Blood Pressure Lability During Cardiac Surgery Is Associated With Adverse Outcomes Solomon Aronson, Edwin G. Avery, Cornelius Dyke, Joseph Varon, Jerrold

Blood Pressure Lability Blood Pressure Lability During Cardiac Surgery Is During Cardiac Surgery Is Associated With Adverse Associated With Adverse

OutcomesOutcomes

Solomon Aronson, Edwin G. Avery, Cornelius Solomon Aronson, Edwin G. Avery, Cornelius Dyke, Joseph Varon, Jerrold H. LevyDyke, Joseph Varon, Jerrold H. Levy

Presented at the American Society Presented at the American Society of Anesthesiologists (ASA) 2008 Annual of Anesthesiologists (ASA) 2008 Annual

Meeting. October 18–22, 2008, Orlando, FL.Meeting. October 18–22, 2008, Orlando, FL.

BackgroundBackground

Perioperative blood pressure (BP) variability during Perioperative blood pressure (BP) variability during cardiac surgery and intraoperative hemodynamic cardiac surgery and intraoperative hemodynamic abnormalities may be associated adverse outcome abnormalities may be associated adverse outcome including death, stroke, renal dysfunction, perioperative including death, stroke, renal dysfunction, perioperative myocardial infarction (MI), and increased mortality in this myocardial infarction (MI), and increased mortality in this patient populationpatient population

Up to 86% of cardiac surgery patients require intravenous Up to 86% of cardiac surgery patients require intravenous (IV) therapy to actively manage BP(IV) therapy to actively manage BP

Anesth AnalgAnesth Analg 2002:94;1079- 84. 2002:94;1079- 84. Anesth AnalgAnesth Analg 2002:95;273-7. 2002:95;273-7. CirculationCirculation 2007:115;733-42. 2007:115;733-42. HypertensionHypertension 2007;50:630-35. 2007;50:630-35. Anesth AnalgAnesth Analg 2008:107;1122-9, 2008 2008:107;1122-9, 2008

BackgroundBackground

The Evaluation of Clevidipine in the Perioperative The Evaluation of Clevidipine in the Perioperative Treatment of Hypertension Assessing Safety Events Treatment of Hypertension Assessing Safety Events (ECLIPSE) program was performed to compare the safety (ECLIPSE) program was performed to compare the safety and efficacy of clevidipine butyrate intravenous emulsion and efficacy of clevidipine butyrate intravenous emulsion (CLV) with nitroglycerin (NTG), sodium nitroprusside (CLV) with nitroglycerin (NTG), sodium nitroprusside (SNP), and nicardipine (NIC) in the treatment of (SNP), and nicardipine (NIC) in the treatment of perioperative acute hypertension in patients undergoing perioperative acute hypertension in patients undergoing cardiac surgerycardiac surgery

In ECLIPSE, poor perioperative BP control was a In ECLIPSE, poor perioperative BP control was a significant predictor of 30-day mortalitysignificant predictor of 30-day mortality– Patients with poor blood pressure (BP) control are at higher risk of Patients with poor blood pressure (BP) control are at higher risk of

30-day death, stroke, myocardial infarction (MI), and renal 30-day death, stroke, myocardial infarction (MI), and renal dysfunction compared with those with tight control (P<0.01, odds dysfunction compared with those with tight control (P<0.01, odds ratio 1.003, 95% confidence interval 1.001–1.004)ratio 1.003, 95% confidence interval 1.001–1.004)

– In other words, the worse the blood pressure control, the worse the In other words, the worse the blood pressure control, the worse the outcomeoutcome

MethodsMethods

In the present study, data from the ECLIPSE program In the present study, data from the ECLIPSE program were examined further to determine whether the risk of were examined further to determine whether the risk of 30-day adverse clinical outcomes (death, MI, stroke, and 30-day adverse clinical outcomes (death, MI, stroke, and renal dysfunction) increased as systolic BP (SBP) became renal dysfunction) increased as systolic BP (SBP) became progressively more labile outside of a preselected BP progressively more labile outside of a preselected BP target rangetarget range

The ECLIPSE program comprised 3 prospective, The ECLIPSE program comprised 3 prospective, randomized, open-label, parallel comparison studies of randomized, open-label, parallel comparison studies of CLV to NTG or SNP perioperatively, or NIC postoperatively CLV to NTG or SNP perioperatively, or NIC postoperatively in patients undergoing cardiac surgery at 61 medical in patients undergoing cardiac surgery at 61 medical centerscenters

Of the 1964 patients enrolled, 1512 met post Of the 1964 patients enrolled, 1512 met post randomization inclusion criteria of requiring acute randomization inclusion criteria of requiring acute treatment of hypertension based on clinical treatment of hypertension based on clinical determination (modified intent-to-treat population)determination (modified intent-to-treat population)– Five were not included due to missing or incomplete area under the Five were not included due to missing or incomplete area under the

curve (AUC) data, for a total of 1507 patientscurve (AUC) data, for a total of 1507 patients

MethodsMethods

The efficacy of CLV versus comparator drugs for the The efficacy of CLV versus comparator drugs for the treatment treatment of acute hypertension was assessed using AUC analysis of of acute hypertension was assessed using AUC analysis of BP excursions beyond predetermined upper and lower BP excursions beyond predetermined upper and lower limits, normalized per hour (AUCSBP-D)limits, normalized per hour (AUCSBP-D)– These ranges, chosen to reflect standard clinical practice and These ranges, chosen to reflect standard clinical practice and

predefined predefined for analysis purposes, were 65 to 135 mm Hg intraoperatively (from for analysis purposes, were 65 to 135 mm Hg intraoperatively (from chest incision through chest closure) and 75 to 145 mm Hg pre- chest incision through chest closure) and 75 to 145 mm Hg pre- and postoperativelyand postoperatively

In a posthoc analysis, patients were grouped into In a posthoc analysis, patients were grouped into quartiles quartiles (Qs 1–4) as defined by BP lability (Q4 was most labile and (Qs 1–4) as defined by BP lability (Q4 was most labile and

Q1 least labile)Q1 least labile)

MethodsMethods

The primary outcome was the incidence of death, MI, The primary outcome was the incidence of death, MI, stroke, or renal dysfunction at 30 days as assessed by the stroke, or renal dysfunction at 30 days as assessed by the Clinical Endpoints CommitteeClinical Endpoints Committee

Perioperative BP was controlled from preincision through Perioperative BP was controlled from preincision through the perioperative period with CLV (2–16 mg/h titrated to the perioperative period with CLV (2–16 mg/h titrated to BP-lowering effect) versus a comparator (IV NTG, SNP, or BP-lowering effect) versus a comparator (IV NTG, SNP, or NIC), dosed according to institutional practiceNIC), dosed according to institutional practice– Patients were randomized 1:1 to study drugsPatients were randomized 1:1 to study drugs

ECLIPSE Patient CharacteristicsECLIPSE Patient CharacteristicsAUC Study Population (N=1507)

Quartile 1AUC 0–<0.09

(n=376)

Quartile 2AUC 0.09–

<4.77(n=377)


<26.21(n=377)

Quartile 4AUC ≥26.21

(n=377) P Value

Median age, years (IQR)

63.0 (56.0, 72.0)

65.0 (57.0, 72.0)

66.0 (58.0, 73.0)

67.0 (60.0, 75.0)

<0.0001

Male, n (%) 279 (74.2)

289 (76.7)

277 (73.5)

260 (69.0)

0.114

White, n (%) 323 (85.9)

331 (87.8)

312 (82.8)

277 (73.5)

<0.0001

Median BMI, kg/m2 (IQR)

28.7 (25.6, 32.4)

28.7 (25.8, 32.2)

29.3 (25.7, 32.8)

28.0 (24.9, 31.5)

0.684

Screening SBP >160or DBP >105, n (%)

29 (7.7)

29 (7.7)

55 (14.6)

81 (21.5)

<0.0001

History ofhypertension, n (%)

306 (81.4)

323 (85.7)

324 (85.9)

343 (91.0)

0.002

CHF, n (%) 71 (18.9)

50 (13.3)

71 (18.8)

86 (22.8)

0.009

COPD, n 46 (12.2)

65 (17.2)

55 (14.6)

52 (13.8)

0.261Aronson S., et. al. American Society of Anesthesiologists (ASA) Aronson S., et. al. American Society of Anesthesiologists (ASA) 2008 Annual Meeting. October 18–22, 2008, Orlando, FL.2008 Annual Meeting. October 18–22, 2008, Orlando, FL.

ECLIPSE Patient CharacteristicsECLIPSE Patient CharacteristicsAUC Study Population (N=1507)

Quartile 1AUC 0–<0.09

(n=376)


<4.77(n=377)


<26.21(n=377)

Quartile 4AUC ≥26.21

(n=377) P Value

Diabetes, n 119 (31.6)

124 (32.9)

128 (34.0)

167 (44.3)

0.001

Recent MI(<6 months), n (%)

65 (17.3)

65 (17.2)

71 (18.8)

68 (18.0)

0.933

Previous CABG, n (%)

23 (6.1)

11 (2.9)

15 (4.0)

18 (4.8)

0.185

Previous TIA or stroke, n (%)

30 (8.0)

39 (10.3)

45 (11.9)

63 (16.7)

0.001

Median screening SBP, mm Hg (IQR)

131.0 (116.0, 144.0)

133.0 (120.0, 145.0)

138.0 (121.0, 151.0)

140.0 (125.5, 159.5)

<0.0001

Median screening DBP, mm Hg (IQR)

70.0 (64.0, 79.0)

72.0 (64.0, 80.0)

71.0 (65.0, 80.0)

72.0 (62.5, 81.5)

0.196

Median preop serum creatinine, mg/dL (IQR)

1.00 (0.85, 1.18)

1.00 (0.87, 1.13)

1.00 (0.87, 1.15)

1.02 (0.85, 1.21)

<0.0001

Median preop hemoglobin, g/dL (IQR)

14.02 (12.70, 15.20)

14.12 (12.91, 15.10)

14.00 (12.60, 15.24)

13.33 (11.80, 14.80)

<0.0001

Aronson S., et. al. American Society of Anesthesiologists (ASA) Aronson S., et. al. American Society of Anesthesiologists (ASA) 2008 Annual Meeting. October 18–22, 2008, Orlando, FL.2008 Annual Meeting. October 18–22, 2008, Orlando, FL.

ECLIPSE Procedural CharacteristicsECLIPSE Procedural CharacteristicsAUC Study Population (N=1507)

Quartile 1

AUC 0–<0.09

(n=376)


<4.77(n=377)


<26.21(n=377)

Quartile 4AUC

≥26.21(n=377)

Median duration of surgery, h (IQR)

3.32 (2.60, 4.27)

3.30 (2.65, 4.00)

3.13 (2.53, 4.00)

3.33 (2.65, 4.25)

Duration on pump,h (IQR)

1.48 (1.08, 2.00)

1.38 (1.08, 1.83)

1.35 (0.98, 1.73)

1.49 (1.12, 1.98)

Type of primary surgical procedure, n (%)

CABG 263 (69.9)

287 (76.1)

288 (76.4)

276 (73.2)

Valve repair or replacement

46 (12.2)

45 (11.9)

43 (11.4)

42 (11.1)

CABG and valve repair

42 (11.2)

26 (6.9)

24 (6.4)

35 (9.3)

Other 0 (0.0)

1 (0.3)

1 (0.3)

1 (0.3)


ECLIPSE Procedural CharacteristicsECLIPSE Procedural CharacteristicsAUC Study Population (N=1507)

Quartile 1

AUC 0–<0.09

(n=376)


<4.77(n=377)


<26.21(n=377)

Quartile 4AUC

≥26.21(n=377)

Type of repeat surgical procedure, n (%)

CABG 13 (3.5)

10 (2.7)

12 (3.2)

12 (3.2)

Valve repair or replacement

8 (2.1)

3 (0.8)

5 (1.3)

5 (1.3)

CABG and valve repair

4 (1.1)

5 (1.3)

4 (1.1)

6 (1.6)

Other 0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)


ResultsResults

Patients in Q4 (ie, the highest SBP excursions outside a Patients in Q4 (ie, the highest SBP excursions outside a specified range) were found to be at highest risk for 30-specified range) were found to be at highest risk for 30-day adverse clinical outcomesday adverse clinical outcomes

The incidence of adverse outcomes increased as the AUC The incidence of adverse outcomes increased as the AUC increased from Q1 to Q4increased from Q1 to Q4– By Kaplan-Meier analysis, the 30-day risk of having an adverse By Kaplan-Meier analysis, the 30-day risk of having an adverse

clinical outcome was 8.8% Q1, 10.1% Q2, 10.1% Q3, and 14.4% Q4clinical outcome was 8.8% Q1, 10.1% Q2, 10.1% Q3, and 14.4% Q4– The risk of having an event was significantly greater in the Q4 The risk of having an event was significantly greater in the Q4

group when compared with both the Q1 group (P=0.016) and the group when compared with both the Q1 group (P=0.016) and the Q1 through Q3 groups combined (P=0.012)Q1 through Q3 groups combined (P=0.012)

– Significantly fewer patients in Q4 were treated with CLV versus the Significantly fewer patients in Q4 were treated with CLV versus the comparators (P=0.0002)comparators (P=0.0002)

• Q4 (CLV 157: comparators [CMP] 220) versus Qs 1 to 3 Q4 (CLV 157: comparators [CMP] 220) versus Qs 1 to 3 (CLV 594: CMP 536)(CLV 594: CMP 536)

Summary of 30-day Composite Outcome in Patients with Perioperative HypertensionSummary of 30-day Composite Outcome in Patients with Perioperative Hypertension


Summary of 30-day Composite Outcome in Patients with Perioperative HypertensionSummary of 30-day Composite Outcome in Patients with Perioperative Hypertension


ConclusionsConclusions

Cardiac surgery patients with inadequate BP control are Cardiac surgery patients with inadequate BP control are at increased risk of 30-day death, stroke, MI, and renal at increased risk of 30-day death, stroke, MI, and renal dysfunction compared with patients with tight BP controldysfunction compared with patients with tight BP control

CLV appears to offer superior BP control in surgical CLV appears to offer superior BP control in surgical patients patients in this clinical settingin this clinical setting

CLV appears to offer superior perioperative BP control in CLV appears to offer superior perioperative BP control in cardiac surgery patients compared with the combined cardiac surgery patients compared with the combined comparators SNP, NTG, and NIC as shown by the comparators SNP, NTG, and NIC as shown by the decreased number of patients in Q4 who were receiving decreased number of patients in Q4 who were receiving CLVCLV– This observation requires further investigation in prospective, This observation requires further investigation in prospective,

randomized clinical trialsrandomized clinical trials

Documents

Blood Pressure Lability During Cardiac Surgery Is Associated With Adverse Outcomes Solomon Aronson, Edwin G. Avery, Cornelius Dyke, Joseph Varon, Jerrold