Intraoperative Hypotension and Myocardial Infarction Development Among High-Risk Patients Undergoing Noncardiac Surgery: A Nested Case-Control Study : Anesthesia & Analgesia

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Intraoperative Hypotension and Myocardial Infarction Development Among High-Risk Patients Undergoing Noncardiac Surgery: A Nested Case-Control Study

Hallqvist, Linn MD, PhD Student, DESA*,†; Granath, Fredrik PhD; Fored, Michael MD, PhD; Bell, Max MD, PhD*,†

Author Information
Anesthesia & Analgesia 133(1):p 6-15, July 2021. | DOI: 10.1213/ANE.0000000000005391

Abstract

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 hypotensive 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.

See Article, p 2

Hypotension is common after the anesthetic induction,1 and may result from blood loss, fluid shifts, and cytokine release perioperatively. Hemodynamic instability is associated with perioperative cardiac, kidney and cerebral injury, and increased mortality in high-risk surgical patients.2–6 Consensus is lacking regarding optimal blood pressure (BP) thresholds to maintain adequate organ perfusion and oxygenation during anesthesia and surgery. Various definitions of perioperative hypotensive events exist. Multiple studies with binary cut-offs show associations with increased risk of organ damage and mortality.2–4 Individualized intraoperative hypotension (IOH) definitions are theoretically better when investigating the risk of perioperative myocardial5,7 and kidney injury.8 Higher BP may be beneficial for certain high-risk patients.2,3,7,9

Perioperative myocardial infarction (MI) diagnosing 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, characterized by a supply-demand imbalance resulting in myocardial ischemia.12 Isolated cardiac troponin elevation, 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 according 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 hemoglobin (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, https://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 undergoing noncardiac surgery in Sweden between 2007 and 2014. This was collected from 23 Swedish hospitals 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 cardiac-, obstetric-, minor, and ambulatory care surgeries and if valid surgery codes or American Society of Anesthesiologists (ASA) physical status were unavailable.

F1
Figure 1.:
Participant flowchart. ASA indicates American Society of Anesthesiologists.

Cases were patients developing MI <30 days postsurgery 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, cardiovascular 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, cumulative incidence sampling. Description of the source population and case-control selection is found in Figure 1.

Data Collection

Electronic medical records validated MI diagnoses and comorbidities. Information retrieval was performed 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, preoperative anesthetic consultation or documentations from the primary health care. Lowest Hb and highest creatinine values, included in routine laboratory testing within a week before surgery, and postoperative days 1–3, were registered. Intraoperative medical 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 anesthetic charts, including BP, has previously been validated, detailed in Supplemental Digital Content 2, BP Validation, https://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 incidence among controls; ≤20, 21–40, 41–50, or >50 mm 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 subclassified 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 categorical variables as percentages. For comparison of linear and categorical variables, Mann-Whitney U test or χ2 tests were used. Statistical tests are 2-sided, P values <.05 considered significant. Several descriptive 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, https://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 corresponding case, based on the strong risk factors of MI identified in the Orbit cohort study,18 thus maximizing the possibility—power—to study potential confounding effect of intraoperative risk factors. In the analysis phase, confounding was further assessed using multivariable conditional logistic regression; preoperative, unmatched, risk factors; preoperative BP, DM, ischemic heart disease (IHD), and intraoperative risk factors; 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 absolute 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 comorbidity, or DM.
  2. Low risk: same as group 1, but with 2 or 3 factors described in risk group 3 below.
  3. Medium risk: age 65–79, ASA physical status II, medium-risk surgery, cardiovascular comorbidity without previous MI, DM.
  4. High risk: same as group 3 but with 2 or 3 factors 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, urologic, 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 sampled 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.

Sensitivity Analysis

We assessed effect modification by preoperative BP, risk group, MI day, and tachycardia. Internal stratified analyses of preoperative BP (<140 vs ≥140 mm Hg), risk group; low (1–3) versus high (4–5), postoperative day of MI diagnose (day 1–2 versus >day 2), and tachycardia (yes/no) were performed together with interaction tests.

RESULTS

Study Participants

Table 1. - Characteristics of Cases and Controls
Matched variables Cases
n = 326
Controls
n = 326
P
Age 78 (68–85) 78 (68–85) .995
Female sex 146 (44.8) 146 (44.8) 1
ASA physical status
 I 3 (0.92) 3 (0.92) 1
 II 51 (15.6) 51 (15.6) 1
 III 238 (73) 238 (73) 1
 IV 34 (10.4) 34 (10.4) 1
Cardiovascular disease
 None 39 (12) 40 (12) .914
 No previous MI 209 (64) 210 (65)
 Including previous MI 78 (24) 76 (23)
Surgery status
 Elective 145 (44) 145 (44) 1
Year of surgery
 2007–2008 37 (12) 38 (12) .983
 2009–2010 63 (19) 64 (19)
 2011–2012 113 (31) 114 (31)
 2013–2014 111 (34) 112 (34)
Hospital
 Karolinska 133 (41) 133 (41) 1
 Lund 53 (16) 53 (16)
 Malmö 140 (43) 140 (43)
Type of surgery
 Gastrointestinal surgery 55 (17) 55 (17) 1
 Urology 32 (10) 32 (10)
 Orthopedics surgery 122 (37) 122 (37)
 Vascular 56 (17) 56 (17)
 Neuro 33 (10) 33 (10)
 Gynecology 6 (2) 6 (2)
 ENT surgery 12 (4) 12 (4)
 Breast 4 (1) 4 (1)
 Ophthalmology 2 (0.5) 2 (0.5)
 Dermatology 4 (1) 4 (1)
Duration of surgery >3 h 70 (21) 67 (21) .864
Not matched variables Cases
n = 326
Controls
n = 326
P
Comorbidities
 IHD 152 (47) 110 (34) <.001
 AF 64 (20) 76 (23) .255
 CHF 75 (23) 57 (17) .079
 DM 93 (29) 62 (19) .004
Preoperative data
 Hb 125 (112–138) 126 (112–139) .450
 Creatinine 88 (70–127) 83 (67–104) .006
 Blood pressure (SBP, mm Hg) 150 (140–160) 133 (125–140) <.001
Intraoperative data
 Blood pressure (SBP, mm Hg) 80 (65–90) 90 (80–110) <.001
 Hypotensiona (SBP, mm Hg) 70 (55–80) 40 (20–50) <.001
 Hypotensionb (%) 47 (39–54) 30 (17–38) <.001
 Tachycardia (>110 bpm) 81 (25) 23 (7) <.001
 Hypoxia (Sao 2 <90%) 21 (6) 2 (0.5) <.001
Anesthesia
 General 166 (51) 158 (48) .168
 General and regional 43 (13) 37 (11)
 Regional: spinal/epidural 90 (28) 113 (35)
 Local anesthesia 27 (8) 18 (6)
Postoperative data
 Hb (g/L) 99 (90–111) 109 (96–121) <.001
 Hb <85 g/L 40 (12) 13 (4) <.001
 Blood loss (mL) 200 (50–500) 100 (0–300) <.001
 Blood loss >1800 mL 24 (7) 9 (3) <.001
 Blood loss and/or low Hbc 61 (19) 22 (7) <.001
 Fluid balance (mL) 1000 (440–1800) 600 (300–1145) <.001
 Fluid balance >2000 mL 69 (21) 28 (9) <.001
 AKI 109 (37) 34 (12) <.001
MI type
 1 59 (18) N/A N/A
 2 267 (82)
Time to MI (d) 2 (1–7) N/A N/A
Mortality
 Day 31–90 17 (5) 18 (5) .862
 Day 91–365 39 (12) 26 (8) .065
Abbreviations: AF, atrial fibrillation; AKI, acute kidney injury; ASA, American Society of Anesthesiologists; CHF, congestive heart failure; DM, diabetes mellitus; ENT, ear, nose, and throat; Hb, hemoglobin; IHD, ischemic heart disease; MI, myocardial infarction; N/A, not applicable; Sao2, arterial oxygen saturation; SBP, systolic blood pressure.
aDecrease in SBP in mm Hg, from baseline for >5 min.
bDecrease in SBP in percent, from baseline for >5 min.
cBlood loss (>1800 mL) and/or Hb <85 g/L.

In total, 326 cases met the inclusion criteria and were successfully matched with 326 controls (Figure 1). Table 1 shows baseline and perioperative characteristics. Cases had more DM and more frequently previous 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 intraoperative 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 commonly 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 pressure (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 intraoperative risk events: blood loss (>1800 mL), Hb <85 g/L, hypoxia (Sao2 <90%), and fluid balance (>2000 mL).

Table 2. - ORs of MI in Relation to Intraoperative Hypotension
Risk factor Cases
n (%)
Controls
n (%)
OR (unadjusted) (95% CI) OR (adjusteda) (95% CI) OR (adjustedb) (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.
aAdjusted for preoperative risk factors: SBP, IHD, and DM.
bFurther adjusted for intraoperative risk factors: blood loss (>1800 mL), Hb <85 g/L, hypoxia (Sao2 <90%), and fluid balance (>2000 mL).
cDecrease in SBP (mm Hg) from baseline for >5 min.

F2
Figure 2.:
Odds ratios (log scale) of MI in relation to intraoperative hypotension. *Decrease in SBP (mm Hg) from baseline for >5 min. Adjusted for preoperative risk factors: SBP, IHD, and DM. Further adjusted for intraoperative risk factors: blood loss (>1800 mL), Hb <85 g/L, hypoxia (Sao 2 <90%), and fluid balance (>2000 mL). DM indicates diabetes mellitus; Hb, hemoglobin; IHD, ischemic heart disease; MI, myocardial infarction; Sao 2, arterial oxygen saturation; SBP, systolic blood pressure.

The right panel of Table 3 displays absolute risks of MI in relation to IOH together with estimated incidence 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 (ie, SBP drop >50 mm Hg) decreased with increasing risk factor burden (P = .005). The left panel of Table 3, displaying Orbit study results,18 shows that 19% of surgeries are characterized as very high risk, with 76% of MI’s occurring in these patients. The corresponding fraction among cases in this study was 75%.

Table 3. - MI Risk in Relation to Intraoperative Hypotensive Events and Preoperative Risk Group
Orbit studya Case-control study
Risk group(1–5) No. of operations (%) No. of MI (%) MI per 1000 No. of MI (%) MI risk per 1000 operations (% with 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.
aData from Orbit.18
bEstimated from the controls in this study (P = .005 for difference between risk groups).
cDecrease in SBP (mm Hg) from baseline for >5 min.

Absolute decrease in mm Hg, from individual preoperative BP baseline, was selected as main IOH definition. Multivariable comparison of the 3 final models based on different IOH definitions yielded similar odds estimates. The AIC test favored the models with IOH defined as a relative to baseline measure, ahead of the model with absolute BP thresholds (AIC value 226), while data do not clearly support discrimination between the models based on absolute and relative change from baseline BP (AIC value 214 vs 210); results are shown in Supplemental Digital Content 3, Table 2, https://links.lww.com/AA/D363.

Results From Sensitivity Analyses

There was no evidence of effect modification between preoperative BP or intraoperative tachycardia and IOH. Although not significant, a more pronounced effect of IOH in higher-risk patients compared to lower-risk patients was observed, as in MI development on postoperative days 1–2 compared to later diagnosed MI cases; results are detailed in Supplemental Digital Content 3, Table 1, https://links.lww.com/AA/D363. None of the interaction tests involving these covariates were significant.

MORTALITY

Table 4. - Mortality Rates in Patients Developing MI Within 30 d After Surgery
Mortality Case Controls OR (adjusteda) HR (unadjusted) HR (adjustedb)
n = 326 (%) n = 326 (%)
<30 da 88 (27) N/A 5.49 (4.76–6.32)
Day 31–90 17 (7) 18 (8) 1.14 (0.57–2.29) 1.02 (0.47–2.19)
Day 91–365 39 (20) 25 (9) 2.12 (1.27–3.55) 2.01 (1.19–3.38)
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.
aData 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.
bAdjusted for diabetes mellitus and ischemic heart disease.

In Table 4, results from mortality analyses are presented. At 30 days postoperatively, 88 of 326 (27%) cases were deceased. There was no difference in IOH occurrence among patients with fatal (<30 days) and nonfatal MI, adjusting for age, sex, ASA physical status, and comorbidities in logistic regression (P = .84). Day 91–365, 39 cases (20%) and 26 controls (9%) died. Crude HR was 2.12 (95% CI, 1.27-3.55), adjustment for DM and IHD resulted a HR of 2.01 (95% CI, 1.19-3.38). During 31–90 days, there was no difference in mortality between cases and controls.

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 majority 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-resolution 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 recordings (Supplemental Digital Content 2, BP Validation, https://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 patients belonging to higher risk groups and in MI cases diagnosed within 2 days of surgery.

LIMITATIONS

The source population is collected from large registries and databases, with possible reporting bias, coding 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 routinely 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 possibility 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 clinical signs and ischemic symptoms were excluded to minimize the risk of reversed causation. Additionally, an observed episode of IOH may increase the likelihood 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 available in the registry data; controls were sampled among patients alive and MI-free at day 30. This cumulative density sampling will overestimate relative risk; however, since MI is a rare event, the overestimation is small.24 Furthermore, this sampling scheme precludes estimation of 30-day mortality related to MI. A previous study of our source population showed perioperative MI increasing 30-day mortality 5-fold. 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 limited. 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 studies,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 associations 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, fulfilling the universal definition, are included, myocardial 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 individual 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 specific 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 mortality.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 hypertension.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 comparable in their ability to discriminate patients with myocardial injury from those without.9 A randomized study showed that targeting an individualized 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. 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 postsurgery. Perioperative MI is an overall rare condition explaining why these striking findings have not been identified previously. Patients developing MI postsurgery are at increased risk of other complications, such as respiratory failure, pneumonia, wound infection, deep venous thrombosis, and confusion. 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, irrespective 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 significantly 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 hemodynamic instability can be prevented in most clinical 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 undergoing extensive surgery. Avoiding IOH, by an attentive and meticulous anesthetic treatment during and after surgery, could lower the risk of perioperative MI, as well as other postoperative complications, 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 population of patients with a high-risk burden undergoing surgery suggests that increased vigilance of BP control in these patients may be beneficial.

DISCLOSURES

Name: Linn Hallqvist, MD, PhD Student, DESA.

Contribution: This author helped with the study design; acquisition of data, statistical analysis, and interpretation of data; manuscript writing.

Name: Fredrik Granath, PhD.

Contribution: This author helped with the study design; statistical analysis and interpretation of data; supervising the scientific process.

Name: Michael Fored, MD, PhD.

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.

REFERENCES

1. Jor O, Maca J, Koutna J. Hypotension after induction of general anesthesia: occurrence, risk factors, and therapy. A prospective multicentre observational study. J Anesth. 2018; 32:673–680.
2. Walsh M, Devereaux PJ, Garg AX. Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension. Anesthesiology. 2013; 119:507–515.
3. Sun LY, Wijeysundera DN, Tait GA, Beattie WS. Association of intraoperative hypotension with acute kidney injury after elective noncardiac surgery. Anesthesiology. 2015; 123:515–523.
4. Monk TG, Bronsert MR, Henderson WG. Association between intraoperative hypotension and hypertension and 30-day postoperative mortality in noncardiac surgery. Anesthesiology. 2015; 123:307–319.
5. Hallqvist L, Mårtensson J, Granath F, Sahlén A, Bell M. Intraoperative hypotension is associated with myocardial damage in noncardiac surgery: an observational study. Eur J Anaesthesiol. 2016; 33:450–456.
6. Devereaux PJ, Sessler DI. Cardiac complications in patients undergoing major noncardiac surgery. N Engl J Med. 2015; 373:2258–2269.
7. van Waes JA, van Klei WA, Wijeysundera DN, van Wolfswinkel L, Lindsay TF, Beattie WS. Association between intraoperative hypotension and myocardial injury after vascular surgery. Anesthesiology. 2016; 124:35–44.
8. Hallqvist L, Granath F, Huldt E, Bell M. Intraoperative hypotension is associated with acute kidney injury in noncardiac surgery: an observational study. Eur J Anaesthesiol. 2018; 35:273–279.
9. Salmasi V, Maheshwari K, Yang D, et al. Relationship between intraoperative hypotension, defined by either reduction from baseline or absolute thresholds, and acute kidney and myocardial injury after noncardiac surgery: a retrospective cohort analysis. Anesthesiology. 2017; 126:47–65.
10. Botto F, Alonso-Coello P, Chan MT, et al.; Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Writing Group, on behalf of The Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Investigators; Appendix 1. The Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Study Investigators Writing Group; Appendix 2. The Vascular events In noncardiac Surgery patIents cOhort evaluatioN Operations Committee; Vascular events In noncardiac Surgery patIents cOhort evaluatioN VISION Study Investigators. Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes. Anesthesiology. 2014; 120:564–578.
11. Devereaux PJ, Biccard BM, Sigamani A, et al. Association of postoperative high-sensitivity troponin levels with myocardial injury and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2017; 317:1642–1651.
12. Thygesen K, Alpert JS, Jaffe AS, et al.; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of Myocardial Infarction (2018). Circulation. 2018; 138:e618–e651.
13. Collinson P, Lindahl B. Type 2 myocardial infarction: the chimaera of cardiology? Heart. 2015; 101:1697–1703.
14. Devereaux PJ, Xavier D, Pogue J, et al.; POISE (PeriOperative ISchemic Evaluation) Investigators. Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery: a cohort study. Ann Intern Med. 2011; 154:523–528.
15. Puelacher C, Lurati Buse G, Seeberger D, et al.; BASEL-PMI Investigators. Perioperative myocardial injury after noncardiac surgery: incidence, mortality, and characterization. Circulation. 2018; 137:1221–1232.
16. Van Waes ARJ, Nathoe MH, De Graaff CJ, et al. Myocardial injury after noncardiac surgery and its association with short-term mortality. Circulation. 2013; 127:2264–2271.
17. Thygesen K, Alpert JS, Jaffe AS, et al.; Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Circulation. 2012; 126:2020–2035.
18. Hallqvist L, Granath F, Bell M. Myocardial infarction after noncardiac surgery in Sweden: a national, retrospective observational cohort study. Br J Anaesth. 2020; 125:47–54.
19. Ludvigsson JF, Andersson E, Ekbom A. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011; 11:450.
20. Brooke HL, Talbäck M, Hörnblad J. The Swedish cause of death register. Eur J Epidemiol. 2017; 32:765–773.
21. Wettermark B, Hammar N, Fored CM. The new Swedish Prescribed Drug Register–opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol Drug Saf. 2007; 16:726–735.
22. Swedeheart R. Accessed August 1, 2020. http://kvalitetsregister.se/englishpages/findaregistry/registerarkivenglish/nationalqualityregistryforenhancementanddevelopmentofevidencebasedcareinheartdiseaseswedeheart.2244.html.
23. Kellum JA, Lameire N; KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care. 2013; 17:204.
24. Vandenbroucke JP, Pearce N. Case-control studies: basic concepts. Int J Epidemiol. 2012; 41:1480–1489.
25. Sessler DI, Khanna AK. Perioperative myocardial injury and the contribution of hypotension. Intensive Care Med. 2018; 44:811–822.
26. Futier E, Lefrant JY, Guinot PG, et al.; INPRESS Study Group. Effect of individualized vs standard blood pressure management strategies on postoperative organ dysfunction among high-risk patients undergoing major surgery: a randomized clinical trial. JAMA. 2017; 318:1346–1357.
27. Bijker JB, van Klei WA, Kappen TH, van Wolfswinkel L, Moons KG, Kalkman CJ. Incidence of intraoperative hypotension as a function of the chosen definition: literature definitions applied to a retrospective cohort using automated data collection. Anesthesiology. 2007; 107:213–220.
28. Asfar P, Meziani F, Hamel JF, et al.; SEPSISPAM Investigators. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014; 370:1583–1593.
29. Palmer BF. Renal dysfunction complicating the treatment of hypertension. N Engl J Med. 2002; 347:1256–1261.
30. Strandgaard S, Olesen J, Skinhoj E, Lassen NA. Autoregulation of brain circulation in severe arterial hypertension. Br Med J. 1973; 1:507–510.
31. Devereaux PJ, Goldman L, Cook DJ, Gilbert K, Leslie K, Guyatt GH. Perioperative cardiac events in patients undergoing noncardiac surgery: a review of the magnitude of the problem, the pathophysiology of the events and methods to estimate and communicate risk. CMAJ. 2005; 173:627–634.
32. Devereaux PJ, Goldman L, Yusuf S, Gilbert K, Leslie K, Guyatt GH. Surveillance and prevention of major perioperative ischemic cardiac events in patients undergoing noncardiac surgery: a review. CMAJ. 2005; 173:779–788.
33. Devereaux PJ, Chan MT, Alonso-Coello P, et al. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2012; 307:2295–2304.

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