Changes in hemodynamic variables during hypothermic cardiopulmonary bypass

J

THoRAc CARDIOVASC SURG

1990;100:134-44

Changes in hemodynamic variables during hypothermic cardiopulmonary bypass Effects offlow rate, flow character, and arterial pH During hypothermic cardiopulmonary bypass, the effects on hemodynamic variables of alternating pump flow rate between 1.5 and 2.0 L . min-I. m- 2, flow character between nonpulsatile and pulsatile perfusion, and acid-base management between pH- and alpha-stat control were studied in a crossover factorial experiment Twenty-four patients who were undergoing elective coronary artery bypass grafting were studied during stable hypothermic (270 to 29 0 C) cardiopulmonary bypass. A minimum of two (when time aUowed, three) consecutive 100minute periods (period 1, 2, or 3) were investigated. Only stage of the study period during cardiopulmonary bypass, flow rate, and interaction between stage and acid-base management were found to have significant effects on mean arterial pressure. In aU patients, there were average increases in mean arterial pressure from period 1 to period 2 of 9.4 (95% confidence interval 5.8, 13.0) mm Hg, from period 2 to period 3 of 6.3 (95 % confidence interval 1.2, 11.4) mm Hg, and from period 1 to period 3 of 15.7 (95% confidence interval 10.6,20.9) mm Hg. At 2.0 L . min-I. m- 2, mean arterial pressure was 7.2 (95% confidence interval 1.6, 12.9) mm Hg higher than at 1.5 L . min-I. m- 2• Peripheral vascular resistance was significantly affected only by stage and flow rate. There were, in aU patients, mean increases in peripheral vascular resistance from period 1 to period 2 of 239 (95% confidence interval 135, 343) dynes. sec . cm-s, from period 2 to period 3 of 85 (-64, 234) dynes. sec . cm", and from period 1 to period 3 of 324 (95% confidence interval 175, 473) dynes . sec . cm- s. At 1.5 L· min-I. m- 2, the peripheral vascular resistance was 316 (95% confidence interval 152, 480) dynes. sec . cm-s higher than at 2.0 L . min-I. m- 2• Alteration in flow rate, but not flow character or arterial pH, had a significant effect on peripheral vascular resistance. It is hypothesized that the increase in peripheral vascular resistance during the course of cardiopulmonary bypass results from an active capillary mechanism, whereas the increase that is associated with reduction in flow rate reflects a passive mechanism. The increase in peripheral vascular resistance with decrease in flow rate indicates impaired tissue perfusion, unlike that occurring with stage.

R. P. Alston, MB, ChB, FFARCS, L. Murray, BSc, and A. D. McLaren, MA, Glasgow, Scotland

Since its introduction into clinical practice more than 30 years ago, cardiopulmonary bypass (CPB) has been known to cause profound derangements of hemodynamic variables. Although many aspects of this disorder have From the Departments of Anaesthesia and Statistics, University of Glasgow, Glasgow, Scotland. Received for publication Jan. 5, 1989. Accepted for publication Aug. 30, 1989. Address for reprints: R. Peter Alston, MB, ChB, University Department of Anaesthesia, Level 2, Queen Elizabeth Bldg., Royal Infirmary, 8..16, Alexandra Parade, Glasgow, G3l 2ER, Scotland, United Kingdom.

12/1/16592

134

been studied in the past, much of the underlying pathophysiology remains unclear. Moreover, there have been major changes in CPB technique through the years. Hypothermia, hemodilution, alpha-stat acid-base management, low flow rates, and pulsatile perfusion are all now commonly used during CPB, and each of these techniques may influence hemodynamic variables. It is apparent from the literature that there are hemodynamic effects of some CPB techniques that either have not been studied within recent years or that remain disputed. These techniques were identified as low flow rates, I flow character, that is, nonpulsatile or pulsatile perfusion,"!' and acidbase management, that is, pH-stat or alpha-stat contro1. 16- 18

Volume 100 Number 1

CPB: Effects on hemodynamic variables 1 3 5

July 1990

Table II. Durations (minutes)

Table I. Demographic details Mean Age (yr) Height (m) Weight (kg)

Surface area (m2)

54 1.71

76.1 1.87

Standard deviation 9.2 0.06 9.4 0.14

Clinical CPB practice is the product of a combination of various techniques. It is reasonable to hypothesize that different combinations may interact to produce either beneficial or detrimental effects, yet previous studies have not addressed this possibility. Factorial experiments allow study not only of main effects but also of interactions.'?' 20 Therefore, their application to CPB should allow determination of the most effective combination of techniques. For these reasons, a factorial experiment was undertaken, the aim of which was to study the main effects of pump flow rate, flow character, acid-base management, and any interaction between these factors on hemodynamic variables during hypothermic CPB.

Methods Patient details. Approval for the study was obtained from the local hospital ethics committee. Patients scheduled for elective coronary artery bypass grafting and who had given informed consent were admitted to the study. Those patients with carotid artery stenosis, cerebrovascular disease, severe hepatic or renal disease, or diabetes mellitus were excluded. Twenty-one patients studied were male and three were female. All were receiving one or more of the following antianginal therapies: atenolol, propranolol, isosorbide nitrate, nifedipine, and glyceryl trinitrate (sublingual or transcutaneous). Demographic details and relevant durations are presented in Tables I and II. Anesthesia. Patients received their routine medication on the day of operation. Premedication consisted of lorazepam (2 to 4 mgorally) on the night before the operation and temazepam (20 to 50 mg orally) about I hour before the operation. Anesthesia was induced with fentanyl (5 J.Lg • kg" intravenously) followed by a sleep dose of midazolam intravenously. Neuromuscular blockade was then obtained with vecuronium (0.15 mg . kg-I), and the trachea was intubated. The lungs were ventilated with oxygen (50%) and nitrous oxide (50%) to maintain eucapnia. Anesthesia and neuromuscular blockade were maintained with infusions of fentanyl (0.1 J.Lg . kg-I. min"! intravenously) and vecuronium (2.5 J.Lg • kg-I. min-I intravenously) throughout the procedure. Before CPB, isoflurane was administered up to a vaporizer setting of 3%, when sodium nitroprusside or glyceryl trinitrate was given by intravenous infusion as required to control systemic arterial pressure. All vasoactive drugs were discontinued at the start of CPB. Cardiopulmonary bypass. The operations were performed by the same surgical team. Heparin (3 mg . kg") was administered before cannulation. Both venae cavae were cannulated with two straight polyvinyl beveled and bell-tipped cannulas (8 mm diameter) (Bentley Laboratories, Inc., Irvine, Calif.). A right-angled tapered cannula with a terminal diameter of 6 mm

Mean

Standard deviation

Induction of anesthesia

91

24

CPB

98

Crossclamp

56

23 14

Table III. Averaged values of hematocrit (%) for all six combinations of stage and flow rate Pumpflow rate (L. min-I. m- 2) Period

2.0

1.5

I

27.2 27.5 26.5

27.2 27.6 29.5

2 3

(Gambrio Dialysatoren KG, Henchigen, Federal Republic of Germany) was inserted into the aorta so that the tip pointed toward the arch. The CPB circuit consisted of a bubble oxygenator (BOS 10, Bentley), and a roller pump (10-00-00, Stockert Instrumentes, Munchen, Federal Republic of Germany) that could be controlled to produce nonpulsatile or pulsatile perfusion with the use of a pulsatile control unit (EC 26, Stockert Instrumentes). When the pump was used in the pulsatile mode, it was set to deliver a pulse rate of 70 . min- 1 with a pulse run time at 50% of total cycle length. Throughout the course of the study, the pump was regularly volumetrically calibrated with water at room temperature. The circuit was primed with lactated Ringer's solution 21, mannitol (20%/100 ml), potassium chloride (15 mmol) , and heparin (8000 U). An arterial filter (CI040, Bentley) and a GasSTAT cell (Cardiovascular Devices, Irvine, Calif.) were inserted into the arterial line. During induction of hypothermia and rewarming, the flow rate was set at 2.4 L . min-I. m- 2. Arterial pH and carbon dioxide and oxygen tensions were measured during CPB with the use of an inline monitor (GasSTAT, Cardiovascular Devices). Arterial pH was controlled by manipulation of the gas concentrations (oxygen 100% and/or oxygen 95% and carbon dioxide 5%) or flow rate supplied to the oxygenator, or both. The perfusionists were instructed to maintain arterial pH as closely as possible to 7.4. The GasSTAT was switched to the mode that displayed the results at the actual blood temperature for pH-stat control and to the one that internally corrected the results to 37° C for alpha-stat control. 21- 23 During CPB, hypotension was defined as a sustained decrease in mean systemic arterial pressure (MAP) below 35 mm Hg and was treated with intravenous boluses of methoxamine 2 mg as required to maintain the MAP above this level. Similarly, hypertension (MAP> 95 mm Hg) was corrected using an intravenous infusion of sodium nitroprusside. Hypovolemia was defined as a reservoir level less than 400 ml and was treated with lactated Ringer's solution. Measurements. Systemic arterial pressure was measured with a 20 g Teflon cannula (Quick Cath, Travenol Laboratories, Ltd, Thetford, United Kingdom) inserted percutaneously into

136

The Journal of Thoracic and Cardiovascular Surgery

Alston, Murray, McLaren

Table IV Pulsatiiefpll-stat Group

Period I

Flow rate

2 3 I

2 3

Variable High flow Low flow High flow Low flow High flow Low flow

Patient

5

Pulsatile/alpha-stat

SAP

DAP

MAP

CVP

PVR

97 74

48 44

65 54

3 10

1244 1185

71 93 93

40 49 53

51 64 66

-3

1493 1350 1888

-I

-3

Patient

2 6

High fiowtpli-siat Patient I Flow character

2 3 I

2 3

Pulsatile Nonpulsatile Pulsatile Nonpulsatile Pulsatile Nonpulsatile

9 13

SAP

DAP

MAP

CVP

PVR

82 74

48 57

59 65

2 2

1058 1180

80 88 91

64 58 69

71 70 80

8 8 0

1242 1237 849 PVR

Arterial pH

2 3 1 2 3

988 1538 1480 1530 1786

SAP

DAP

MAP

17

52 70

21

61 70

33 44 44 43 52

41 55 55 50 60

4 3 -2 -4 -3

72

MAP

CVP

63 67 63 34 48 52

73 75 36 36 53 58

2 0 5 I

2 8

PVR

1482 2132 1392 942 1042 1375

Patient

10 14

SAP

DAP

MAP

CVP

PVR

54 73 88 73 90 86

42 60 63 57 51 62

47 69 74 79 66 74

I

-3

1051 1529 1646 1473 1398 1534

2 2 -3 1

Low fiowlnonpulsatile CVP

Patient pH-stat Alpha-stat pH-stat Alpha-stat pH-stat Alpha-stat

DAP

85 86 83 39 61 66

High flow/alpha-stat

Low flow/pulsatile I

SAP

Patient

18 22

SAP

DAP

MAP

CVP

PVR

58 90 92

42 69

49

8

77

II

72

61 70

73 67

4 -13 -4

1112 1831 2089 2654 2772

85

72

78

SAP, Systolic arterial pressure: DAP, diastolic urtcrial pressure; MAP, mean arterial pressure; CVP, central venous pressure; PYR, peripheral vascular rcsis-

tance.

the left radial artery. The cannula was connected to a transducer (Trantec 800, American Bentley) with the use of a pressure dome set primed with heparinized physiologic normal saline. Central venous pressure (CYP) was measured with a 7-gauge cannula (Arrow International Inc., Reading, Pa.) inserted into the right internal jugular vein using the Seldinger technique and connected as the arterial line. The transducer were connected to a Patient Data Monitor (536, Kone Corporation, Ospoo, Finland). Transducers were zeroed and manometrically calibrated, and they were then maintained manometrically zeroed to the midaxillary line throughout the operation. Hemodynamic data were repeatedly recorded during each la-minute study period, with the use of an Apple lIe computer (Apple Computer Inc., Cupertino, Calif.), onto magnetic disks." Data for each variable were averaged, and this mean was used in all analyses. Peripheral vascular resistance (PYR) was calculated with the use of the standard formula from the MAP, CYP, and pump flow rate. Nasopharyngeal temperature was measured with the use of a thermistor temperature probe (YST 700, Yellow Springs Instrument Co., Yellow Springs, Ohio) and the temperature module of the Patient Data Monitor. Arterial temperature was measured using the GasSTAT monitor. Both temperatures were controlled between 27° and 29° C during the periods of study. A computerized system was used to enhance the degree of temperature and arterial pH control." Blood samples were aspirated from the arterial and venous lines'at the end of each period for measurement of oxygen con-

tent, saturation, and tension, as well as pH, carbon dioxide tension, base excess, and lactate. Details of the measureinent techniques and results have been presented previously.s' Study design. The study design has been described in detail previously.P In brief, patients were randomly allocated to one of three groups of eight in a crossover factorial experiment. 19.20 In one group, alteration in flow rate between 1.5 and 2.0 L . min- t • m- 2 was studied, in another flow character, which was altered between nonpulsatile or pulsatile perfusion, was studied, and in a third group, acid-base management, which was either according to pH-stat or alpha-stat principles. It was planned to have three consecutive l Osminute periods of study for each patient during stable hypothermic CPS, although the design allowed for a minimum of two. Rewarming was dictated by the surgeon on clinical indications. Only 10 of a possible 24 third periods were obtained because of shortage of time available for study at stable hypothermia. Statistical analysis. Data from all 24 patients were analyzed with the use of multiple statistical modeling and factorial analysis of variance on a main frame computer with a GUM program.P Factors for individual patient, stage of the study period during CPS, the three variables studied, and, when appropriate, interaction between the variables were applied to the results so that the simplest significant model that described the data could be determined. Because group construction was heterogeneous whereas the change induced was homogeneous, some results are presented as mean within patient changes with 95% confidence interval of the mean in parentheses (95% con-

Volume 100

CPB: Effects on hemodynamic variables 1 3 7

Number 1 July 1990

Nonpulsatilefalpha-stat

Nonpulsatiletpll-stat Patient

3 7

SAP

DAP

MAP

CVP

PVR

66 66 60 51 70

57 57 80 44 54

61 61 84 47 60

-14 -14 -10 0 -2

1544 2034 1937 1495 1462

Patient

4 8

SAP

DAP

MAP

CVP

PVR

76 82 87 43 83 70

61 71 80 34 65 62

68

11 4 8 -21 -8 -7

1334 2333 1866 1852 1946 2358

SAP

DAP

MAP

CVP

PVR

II

58 53

45 47

15

63 73

47 43

87 38 74 70

Lowflowlalpha-stat

Lowflow/pH-stat

Patient

77

CVP

PVR

Patient

SAP

DAP

MAP

50 50

0 I

1426 1383

12

67 71

41 53

51 62

9 8

53 53

-18 -20

2112 2196

16

58 62

44 53

50 57

-11 -11

1793 1768

High flowtpulsatile

1224 1157

High flowfnonpulsatile

Patient

SAP

DAP

MAP

CVP

PVR

Patient

SAP

DAP

MAP

CVP

PVR

19

66 79

48 63

1 2

1118 1474

20

95 109

73 87

84 98

0 -7

1674 2105

23

84 90

37 52 61 70

70 73

2 2

1489 1533

46 52 70

37 42 55

41 47 62

I

24

1 -2

911 1044 1472

fidence interval [Clj). The level of statistical significance was taken as 5% (p < 0.05).

Results Temperature. In all but five periods, the 95% confidence intervals for the means of the repeated arterial temperature measurements fell within the preset target range (27 0 to 29 0 C). In those five periods, the confidence intervals lay within 26° to 27° C and were allduring pe-

Arterial pH. For the purposes of all analyses, only pH results as measured by the bench blood gas analyzer were used: all GasSTAT values were ignored because they were found to correlate less than completely with those obtained by bench blood gas analysis (0.826; p < 0.01).20 Analyses of arterial pH results as measured by bench blood gas analyzer (at 37° C and uncorrected for patient temperature) revealed that 95% confidence intervals of the means during pH-stat and alpha-stat periods were,

riod 1 in separate patients. Without exception, the 95%

respectively, 7.216, 7.250 and 7.325, 7.363. Because

confidence intervals for the means of the repeated nasopharyngeal temperature measurements lay within the preset range. Details of the arterial and nasopharyngeal temperature are given elsewhere." Hematocrit. During all periods, the mean hematocrit was 27.6% (95% CI 26.4%, 28.8%). Analyses revealed that the simplest significant model describing the data included patient, stage of study period during CPB, pump flow rate, and a factor for the interaction between stage and pump flow rate. Tabulation of the average hematocrit values for all six combinations of stage and pump flow rate (Table III) shows that there were minimal differences in hematocrit during periods 1 and 2, but by period 3 hematocrit was on average 3% less at the high than at the low flow rate.

these intervals did not include the expected target values (pH-stat, 7.27 and alpha-stat, 7.40), arterial results were treated as a continuous regression variable in all further analyses.i" Pulse pressure. Through examination of systolic and diastolic arterial pressures (Table IV), the mean pulse pressure during periods of pulsatile perfusion was found to be 23.7 (95% CI 19.3, 28.0) mm Hg, whereas it was 14.1 (95% CI 12.1, 16.0) mm Hg during nonpulsatile perfusion. The mean within-patient change in pulse pressure produced by alternating flow character between nonpulsatile and pulsatile was 11.5 (95% CI 5.9,17.1) mm Hg. Because there was a sizable pulse pressure in periods of nonpulsatile perfusion and a large variability in pulse pressure during periods of pulsatile perfusion, pulse

138

The Journal of Thoracic and Cardiovascular Surgery

Alston, Murray, McLaren

f1MAP (mmHg) 40

6. PYR.

(dynes s. cm:- 5

•

)

1000

30 20 10

o

.! I .~ ·a t ~: r-----~-•

o

-10

• •

-30

••

-40

High flow -Low flow

•

~

o -----.--------

-20

500

Pulsatile -nonpulsatile

pHA- pH37

o -500

I

-----:-I-------:t------~~

• o -1000

o.

I

•

High flow

-Low flow

• • Pulsatile -nonpulsa tile

pHA- pH37

Fig. 1. Line plot of within-patient changes in mean arterial pressure (MAP) produced by alternation in pump flow rate between 1.5 and 2.0 L· min-I. m- 2, flow character between pulsatile and nonpulsatile perfusion, and arterial pH between pH-stat (pHA) and alpha-stat (pH37) control. Closed circles represent changes occurring from period I to period 2, and open circles those occurring between periods 2 and 3. Vertical bars represent unadjusted 95% confidence intervals of the means and indicate a significant difference when they do not include zero.

Fig. 2. Line plot of within-patient changes in peripheral vascular resistance (PVR) produced by alternation in pump flow rate between 1.5 and 2.0 L . min-I. m- 2, flow character between pulsatile and nonpulsatile perfusion, and arterial pH between pH-stat (pHA) and alpha-stat (pH37) control. Closed circles represent changes occurring from period I to period 2, and open circles those occurring between periods 2 and 3. Vertical bars represent unadjusted 95% confidence intervals of the means and indicate a significant difference when they do not include zero.

pressure was also treated as a continuous regression variable in all further analyses. Mean arterial pressure. Within-patient changes in MAP produced by the alternations in pump flow rate, flow character, and arterial pH are plotted in Fig. 1. Analyses of MAP data (Table IV) revealed that, when all other variables were excluded, both patient and stage of the study period during CPB were individually significant (F = 8.323). When the variables under study were included, only flow rate was found to have a significant effect (F=4.765; critical value = 4.184). If only patient stage and flowrate were fitted to the model, the combined effect of flow character and arterial pH on MAP were nonsignificant (F = 1.302; critical value = 3.334). On average, MAP was 7.2 (95% CI 1.6, 12.9) mm Hg higher at 2.0 compared with 1.5 L . min-I. m- z. There were mean increases in MAP from period 1 to period 2 of 9.4 (95% CI 5.8, 13.0) mm Hg, from period 1 to period 3 of

15.7 (95% CI 10.6,20.9) mm Hg, and from period 2 to period 3 of 6.3 (95% CI 1.2, 11.4). Tabulation of the average values of MAP for all six combinations of flow rate and stage during both pH-stat and alpha-stat control (Table V) shows not only the main effects of stage and flow rate but also the significant interaction between arterial pH and stage on MAP. There is little or no difference in MAP between pH-stat and alpha-stat during period 1, but by period 2, MAP is higher with alpha-stat control than with pH-stat control. This interaction between stage, arterial pH, and MAP is continued in period 3. Peripheral vascular resistance. Within-patient changes in PVR resulting from alteration in flow rate, flow character, and arterial pH are plotted in Fig. 2. Modeling of the PVR data (Table IV) revealed that, if all other variables were excluded, patient and stage of the study period during CPB were individually significant

Volume 100

CPR: Effects on hemodynamic variables

Number 1 July 1990

t:. V02 (ml. rnirr" m-2)

Table V. AveragedMAPs (mm Hg) for all six

combinations of stage and flow rate during attempted pH-stat and alpha-stat control pll-stat control Pump/low rate IL. min-I. m- 2)

Alpha-stat control Pump flow rate IL. min-I. m- 2)

Period

2.0

1.5

2.0

1.5

1 2 3

58.3 62.9 72.2

53.0 57.5 66.9

58.3 71.9 76.1

53.0 66.5 70.7

50

--.

o -,

-,

-,

-,

,

.

40

o

"-,,-

•

-,

-,

-,

30

"-

0

"-,,-

o

"- -,

Table VI. Averaged PVR idynes- sec- cm-5) for all

six combinations of stage and pump flow rate

-1000

-500

t:.P.V.R. (dynes. s cm- 5 )

Pump/low rate IL . min-I. m- 2) 2.0

1.5

I 2 3

1269 1508 1593

1585 1823 1908

• •

"-,,-

o

Period

13 9

20

"-

"-,,- 10 ~

"-

• • -10

500

1000

-20

Y =7.3 + (-0.035x) r= 0.648 p<0.01

-30 -40 -50

(F = 10.706). When the variables under study were fitted to the model, only flow rate was found to have a significant effect on PVR (F = 15.892, critical value = 4.184). If only patient, stage and flow rate were included in the

model, the combined effects offlow character and arterial pH on PVR were nonsignificant (F =1.745, critical

value = 3.334). Tabulation of the average PVR for all six combinations of flowrate and stage (Table VI) shows that there were mean increases from period 1to period 2 of239 (95% CI 135,343) dynes. sec . cm- 5, from period 1 to period 3 of 324 (95% CI 175, 473) dynes· sec . cm- 5, and from period 2 to period 3 of 85 (95% CI -64, 234) dynes. sec· cm- 5. There was a mean increase in PVRof 316 (95% CI 152,480) dynes. sec· cm- 5 at the low compared with the high flow rate. No significant interactions between the variables were found. There was a significant correlation between within-patient changes in PVR and contemperaneous systemic oxygen uptake (V0 2) measurements (previously presentedr'") that were produced by alteration in pump flow rate between high and low (Figs. 3 and 4). CVP. Analyses of the CVP data (Table IV) demonstrated no significant relationships with any of the variables investigated. Vasoactive drugs. There were no significant relationships between any of the variables investigated and the administration of sodium nitroprusside or methoxamine (Table VII).

Fig. 3. Relationship of within-patient changes in systemic oxygen uptake (V0 2) with those of peripheral vascular resistance (PVR) produced by alternation in flow rate between 1.5 and 2.0 L. min-I. m- 2. Closed circles represent changes occurring

from period 1toperiod 2, and open circles those occurring between periods 2 and 3.

Arterial pressure

Tissue pressure

Venous pressure

Fig. 4. Starling resistor.

Discussion The main findings of this study are that MAP was significantly lower and PVR significantly higher at 1.5 compared with 2.0 L . min-I. m- 2 and that there were progressive and significant increases in MAP and PVR during the course of CPB. Study design. One of the great difficulties in comparing previous studies is the wide variety of anesthetic and

140

The Journal of Thoracic and Cardiovascular Surgery

Alston. Murray, Mclaren

Table VII. Incidence and distribution of sodium nitroprusside (SNP) and methoxamine (M) administration

Patient I

2 3 4

5 6 7 8 9 10 II

12 13 14 15 16 17 18 19 20 21 22 23 24

Period /: 2.0 L . min"! .

Period 2: /.5 L . min"! .

0 SNP 0 0 1.5 L . min-I. m- 2 0

0 SNP 0 0 2.0 L . min-I. m- 2 SNP 0 0 0 Nonpulsatile 0 0 0 0 Pulsatile SNP SNP 0 SNP Alpha-stat 0 SNP 0 SNP pH-stat 0 SNP SNP

m- 2

M

0 M

Pulsatile 0 0 0 0 Nonpulsatile 0 0 0 0 pl-l-stat M

0 0 0 Alpha-stat 0 SNP SNP

m- 2

Period 3: 2.0 L . min:' .

m- 2

SNP SNP 1.5 L . min-I. m- 2 SNP 0 0 Pulsatile 0

Nonpulsatile SNP SNP

pH-stat 0

Alpha-stat

surgical techniques employed. Anesthetic agents vary widely in their effects from being potent vasodilators to having minimal hemodynamic effects. 26 , 27 For this reason,care wastaken in the presentstudy to employagents that have minimal effects, and these were given as constant infusions to provide a steady state. Care was also taken to standardize surgical technique by studying patients from one surgical team undergoing operations for coronary artery disease. Factorial experiments are unusual in clinical CPB research although well establishedin other research fields.!" 20 Argumentsfor the use of a factorial design in the present study have been presented previously.P' At the outset, the variables in the study were dichotomized. Dichotomization of what are essentially continuous variables is, perhaps, artificial,althoughit isa commonclinicalpractice,that is,lowor high flow, pulsatileor nonpulsatile, and pH-stat or alpha-stat.

.

Where the data showed a high variabilityas with the pH and pulsepressureresults,this variabilitywas readilyaccommodated in the analyses by treating these data as continuous regression variables. Ideally,no vasoactive agents shouldhave been administeredduringthisstudy.Because ofconcernthat cerebral damage may result from hypotension and that hypertensioncouldcause aortic disruption at the cannulationsite, methoxamine and sodium nitroprusside were administered as appropriate to control MAP between 35 and 95 mm Hg. Although no statistical relationship was found between the administration of methoxamine or sodium nitroprusside and the variables investigated, the administration of these drugs may have influenced the resultsin some patients. Hematocrit. The interaction between stage and flow rate on hematocritwasa surprisingfinding. A reasonable explanation for this finding might be that the effectofongoing hemorrhage would have reached a sufficient amount by period3 to the extent that hypovolemia would be apparent if high flow was used but disguised by a low flow rate. Thus, low reservoir volumes would have occurred whenhighflow rate wasusedand wouldbe treated with lactated Ringer's solution producing hemodilution, whereas this would not have happened if low flow were employed. However, it is unlikely that this interaction, of sucha smallsize,wouldhaveany significant effecton hemodynamic variables. Flow rate. The finding of an increasein PVR.withreductionin flow rate in this study confirms the recognized inverse relationship between these twovariables.': 28 Vasoconstriction may havebeenproducedby reflex increases in circulatingcatecholamines or sympathetictone in response to hypotension. Another explanation for this relationshipmay be a passive mechanismacting at the capillarylevel. Capillaries behaveasStarling resistors. Before flow will start in a capillary, the pressure at the arterial end must exceed that at the venous end, which in tum mustexceedthe closing pressureexertedbythe surrounding tissue(Fig. 4). Thus, unlikea rigidtube in whichflow increases linearly with pressure, flow commences in a capillaryat the criticalclosing pressureand then increases exponentially with pressure'? (Fig. 5). In the present study,the increasein PVRat the lowercomparedwiththe higherflow rate may representa proliferation of capillaries in which the critical closing pressure is no longerexceeded. Thus the increase in PVR with decreasing flow rate wouldindicateimpairedtissueperfusion. Indeed,this hypothesis is confirmed not only by the concomitant mean decrease in systemic oxygen uptake of 18 ml . min-I. m- 2,24 but also by the significant correIa-

Volume 100 Number 1

CPB: Effects on hemodynamic variables 141

July 1990

tion between the within-patientchange in PVR and systemicoxygen uptake that resultedfrom alteration in flow rate. That tissue perfusion was impaired at 1.5 compared with 2.0 L . min-I. m- 2is of concernbecausesuch flow rates and lowerlevels are commonly used in conjunction with hypothermic CPB. Flowrate is cut back during hypothermicCPB on the basis of improvement in myocardial preservation, less hemolysis, and a clearer surgical field. 30-32 The physiologic rationale of this maneuver is that, as hypothermia decreasesmetabolicrate, sufficient oxygen willstill be delivered to the tissues, despitethe reduced flow, to maintain aerobic metabolisrn.I"31 The findings of this study wouldsuggest that no matter how much metabolism is reduced by hypothermia, there are increasing areas of tissue hypoperfusion associated with decreasing flow to low levels. Progressive vasoconstriction. During the course of CPB there were progressive increasesin MAP and PVR that are well recognized phenomena of CPB.33 This inexorableincreasein PVR, as with the rise that was associatedwith reductionin flow rate, might indicate impairment of tissue perfusion. Systemic oxygen uptake, however, did not significantly change during the courseof the study, and, in fact, there was a small but significant decrease in lactate concentration.l" The disparity in metabolic effects wouldindicatethat differentmechanisms are causing the rise in PVR. Unlike the passive mechanism responsible for the effectsof flow rate on PVR, the progressive increaseduring CPB may result from activevasoconstriction of metarteriolesand precapillarysphincters. Angiotensin 2, catecholamines, and vasopressin have been associated with this rise,II,12 although the exact mechanism for this hemodynamic derangement remains unclear. If the rise in PVR is due to an increase in vasomotortonerather than capillaryclosure, this may explain why tissue metabolism was unimpaired. This hypothesized difference in mechanism of effect on PVR might also explain why Evans and colleagues.r' using sodium nitroprusside, were unable, despite producing a significant decrease in PVR, to detect any change in systemic oxygen uptake because sodium nitroprusside acts by reducing vasomotor tone. One of the hemodynamic benefits of pulsatile over nonpulsatile perfusion is prevention of the ineluctableincreasein MAP and PVR that occursduring CPB.II,12 In the present study, interaction betweenstage of the study period during CPB and flow character was specifically examined for in the statisticalmodeling, and yet pulsatile perfusion did notsignificantly amelioratethe risein MAP or PVR. Previous studies have also failed to find any dif-

flow

Rigid tube

pressure flow

Capillary

critical closing pressure

t

pressure Fig. 5. Pressure flow relationship in rigid tube and capillary tube,

ference in the rise in MAP and PVR with pulsatile perfusion.v" 13 It is difficult to explainthese contrary he-

modynamic findings unless there are important differences between the studies in other procedures of CPB technique or anesthetic management. Flow character. Pulsatile perfusion has also been stated to be hemodynamically superior to nonpulsatile perfusionon the basisthat it producesa lowerPVR. 15 Indeed, many animal and human studieson flow character have found lower PVR associated with the use of a pulsatile flow character.v- 7,8,10, II Unfortunately, some of thesestudiesare of dubiousstatisticalvalidity." Also,it is impossible to attribute any difference in PVR to flow character alonein studiesin whichthe flow rate is higher

142

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in the pulsatile than in the nonpulsatile group because of the inverse relationship between flow rate and PVR. 4, 5, 12 Like the present study, a number of animal and human studies have also failed to demonstrate that flow character has any significant influence on hemodynamics,8,9, 13, 14 and one even found pulsatile perfusion to increase PVR.6 Hickey, Buckley, and Philbin l 5 dismissed these findings on the grounds that high flow rates (> 100 ml . kg-I. min-I) were used and that only with lower rates of flow (60 to 100 ml . kg-I. min-I), which are commonly employed, do the differences become apparent. Both flow rates used in this study were at the low range, yet no significant differences could be found. This study can reasonably be criticized on the grounds that there was a sizable pulse pressure during nonpulsatile periods, so that, in fact, a comparison of two forms of pulsatile perfusion was made.P In consideration of the present study's findings, it should be noted that pulse pressure may not be the best method of quantifying pulsatile perfusion" and that the Stockert roller pump has been found to generate less pulsatile power than other pumps and the human heart.l" Thus, the present study cannot exclude that there are differences in hemodynamics between truly nonpulsatile and pulsatile perfusion. However, nonpulsatile and pulsatile perfusion are commonly produced in a similar way during clinical practice, and therefore the present comparison is valid. Furthermore and unlike many previous studies, this study continuously quantified the pulsatile component of the flows under investigation and demonstrated a substantive difference in pulse pressure between nonpulsatile and pulsatile perfusion.P Arterial pH. Conventionally, the aim of acid-base management during CPB has been to guard the pH at 7.4, and this concept was adopted into hypothermic CPR To maintain the arterial pH at 7.4 (corrected for patient temperature) during hypothermia according to this pHstat approach usually requires the addition of carbon dioxide and results in an increased total carbon dioxide content of the blood. In recent years, because of the work of Rahn, Reeves, and Howell and colleagues'T" on poikilotherms, there has been a move toward the use of an alpha-stat form of acid-base management in which the carbon dioxide content is kept constant and the arterial pH is allowed to become relatively alkalotic.P: 23 Although some aspects of these different approaches to acid-base management have been studied,40,41 accurate investigation of their systemic hemodynamic effects during hypothermic CPB in man have not. Despite use of in-line monitoring and a computerized system to enhance control, poor arterial pH control was achieved in this study. This poor control resulted from the

The Journal of Thoracic and Cardiovascular Surgery

combination of using a bubble oxygenator that has poor carbon dioxide exchange characteristics during hypothermia-' and a less than complete correlation between arterial pH measurement by the in-line blood gas monitor and bench blood gas analyzer.f Because of the poor correlation, the study's analyses fell back on results from the bench blood gas analysis, which has to remain the gold standard for pH measurement. As the target values for alpha-stat and pH-stat control were not accurately obtained, the present study is not a true comparison of pHstat and alpha-stat control. A significant difference in arterial pH was induced, however, and the results should give an indication of the likely difference in effects between the two forms of acid-base management. Previously, Bove, West, and Paskanik'" were unable to demonstrate any significant differences in systemic or regional hemodynamics in dogs during CPB at 20° C between pH-stat and alpha-stat control. Human studies at or near normothermia have shown variable findings; Paterson 17 found that hypocapnea produced an increase in MAP, whereas Springer and colleagues'f could demonstrate no significant difference in PVR when arterial carbon dioxide tension was altered by 5 mm Hg. Interestingly, in the present study arterial pH had little or no effect on MAP during period 1, but by period 2, MAP was higher with alpha- than with pH-stat control, and this difference was maintained in period 3. That MAP should be higher at a lower arterial carbon dioxide tension and higher arterial pH and vice versa, would fit with the known vasoactive effects of these variables." Commensurate changes in PVR, however, would also have been expected to occur, although, possibly, the study simply failed to detect the change because of the increased variability introduced into the calculated PVR by the CVP data. The lack of difference in MAP during period 1 is more difficult to explain, although perhaps it is due to initial vasomotor paralysis, after which tone is progressively regained and thevessels again become sensitive to changes in carbon dioxide pressure. Whether these systemic hemodynamic effects have clinical importance is doubtful, although the choice of acid-base management may have important regional effects, for example, on cerebral blood flow,40 and there is some evidence suggesting that poor arterial pH and carbon dioxide pressure control has an adverse effect on neurologic outcome." In conclusion, this study has found that during hypothermic CPB increases in PVR are associated both with the progression of CPB and with a decrease in flow rate. Neither change in flow character nor arterial pH had any significant effect on PVR. Active vasoconstriction may account for the inexorable rise in PVR during CPB, but it does not impair tissue perfusion. In contrast, passive

Volume 100 Number 1 July 1990

capillary closure may cause the increase in PVR on reduction of flow rate to low levels,and this increase is associated with impaired tissue perfusion. We wish to thank K. G. Davidson, D. Miller, and V. Richards for their willing cooperation. Recognition is also due to the Departments of Medical Illustration and Perfusion and to I. MacDonald and J. McNicol, of the University Department of Anaesthesia at the Glasgow Royal Infirmary, for their able assistance and without whom this study would not have been possible. Finally, we are grateful to Bentley UK, who supplied the GasSTAT monitor for the purpose of this study. REFERENCES I. Galletti PM, Brecher GA. Heart lung bypass. New York: Grune & Stratton, 1962:194-212. 2. Dunn J, Kirsh MM, Harness J, Carroll M,Straker J,Sloan H. Haemodynarnic, metabolic and haematologic effects of pulsatile cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1974;68:138-47. 3. Jacobs LA, Klopp EH, Seamone W, Topaz SR, Gott VL. Improved organ function during cardiac bypass with a roller pump modified to deliver pulsatile flow. J THORAC CARDIOVASC SURG 1969;58:703-12. 4. Chiu I-S, Chu S-H, Hung CR. Pulsatile flow during routine cardiopulmonary bypass. J Cardiovasc Surg (Torino) 1984;25:530-6. 5. Trinkle JK, Helton NE, Wood RE, Bryant LR. Metabolic comparison of a new pulsatile pump and roller pump for cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1969;58:562-9. 6. Ogata T, Ida Y, Nonayama A, Takeda J, Sasaki H. A comparative study of the effectiveness of pusatile and nonpulsatile flow in extracorporeal circulation. Arch Jpn Clin 1960;29:59-66. 7. De Bois WJ, Sharon I, Shevde K. Improved circulation during hypothermic cardiopulmonary bypass utilizing a pulsatile device. Anaesth Analg 1987;66:839. 8. Boucher JK, Rudy LW, Edmunds LH. Organ blood flow during pulsatile cardiopulmonary bypass. J Appl Phsiol 1974;36:86-90. 9. Singh RKK, Barratt-Boyes BG, Harris EA. Does pulsatile flow improve perfusion during hypothermic cardiopulmonary bypass? J THORAC CARDIOVASC SURG 1980;79:82732. 10. Sheppard RB, Kirklin JW. Relation of pulsatile flow to oxygen consumption and other variables during cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1969; 58:694-701. II. Taylor KM, Bain WH, Russel M, Brannan JJ, Morton JJ. Peripheral vascular resistance and angiotensin II levels during pulsatile and nonpulsatile cardiopulmonary bypass. Thorax 1979;34:594-8. 12. Levine FH, Philbin D M, Kono K, et al. Plasma vasopressin levels during cardiopulmonary bypass with and without pulsatile flow. Ann Thorac Surg 1981;32:63-7. 13. Frater RWM, Wakazama S, Oka Y, et al. Pulsatile

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