Influence of Norepinephrine and Phenylephrine on Frontal Lobe Oxygenation During Cardiopulmonary Bypass in Patients with Diabetes Patrice Brassard, PhD,*† Claudine Pelletier, MSc,*† Mickaël Martin, BSc,* Nathalie Gagné, PhD, RRT,† Paul Poirier, MD, PhD,†‡ Philip N. Ainslie, PhD,║ Manon Caouette, CPC,§ and Jean S. Bussières, MD†¶ Objective: Although utilization of vasopressors recently has been associated with reduced cerebral oxygenation, the influence of vasopressors on cerebral oxygenation during cardiopulmonary bypass in patients with diabetes is unknown. The aim of this study was to document the impact of norepinephrine and phenylephrine utilization on cerebral oxygenation in patients with and without diabetes during cardiopulmonary bypass. Design: Prospective, clinical study. Setting: Academic medical center. Participants: Fourteen patients with diabetes and 17 patients without diabetes undergoing cardiac surgery. Interventions: During cardiopulmonary bypass, norepinephrine (diabetics n ¼ 6; non-diabetics n ¼ 8) or phenylephrine (diabetics n ¼ 8; non-diabetics n ¼ 9) was administered intravenously to maintain mean arterial pressure above 60 mmHg. Measurements and Main Results: Mean arterial pressure, venous temperature, arterial oxygenation, and frontal lobe oxygenation (monitored by near-infrared spectroscopy) were recorded before anesthesia induction (baseline) and

continuously during cardiopulmonary bypass. Frontal lobe oxygenation was lowered to a greater extent in diabetics versus non-diabetics with administration of norepinephrine (–14 ⫾ 13 v 3 ⫾ 12%; p o 0.05). There was also a trend towards a greater reduction in cerebral oxygenation in diabetics versus non-diabetics with administration of phenylephrine (–12 ⫾ 8 v –6 ⫾ 7%; p ¼ 0.1) during cardiopulmonary bypass. Conclusions: Administration of norepinephrine to restore mean arterial pressure during cardiopulmonary bypass is associated with a reduction in frontal lobe oxygenation in diabetics but not in patients without diabetes. Administration of phenylephrine also were associated with a trend towards a greater reduction in frontal lobe oxygenation in diabetics. The clinical implications of these findings deserve future consideration. & 2013 Elsevier Inc. All rights reserved.

A

with impairment.11 Conversely, when the reduction in cerebral oxygenation is prevented or corrected, neurologic outcomes,14 including the rate of stroke, are reduced15 in cardiac patients. Given that post-surgery neurologic impairment is more frequent in patients with diabetes versus those without diabetes16 and that diabetes predicts postoperative stroke,17 maintenance of cerebral oxygenation in patients with diabetes during CPB is of particular clinical importance. Although vasopressors are thought to maintain cerebral blood flow and thus cerebral oxygenation, administration of norepinephrine or phenylephrine appears to reduce cerebral oxygenation, assessed via near-infrared spectroscopy (NIRS) and SjvO2, in normotensive men and women undergoing elective non cardiac surgery and experiencing anesthesiainduced hypotension.18–20 The reduction of cerebral oxygenation

HIGH INCIDENCE of cognitive impairments and perioperative stroke has been reported in patients who have undergone cardiac surgery.1 Duration of cardiopulmonary bypass (CPB), atheromatous and gaseous cerebral emboli, regional hypoperfusion, concurrent cerebrovascular disease, and advanced age are among the factors that could explain this phenomenon.2,3 Also, reduced perfusion pressure could affect cerebral blood flow during CPB, which potentially mediates postoperative cognitive dysfunction.4 The incidence of hypotension induced by general anesthesia seems to be most important in patients with diabetes, and a higher percentage of patients with diabetes need vasopressor support to correct for anesthesia-induced hypotension.5 It should be noted that a reduction in blood pressure might not necessarily lead to cerebral ischemia as long as effective cerebral autoregulation is present. Diabetes also seems to adversely affect cerebral autoregulation when these patients are placed on CPB6; thus, patients with diabetes are likely to have a reduced capacity to maintain cerebral blood flow and oxygenation when facing hypotension. Consistent with this notion, patients with diabetes demonstrate frequent cerebral desaturations, as measured by jugular venous oxygen saturation (SjvO2), during normothermic CPB.7,8 Together, these observations suggest that patients with diabetes are at risk of developing hypotension during anesthesia and CPB that will need vasopressor support. To preserve perfusion of vital organs including the heart, kidneys and the brain during CPB, mean arterial pressure (MAP) is usually kept above 60 mmHg,9 a level often called the lower level of cerebral autoregulation. Vasopressors such as norepinephrine or phenylephrine commonly are used to maintain MAP 460 mmHg10 and theoretically help maintain cerebral oxygenation. Indeed, cerebral desaturation during a CPB is associated with post-surgery neurological impairment,11–13 although not all episodes of cerebral desaturation are associated

KEY WORDS: cardiopulmonary bypass, diabetes mellitus, frontal lobe, norepinephrine, phenylephrine

From the *Department of Kinesiology, Faculty of Medicine, Université Laval, †Research Center of the Institut universitaire de cardiologie et de pneumologie de Québec, ‡Faculty of Pharmacy, Université Laval, Québec, Canada; §Centre for Heart, Lung and Vascular Health, School of Health and Exercise Sciences, University of British Columbia–Okanagan, Kelowna, British Columbia, Canada;, and the ║Departments of Cardiac Surgery and ¶Anesthesiology, Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, Canada. This work was supported by a grant from the Institut universitaire de cardiologie et de pneumologie de Québec. Address reprint requests to Patrice Brassard, PhD, PEPS–Université Laval, Department of Kinesiology, Faculty of Medicine, 2300 rue de la Terasse, room 2122, Québec (Qc) GIV OA6, Canada. E-mail: [email protected] © 2013 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2013.09.006

Journal of Cardiothoracic and Vascular Anesthesia, Vol ], No ] (Month), 2013: pp ]]]–]]]

1

2

BRASSARD ET AL

induced by the administration of vasopressors could increase the risk of cerebral ischemia in patients with diabetes who are already at risk for the development of vascular cognitive impairments, transient ischemic attack, and stroke.21,22 However, the influence of vasopressors such as norepinephrine and phenylephrine on NIRS-derived cerebral oxygenation during CPB in patients with diabetes is unknown. Accordingly, the aim of this study was to quantify any changes in cerebral oxygenation (ScO2) during administration of vasopressors (norepinephrine and phenylephrine) during CPB in patients with and without diabetes. The authors hypothesized that the utilization of norepinephrine and phenylephrine during CPB in cardiac surgery will decrease cerebral oxygenation as assessed by NIRS, to a greater extent, in patients with type 2 diabetes versus patients without type 2 diabetes. METHODS Fourteen patients with diabetes and 17 patients without diabetes undergoing cardiac surgery (Table 1) were recruited in this prospective study after providing written informed consent as approved by the local ethics committee according to the principles established in the Declaration of Helsinki. The inclusion criteria were patients undergoing cardiac surgery with or without diagnosed diabetes aged from 40 to 90 years. Patients were considered as diabetics if a diagnosis of diabetes was in their medical records and treated with anti-diabetic therapy. Exclusion criteria were the documented presence of cerebrovascular diseases (transient cerebral ischemia, carotid stenosis and stroke). On arrival in the operating room, patients were receiving supplemental oxygen by a 2-L/min nasal cannula. ECG, arterial O2 saturation, and cerebral oxygenation monitors were installed before anesthesia induction. An intravenous infusion of saline was started, and an intraarterial catheter was inserted in the left radial (norepinephrine series: diabetics: 3 out of 6 patients and non-diabetics: 7 out of 8 patients; phenylephrine series: diabetics: 7 out of 8 patients and non-diabetics: 6 out of 9 patients) or brachial artery for continuous blood pressure monitoring and intermittent blood sampling. Following induction of anesthesia with sufentani (1-3 μg/kg) and propofol (1.0 mg/kg), patients were intubated orally after muscle relaxation with rocuronium (1.5 mg/kg), and anesthesia was maintained with sevoflurane and a propofol infusion of 40 μg/kg/min. Controlled ventilation was established and adjusted for an end-tidal carbon dioxide tension (PetCO2) between 35 and 42 mmHg. An inspired O2 fraction of 0.6 to 1.0 was used with volume-controlled mechanical ventilation. A blood sample was taken 5 to 15 minutes after induction of anesthesia for arterial blood gases, blood glucose, and hematocrit. The CPB circuit was primed with a crystalloid, non-glucosecontaining solution, and a non-pulsatile pump flow rate of 1.9 to 2.5 L/min/m2 was maintained as continuously recorded. The temperature of CPB was tepid bypass 341 C to 351C. A membrane oxygenator and a 40-Um arterial line filter were used. Cold blood cardioplegia was used in both groups with a hot shot before cross-clamp removal. In addition to routine monitoring, continuous in-line blood gas in arterial and venous lines was monitored during CPB using optical fluorescence and a reflectance-based in-line system (Terumo Cardiovascular Systems, Ann Arbor, MI). Cerebral oxygenation continuously was measured but values were hidden from the perfusionist. Alpha-stat blood gas strategy was used in both groups to adjust arterial carbon dioxide tension (PaCO2) to normocapnic levels (35-42 mmHg). During the CPB period, anesthesia was maintained by propofol infusion (40 μg/kg/min) and sevoflurane, 1% to 2%, if necessary. In both groups, as part of the authors’ institutional protocol, hematocrit was adjusted above 23% with the transfusion of blood as necessary.

During CPB, norepinephrine (diabetics: n ¼ 6; non-diabetics: n ¼ 8) or phenylephrine (diabetics: n ¼ 8; non-diabetics: n ¼ 9) were administered randomly (computerized random numbers) in order to maintain MAP above 60 mmHg. More specifically, vasopressors were administered (when needed) throughout the CPB period to keep MAP above 60 mmHg. Of note, randomization of vasopressors was performed before the patients’ arrival in the operating room. MAP, arterial O2 saturation, and ScO2 were recorded before induction of anesthesia (during which patients were receiving supplemental oxygen via a 2-L/ min nasal cannula) and continuously during CPB. PaCO2 was measured following the induction of anesthesia and every 30 minutes during CPB. Blood samples were taken throughout CPB for arterial blood gases, blood glucose, and hematocrit. MAP, venous temperature, arterial O2 saturation, ScO2, and PaCO2 related to CPB represent an average of each measurement monitored over the entire CPB. Of note, periods of low flow during CPB, characterized as abrupt drops in CPB pump flow associated with sudden reductions in ScO2, were excluded from the analysis to rule out the influence of this state on ScO2. Specifically, the authors removed 1 minute before, during and after periods of low flow during CPB for a total of 3 minutes for each subject, which represented only 4% of the total CPB time (82 ⫾ 31 min) for the study population. The percentage of total CPB time during which ScO2 was reduced by 15% from the baseline value monitored before the induction of anesthesia and the quantity of vasopressors for the period during which ScO2 was reduced during CPB was then calculated. MAP was measured through a transducer placed at the heart level and connected to a monitor. Venous temperature was monitored continuously through sensors incorporated into the CPB pump. PaCO2, blood glucose, and hematocrit were measured from arterial blood samples taken throughout CPB. Arterial O2 saturation was monitored by finger pulse oximetry. The ScO2 was monitored by NIRS (INVOS Cerebral Oximeter, Somanetics, Troy, MI) as previously reported.19 Changes in ScO2 parallel those in SjvO2 and middle cerebral artery mean flow velocity15 and NIRS detects cerebral hypoperfusion during surgery.16 Values reported for ScO2 account predominantly for hemoglobin oxygenation in the frontal lobe cortex. For data that were distributed normally, a Student’s t test was performed to evaluate changes between groups at baseline and changes from baseline to CPB (deltas), and the Mann-Whitney test was used otherwise for the remaining variables (diabetics v non-diabetics for each vasopressor). Of note, this study was not designed to compare the impact of norepinephrine and phenylephrine on cerebral oxygenation in these subjects. Pearson’s correlation was used to assess associations between dependent variables of interest. The authors’ sample size was a convenience sample, as the expected biologic effect previously had not been known and thus could not have been used in a formal power analysis. The authors’ intent was, thus, to obtain preliminary data in order to perform power analysis for subsequent studies. Results are presented as mean (SD), and a p value o 0.05 was considered statistically significant (GraphPad Prism version 5.04 for Windows, GraphPad Software, La Jolla, CA).

RESULTS

Baseline characteristics including age, sex, body weight, height, medication, comorbidities, and type of surgical interventions are presented for each subject in Table 1. Age, body weight, height, and body mass index were similar between patients with and without diabetes (Tables 2 and 3). Baseline blood glucose was similar between patients with diabetes compared to patients without diabetes who received norepinephrine (Table 2). Patients with diabetes who received phenylephrine had higher blood glucose, and lower

Subjects

Duration (y)

Non-diabetic group 1 –

Body Weight

Height

Sex

Age (y)

(kg)

(cm)

Men

89

68

169

Medication

Diagnosis

Acetylsalicylic acid, Metoprolol, Rosuvastatin Acetylsalicylic acid, Bisoprolol, Atorvastatin Acetylsalicylic acid, Bisoprolol, Rosuvastatin, Furosemide, Levothyroxine

Severe aortic valve stenosis; coronary artery disease Severe aortic valve stenosis; severe mitral valve insufficiency Coronary artery disease

2

–

Men

65

83

170

3

–

Men

79

79

158

4

–

Women

69

98

168

Acetylsalicylic acid, Atorvastatin, Furosemide, Levothyroxine

Mitral valve endocarditis

5

–

Men

55

89

173

Coronary artery disease

6

–

Women

48

68

155

7

–

Men

43

87

172

8

–

Men

50

78

170

9

–

Men

56

69

165

10

–

Men

79

56

172

11

–

Women

73

61

160

Acetylsalicylic acid, Metoprolol, Atorvastatin Acetylsalicylic acid, Rosuvastatin, Levothyroxine, Salbutamol Acetylsalicylic acid, Amlodipine, Carvedilol, Furosemide, Perindopril, Spironolactone Acetylsalicylic acid, Rosuvastatin, Oxazepam Acetylsalicylic acid, Bisoprolol, Rosuvastatin Acetylsalicylic acid, Atenolol, Amiodarone, Dutasteride, Rosuvastatin Acetylsalicylic acid, Atorvastatin, Diltiazem

12

–

Men

64

85

172

13

–

Men

77

68

163

14

–

Men

76

79

167

15

–

Men

71

89

178

16

–

Men

58

93

180

Acetylsalicylic acid, Atorvastatin, Clopidogrel, Furosemide, Metoprolol Acetylsalicylic acid, Atenolol, Atorvastatin, Ezetimide Acetylsalicylic acid, Bisoprolol, Furosemide, Perindopril, Rosuvastatin Acetylsalicylic acid, Bisoprolol, Rosuvastatin, Warfarin

Severe aortic valve stenosis Severe aortic valve insufficiency

Coronary artery disease Coronary artery disease Severe aortic valve stenosis

Coronary artery disease

Comorbidities

Type of Surgery

Systemic hypertension

AVR þ CABG x 1

Systemic hypertension; left bundlebranch block Previous myocardial infarction; auricular fibrillation; systemic hypertension; hypercholesterolemia; chronic kidney disease Systemic hypertension; chronic kidney disease; hypothyroidism; chronic venous insufficiency Recent myocardial infarction; hypercholesterolemia Systemic hypertension; dyslipidemia

AVR þ MVR

Current smoking; chronic obstructive pulmonary disease; severe left ventricular dysfunction Systemic hypertension; dyslipidemia; history of smoking Systemic hypertension; dyslipidemia; current smoking Systemic hypertension

CABG x 5

MVR þ CABG x 1

CABG x 3 Ross procedure AVR

CABG x 5 CABG x 5 AVR þ CABG x 1

CABG x 4

Coronary artery disease

Systemic hypertension; asthma; paroxysmal supraventricular tachycardia Systemic hypertension; auricular fibrillation; left bundle-branch block; dyslipidemia Systemic hypertension

Coronary artery disease; aortic valve insufficiency

Systemic hypertension; dyslipidemia; chronic kidney disease

AVR þ CABG x 4

Coronary artery disease; aortic valve insufficiency

Systemic hypertension; dyslipidemia; mitral valve replacement; coronary artery bypass surgery; left bundlebranch block Systemic hypertension; dyslipidemia

AVR þ CABG x 1

Coronary artery disease

Coronary artery disease

INFLUENCE OF VASOPRESSORS ON BRAIN OXYGENATION IN DIABETIC PATIENTS

Table 1. Baseline Demographic, Clinical, and Surgical characteristics of Study Population Type of Diabetes/

CABG x 5

CABG x 4

CABG x 3

3

4

Table 1 (continued )

Subjects

17

Type of

Body

Diabetes/

Weight

Height

(kg)

(cm)

Duration (y)

–

Sex

Age (y)

54

74

175

Diabetic group 1 Type 2/15

Men

69

89

164

2

Type 2/6

Men

76

63

168

3

Type 2/1

Women

79

66

158

5

Type 2/8

Men

65

72

173

6

Type 2/6

Men

84

78

170

7

Type 2/2.5

Men

43

93

170

8

Type 2/8

Women

72

103

156

9

Type 2/11

Men

56

81

162

10

Type 2/11

Men

65

75

164

11

Type 2/23

Men

64

130

172

12

Type 2/15

Women

68

78

156

14

Type 2/18

Men

77

67

168

Acetylsalicylic acid, Amlodipine, Furosemide, Glyburide, Metformin, Rosuvastatin Acetylsalicylic acid, Bromazepam, Metformin, Metoprolol, Rosuvastatin, Furosemide Acetylsalicylic acid, Atorvastatin, Bisoprolol, Furosemide, Metformin, Esomeprazole Acetylsalicylic acid, Metformin, Metoprolol, Rosuvastatin Acetylsalicylic acid, Glyburide, Metformin, Metoprolol, Rosuvastatin, Furosemide Acetylsalicylic acid, Furosemide, Rosuvastatin, Insulin aspart, Insulin Detemir, Salbutamol, Montelukast Acetylsalicylic acid, Metformin, Gliclazide, Amlodipine, Furosemide Acetylsalicylic acid, Metformin, Rosuvastatin, Clonazepam Acetylsalicylic acid, Furosemide, Ezetimide, Metformin, Metoprolol Acetylsalicylic acid, Atorvastatin, Amlodipine, Furosemide, Metformin, Metoprolol, Ramipril Acetylsalicylic acid, Atorvastatin, Bisoprolol, Metformin, Furosemide, Quinine Acetylsalicylic acid, Bisoprolol, Atorvastatin, Budesonide,

Diagnosis

Comorbidities

Type of Surgery

Coronary artery disease

Chronic obstructive pulmonary disease CABG x 4

Coronary artery disease; severe aortic valve stenosis

Systemic hypertension; dyslipidemia

AVR þ CABG x 1

Coronary artery disease

Systemic hypertension; hypercholesterolemia

CABG x 3

Severe mitral valve insufficiency

Dyslipidemia; tricuspid valve insufficiency; left ventricular dysfunction Systemic hypertension; auricular fibrillation –

MVR

Coronary artery disease Severe aortic valve stenosis

CABG x 3 AVR

Coronary artery disease

Kidney disease; chronic obstructive pulmonary disease

CABG x 3

Severe aortic valve stenosis

Systemic hypertension; chronic kidney disease; dyslipidemia; anemia

AVR

Coronary artery disease

Systemic hypertension; dyslipidemia

CABG x 5

Coronary artery disease; aortic valve Dyslipidemia; current smoking stenosis Coronary artery disease Systemic hypertension; dyslipidemia; thrombophlebitis; pulmonary embolism; current smoking Coronary artery disease Systemic hypertension; hypercholesterolemia

AVR þ CABG x 2

Coronary artery disease

CABG x 3

Systemic hypertension; dyslipidemia; chronic obstructive pulmonary disease

CABG x 3

CABG x 3 BRASSARD ET AL

Men

Medication

Acetylsalicylic acid, Metoprolol, Rosuvastatin Acetylsalicylic acid, Metoprolol, Rosuvastatin, Tiotropium, Budesonide, Salbutamol

CABG x 2 Systemic hypertension; dyslipidemia 158 78 69 Women Type 2/18 16

Abbreviations: AVR, aortic valve replacement; CABG, coronary artery bypass graft; MVR, mitral valve replacement.

CABG x 2 Type 1/39 15

Men

61

97

172

Furosemide, Glyburide, Metformin Coronary artery disease Acetylsalicylic acid, Diltiazem, Insulin glargine, Isophane insulin, Niacin, Ramipril, Rosuvastatin Coronary artery disease Acetylsalicylic acid, Amlopidine, Metformin, Metoprolol, Lorazepam, Ramipril

Systemic hypertension; dyslipidemia

INFLUENCE OF VASOPRESSORS ON BRAIN OXYGENATION IN DIABETIC PATIENTS

5

hematocrit at baseline compared to patients without diabetes (Table 3). Utilization of norepinephrine during CPB was effective at maintaining MAP above 60 mmHg in both diabetics and nondiabetics (63 ⫾ 3 v 64 ⫾ 7 mmHg; p ¼ 0.6). However, the amount of norepinephrine necessary to maintain MAP, over the entire CPB period, was higher in diabetics v non-diabetics (0.06 ⫾ 0.05 v 0.03 ⫾ 0.02 μg/kg/min; p ¼ 0.06). Despite maintained MAP, ScO2 was reduced with the use of norepinephrine in diabetics v non-diabetics during CPB compared to baseline (14 ⫾ 13 v 3 ⫾ 12 %; p ¼ 0.03; Fig 1). In addition, the percentage of the CPB period during which patients had a reduction in ScO2 from baseline by at least 15% (a level associated with cerebral ischemia23) was much greater in diabetics compared to non-diabetics (45 ⫾ 44 v 9 ⫾ 21%; p o 0.05), and it was associated with a trend toward the administration of a higher amount of norepinephrine during the specific period in diabetics (0.05 ⫾ 0.04 v 0.01 ⫾ 0.03 μg/kg/ min; p ¼ 0.06). Although PaCO2 was higher in diabetics compared to non-diabetics at baseline (p ¼ 0.03), the reduction from baseline to CPB tended to be greater in diabetics (p ¼ 0.06; Table 2). Changes in blood glucose from baseline to CPB were similar between groups (p ¼ 0.9; Table 2). CPB pump flow rate and changes in hematocrit were similar between groups while venous temperature during CPB tended to be higher in diabetics versus non-diabetics (Table 2). The FIO2 range targeted during CPB resulted in a similar arterial PO2 between groups (238 ⫾ 32 v 231 ⫾ 18 mmHg; p ¼ 0.6). The amount of blood transfusion during CPB also was similar between groups (908 ⫾ 233 v 831 ⫾ 205 mL; p ¼ 0.6). Anesthesia was maintained by propofol infusion in all patients and by sevoflurane in all diabetics and in 5 of the 8 non-diabetics. The difference in ScO2 between the groups remained after exclusion of the 3 non-diabetics without sevoflurane (p ¼ 0.007). There was no correlation between changes in ScO2 with other variables of interest. Utilization of phenylephrine during CPB also was effective at maintaining MAP above 60 mmHg in diabetics and nondiabetics (63 ⫾ 6 v 60 ⫾ 4 mmHg; p ¼ 0.8). The amount of phenylephrine necessary to maintain MAP, over the entire CPB period, was similar between diabetics and non-diabetics (1.21 ⫾ 1.10 v 0.73 ⫾ 0.53 μg/kg/min; p ¼ 0.3). ScO2 was reduced with phenylephrine in both diabetics and non-diabetics for the entire period of CPB compared to baseline, with a trend toward a difference between groups (-12 ⫾ 8 v -6 ⫾ 7%; p ¼ 0.1; Fig 2). The percentage of the CPB period during which patients had a reduction in ScO2 from baseline by at least 15% (37 ⫾ 40 v 11 ⫾ 21%; p ¼ 0.2) and the amount of phenylephrine utilized during that period (0.95 ⫾ 1.3 v 0.3 ⫾ 0.5 μg/kg/min; p ¼ 0.2) were similar between patients with diabetes and controls. PaCO2 was higher in diabetics compared to non-diabetics at baseline (p ¼ 0.03), and changes from baseline to CPB were similar between groups (p ¼ 0.2; Table 3). CPB pump flow rate and changes in hematocrit were similar between groups while venous temperature during CPB tended to be higher in diabetics v non-diabetics (Table 3). The FIO2 range targeted during CPB resulted in a similar arterial PO2 between groups (259 ⫾ 25 v 254 ⫾ 24 mmHg; p ¼ 0.7). The amount of blood transfusion during CPB also was similar between groups (913 ⫾ 230 v 869 ⫾ 342 mL; p ¼ 0.8). Anesthesia was

6

BRASSARD ET AL

Table 2. Characteristics and Parameters at Baseline and During Cardiopulmonary Bypass in Diabetics v Non-diabetics Who Received Norepinephrine Diabetics

Subjects (n) Age (y) Body weight (kg) Height (cm) Body mass index (kg/m2) Ventilated body weight (kg) MAP (mmHg) Baseline CPB Change from Baseline to CPB ScO2 Baseline (%) CPB (%) Relative change from baseline to CPB (%) Time with a reduction in ScO2 Z15% (min) Time with a reduction in ScO2 Z15% (%) PaCO2 Baseline (mmHg) CPB (mmHg) Changes from baseline to CPB (mmHg) O2 saturation Baseline (%) CPB (%) Changes from baseline to CPB (%) Blood glucose Baseline (mmol/L) CPB (mmol/L) Changes from baseline to CPB (mmol/L) Hematocrit (%) Baseline CPB Change from baseline to CPB Venous temperature during CPB (1C) CPB pump flow rate (L/min/m2) Total time of CPB (min)

Non-diabetics

р

6 65 ⫾ 12 88 ⫾ 21 164 ⫾ 6 33 ⫾ 6 69 ⫾ 6

8 70 ⫾ 11 82 ⫾ 13 170 ⫾ 8 29 ⫾ 4 74 ⫾ 7

– 0.4 0.5 0.2 0.2 0.2

91 ⫾ 15 63 ⫾ 3 28 ⫾ 17

94 ⫾ 7 64 ⫾ 7 30 ⫾ 6

0.6 0.8

60 ⫾ 11 52 ⫾ 12 14 ⫾ 13

61 ⫾ 9 62 ⫾ 8 3 ⫾ 12

0.8

34 ⫾ 33

10 ⫾ 19

0.06

45 ⫾ 45

9 ⫾ 21

o 0.05

41 ⫾ 3 39 ⫾ 2 2 ⫾ 4

38 ⫾ 2 39 ⫾ 1 2⫾2

0.03

0.03 0.06

98 ⫾ 2 100 ⫾ 1 1⫾2

100 ⫾ 0 100 ⫾ 0 2⫾3

0.9

7.3 ⫾ 2.4 8.7 ⫾ 2.4 1.4 ⫾ 2.2

6.0 ⫾ 0.7 7.3 ⫾ 1.2 1.4 ⫾ 0.7

0.2

34 ⫾ 4 21 ⫾ 10 13 ⫾ 12

38 ⫾ 6 29 ⫾ 4 9 ⫾ 3

0.2

34.8 ⫾ 0.7

34.0 ⫾ 0.7

0.06

2.1 ⫾ 0.1 86 ⫾ 26

2.2 ⫾ 0.1 90 ⫾ 34

0.5 0.8

0.7

0.9

0.3

NOTE. Results are mean ⫾ standard deviation. Abbreviations: CPB, cardiopulmonary bypass; MAP, mean arterial pressure; O2, oxygen; PaCO2, arterial carbon dioxide tension; ScO2, frontal lobe oxygenation.

maintained by propofol infusion in all patients and by sevoflurane in all but 1 diabetic and in all non-diabetics. The trend towards a difference in ScO2 between the groups remained after exclusion of the only diabetic without sevoflurane (p ¼ 0.1). There was no correlation between changes in ScO2 with other variables of interest. DISCUSSION

The results of this study suggest that administration of norepinephrine to restore MAP during CPB is associated with a

reduction in ScO2 in diabetics but not in non-diabetics. Administration of phenylephrine is associated with a trend towards a greater reduction in ScO2 in diabetics compared to non-diabetics. Patients with diabetes demonstrate frequent cerebral desaturations, measured by SjvO2, during normothermic CPB.7,8 Such reductions in cerebral oxygenation do not seem to be attributable to a reduction in MAP or PaCO2.8 Instead, cerebral vasculature of patients with diabetes seems unable to adequately compensate for an acute lowering in oxygen delivery to the brain induced by hemodilution at the beginning Table 3. Characteristics and Parameters at Baseline and During Cardiopulmonary Bypass in Diabetics v Non-diabetics Who Received Phenylephrine Diabetics

Subjects (n) 8 Age (y) 70 ⫾ 9 Body weight (kg) 74 ⫾ 14 Height (cm) 166 ⫾ 6 27 ⫾ 7 Body mass index (kg/m2) Ventilated body weight (kg) 71 ⫾ 6 MAP (mmHg) Baseline 90 ⫾ 18 CPB 63 ⫾ 6 Change from Baseline to CPB –27 ⫾ 5 ScO2 Baseline (%) 63 ⫾ 3 CPB (%) 55 ⫾ 6 Relative changes from –12 ⫾ 8 baseline to CPB (%) Time with a reduction in 19 ⫾ 20 ScO2 Z15% (min) 37 ⫾ 40 Time with a reduction in ScO2 Z15% (%) PaCO2 Baseline (mmHg) 40 ⫾ 3 CPB (mmHg) 39 ⫾ 3 Changes from baseline to –1 ⫾ 2 CPB (mmHg) O2 saturation Baseline (%) 99 ⫾ 1 CPB (%) 98 ⫾ 2 Changes from baseline to –2 ⫾ 2 CPB (%) Blood glucose Baseline (mmol/L) 6.9 ⫾1.5 CPB (mmol/L) 7.1 ⫾ 2.0 Changes from baseline to 0.2 ⫾ 1.1 CPB (mmol/L) Hematocrit (%) Baseline 36 ⫾ 4 CPB 26 ⫾ 6 Change from baseline to CPB –10 ⫾ 2 Venous temperature during CPB 34.9 ⫾ 0.5 (1C) 2.2 ⫾ 0.2 CPB pump flow rate (L/min/m2) Total time of CPB (min) 60 ⫾ 21

Non-diabetics

р

9 61 ⫾ 14 74 ⫾ 10 168 ⫾ 6 26 ⫾ 3 73 ⫾ 6

–

88 ⫾ 20 60 ⫾ 4 –28 ⫾ 7 65 ⫾ 6 61 ⫾ 6 –6 ⫾ 7

0.1 0.9 0.5 0.7 0.5 0.9 0.9 0.5 0.1

9 ⫾ 16

0.2

11 ⫾ 21

0.2

36 ⫾ 4 37 ⫾ 3 1⫾4

0.03

99 ⫾ 1 99 ⫾ 1 0⫾1

0.6

5.3 ⫾ 0.6 6.3 ⫾ 1.3 1.0 ⫾ 1.4

0.01

40 ⫾ 3 30 ⫾ 4 –10 ⫾ 3 34.3 ⫾ 0.8

0.03 0.8 0.06

2.3 ⫾ 0.1 93 ⫾ 35

0.3 0.04

0.2

0.04

0.2

NOTE. Results are mean ⫾ standard deviation. Abbreviations: CPB, cardiopulmonary bypass; MAP, mean arterial pressure; O2, oxygen; PaCO2, arterial carbon dioxide tension; ScO2, frontal lobe oxygenation.

INFLUENCE OF VASOPRESSORS ON BRAIN OXYGENATION IN DIABETIC PATIENTS

Fig 1. Relative changes in ScO2 with norepinephrine during cardiopulmonary bypass in patients with and without diabetes. Gray circles, individual data; horizontal bars, mean and SEM.

of CPB.6,7 While MAP per se may not be responsible for these more frequent cerebral desaturations reported in diabetic patients, indicating that interventions with vasopressors may, therefore, be unwarranted, the means by which MAP is maintained or corrected during CPB could influence this reduction in cerebral oxygenation. For example, agents for which the increase in MAP is accounted for by an elevation in total peripheral resistance, such as norepinephrine and phenylephrine, have been associated with an increase24 or no change25 in cerebral vascular resistance. In the context of the current findings, the influence of these vasopressor agents is further discussed. The direct influence of norepinephrine, through its α-adrenergicreceptor agonist properties, on cerebral hemodynamics is ambiguous. Norepinephrine has been reported to have no influence on estimated cerebral perfusion pressure or to elevate estimated critical closing pressure, ie, the estimated perfusion pressure that would be considered with zero cerebral blood flow, as an expression of arterial tone in the absence of changes in intracranial cerebral pressure.26,27 Cerebral blood flow may be unaffected by the administration of norepinephrine,28 or there may be a small reduction in cerebral blood flow.29 Yet, continuous infusion of increasing doses of norepinephrine reduces middle cerebral artery mean flow velocity and cerebral oxygenation estimated by ScO2 as well as SjvO2 in normotensive healthy subjects.19 Phenylephrine, a selective α-adrenergic-receptor agonist, has been reported to increase24 or have no influence25 on cerebral vascular resistance. Phenylephrine also has been reported to increase cerebral blood flow in healthy subjects,24 in anesthetized patients,30 and during CPB,31 although findings reported during CPB remain equivocal.32 In sharp contrast, the utilization of phenylephrine leads to a reduction in ScO2. For example, in normotensive, healthy subjects, Lucas et al33 and the authors’ research group20 reported a reduction in ScO2 with infusion or bolus injection of phenylephrine. In addition, the authors18 and others34 have reported a reduction in cerebral oxygenation following administration of phenylephrine in anesthetized patients undergoing elective surgery and experiencing anesthesia-induced hypotension. A reduction in cerebral oxygenation also has been reported following the use of phenylephrine in patients undergoing carotid endarterectomy.35 Accordingly, recent evidence, including findings from the

7

present study, suggests that phenylephrine is associated with a reduction in NIRS-derived cerebral oxygenation. In this study, both vasoactive drugs were efficient at maintaining MAP above 60 mmHg during CPB in diabetics and non-diabetics. However, the utilization of norepinephrine was associated with a reduction in ScO2 in patients with diabetes only while the use of phenylephrine tended to be associated with a greater reduction in ScO2 in patients with diabetes compared to non-diabetics. Patients with early diabetes have a purported compromise in dynamic autoregulation,36 meaning that their cerebral vasculature is less able to maintain cerebral perfusion for a given change in MAP. Diabetes affects cerebral vessels, eventually leading to alterations in cerebrovascular function, alterations that may be caused by reduced cerebrovascular endothelial nitric oxide production as demonstrated for patients with type-2 diabetes even without clinical evidence of vascular diseases.37 Animal models of type-1 and type-2 diabetes demonstrated that diabetes is associated with lowered endothelium-mediated relaxation in cerebral arteries38 and that cerebral arteries are hyper-responsive to vasopressors.39 Also, it has been shown that patients with diabetes show hyper-responsiveness to norepinephrine infusion.40,41 The mechanisms underlying this apparent hyper-responsiveness remain unclear. However, because of a lack of influence of PaCO2 and since key factors such as MAP before and during CPB, pump flow rate, and changes in hematocrit were consistent between groups of the present study, other factors may be responsible. In regards to the change in ScO2 with the administration of phenylephrine, a restraint in ScO2 by this vasopressor agent may have been induced by a reflex elevation in cerebral vascular resistance triggered by the increase in arterial pressure supported by a low cardiac output.34 Although PaCO2 was maintained during CPB and was similar between diabetics and non-diabetics, PaCO2 at baseline was higher in diabetics v non-diabetics. Thus, a reduction in PaCO2 could have contributed to the decline in cerebral oxygenation in diabetics in the norepinephrine series even though diabetes impairs the cerebrovascular reactivity to CO2.42,43 However, changes in PaCO2 from baseline to CPB were not associated with changes in ScO2 in patients from both groups. Although CPB pump flow rate, the amount of blood transfusion, and changes in hematocrit, in the presence

Fig 2. Relative changes in ScO2 with phenylephrine during cardiopulmonary bypass in patients with and without diabetes. Gray circles, individual data; horizontal bars, mean and SEM.

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BRASSARD ET AL

of an altered cerebral autoregulation,1 could influence cerebral blood flow and eventually cerebral oxygenation, these variables were similar between groups. The difference in venous temperature between the authors’ groups, although not statistically significant, could have influenced changes in ScO2 since cerebral metabolism is reduced with a lowering in temperature1 and changes in body temperature are known to influence skin blood flow.44 A different number of subjects without/under sevoflurane in the authors’ groups during CPB could have influenced changes in ScO2.45,46 However, the exclusion of subjects without sevoflurane did not modify their findings. This study was designed to describe ScO2 responses to the elevation in MAP by norepinephrine and phenylephrine in patients with diabetes compared to patients without diabetes during CPB for cardiac surgery. This study was not randomized nor was it designed to compare the influence of these 2 vasopressors on cerebral oxygenation when administered to correct hypotension during CPB or to investigate the mechanisms associated with changes in cerebral oxygenation during CPB. The authors acknowledge that further studies are warranted (1) to support their findings while strictly controlling for potential confounders such as anesthetic management, PaCO2 and hematocrit, and venous temperature and (2) to investigate which mechanism is responsible for the reduction in cerebral oxygenation during CPB with the utilization of these vasopressors in these patients. The small number of subjects, which could result in a Type-I error, precludes the generalization of these findings to the whole population of patients with diabetes undergoing cardiac surgery. The use of a convenience sample was related to the fact that, to the authors’ knowledge, changes in cerebral oxygenation have not been characterized by NIRS following administration of vasopressors during CPB in patients with diabetes. Although 60 mmHg often is referred to as the lower limit of cerebral autoregulation, this is not necessarily true for all patients undergoing cardiac surgery,47 nor has this so-called lower limit been established clearly within-subjects.48 This represents a potential limitation of this study since cerebral blood flow may or may not, depending on the patient, be autoregulated at this specific MAP. There are often substantial differences in systolic or pulse pressure monitored at different sites (radial v brachial artery),49 and this can have an impact on vasopressor use. However, monitoring MAP in the brachial artery has been shown to offer no advantage to radial artery post CPB.50 The reduction in NIRS-derived cerebral oxygenation following

administration of norepinephrine, at least in awake healthy individuals, partly would be explained by contamination of the NIRS signal by changes in skin blood flow.44 While skin blood flow may influence ScO2, the authors also have reported a reduction in SjvO2 following infusion of norepinephrine in normotensive healthy volunteers19 that cannot be explained by lowered skin blood flow. They cannot exclude that the reduction in ScO2 with the administration of phenylephrine represents an altered cerebral contribution of arterial v venous blood to the NIRS signal.51 Nevertheless, it is hard to reconcile how changes in skin blood flow or arterial-venous partitioning of the NIRS signal could explain the betweengroup differences. The threshold utilized for determination of a 15% reduction in ScO2 was determined in the setting of acute carotid artery occlusion23 and may not be applicable to the setting of CPB during which ischemia is more likely to be related to multiple insults rather than hemispheric reduction in cerebral blood flow. This being acknowledged, this study was not designed to evaluate the consequences of these repetitive changes in cerebral oxygenation. The authors used such a clinically relevant variable (% time of total CPB with ScO2 reduced by 15%) to show that marked changes in ScO2 occur with routine CPB management. They cannot ascertain from the current study, however, if such changes in cerebral oxygenation below this “cut-off” point may result in any localized ischemia in these patients. Finally, Figure 1, which displays the intra-individual responses in ScO2 to norepinephrine and phenylephrine administration, illustrates the typical important variation. This observation demonstrates the potential value of cerebral oximetry in individually optimizing perioperative hemodynamic management. CONCLUSION

The authors’ findings indicate that administration of norepinephrine to restore MAP during CPB is associated with a reduction in ScO2 in diabetics but not in patients without diabetes. Administration of phenylephrine also was associated with a trend towards a greater reduction in ScO2 in diabetics. The clinical implications of these findings deserve future consideration. ACKNOWLEDGEMENTS Paul Poirier is a senior clinical-scientist of the Fonds de recherche du Québec – Santé (FRQS). Patrice Brassard is a Junior 1 Research Scholar of the Fonds de recherche du Québec – Santé (FRQS).

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50. VanBeck JO, White RD, Abenstein JP, et al: Comparison of axillary artery or brachial artery pressure with aortic pressure after cardiopulmonary bypass using a long radial artery catheter. J Cardiothorac Vasc Anesth 7:4, 1993 51. Ogoh S, Sato K, Fisher JP, et al: The effect of phenylephrine on arterial and venous cerebral blood flow in healthy subjects. Clin Physiol Funct Imaging 31:445-451, 2011