragile patients. The reduction in mm
Hg from individual baseline is a clinically appealing
definition, the lowest acceptable threshold could be
easily determined in the OR, before the anesthetic
induction. Importantly, perioperative hemody-
namic instability can be prevented in most clini-
cal situations. Adequate intravascular volume and
organ perfusion can be maintained using vasoactive
drugs and protocolized hemodynamic algorithms to
guide delivery of intravenous fluids and maximize
stroke volume. An increasing population of elderly
patients, with cardiovascular risk factors, are under-
going extensive surgery. Avoiding IOH, by an atten-
tive and meticulous anesthetic treatment during
and after surgery, could lower the risk of periop-
erative MI, as well as other postoperative compli-
cations, improving quality of life for these patients
and reducing costs for the society.
CONCLUSIONS
In patients undergoing noncardiac surgery, IOH
seems to be an important contributor to clinically
significant perioperative MI. The high absolute MI
risk associated with IOH among a growing popula-
tion of patients with a high-risk burden undergoing
surgery suggests that increased vigilance of BP con-
trol in these patients may be beneficial. E
DISCLOSURES
Name: Linn Hallqvist, MD, PhD Student, DESA.
Contribution: This author helped with the study design; acqui-
sition of data, statistical analysis, and interpretation of data;
manuscript writing.
Name: Fredrik Granath, PhD.
Contribution: This author helped with the study design; statis-
tical analysis and interpretation of data; supervising the scien-
tific process.
Name: Michael Fored, MD, PhD.
 Intraoperative Hypotension and Perioperative MI
Contribution: This author helped interpret the data and revise
the manuscript.
Name: Max Bell, MD, PhD.
Contribution: This author helped with the study design;
acquisition of data, interpretation of data; critically revising
the manuscript; final approval of the version to be published,
supervising the scientific process.
This manuscript was handled by: Stefan G. De Hert, MD.
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