Low Systemic Vascular Resistance After Cardiopulmonary Bypass: Incidence, Etiology, and Clinical Importance

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Low Systemic Vascular Resistance After Cardiopulmonary Bypass: Incidence, Etiology, and Clinical Importance T. Carrel, M.D.,* L. Englberger, M.D.,* P. Mohacsi, MUD.,+P. Neidhart, M.D.,++and J. Schmidli, M.D.* "Clinic for Cardiovascular Surgery, tDivision of Cardiology, and fflnstitute for Anesthesiology and Intensive Care Medicine, University Hospital Berne, Berne, Switzerland ABSTRACTBackground: Low systemic vascular resistance during and immediately after cardiac surgery in which cardiopulmonary bypass i s utilized is a well-known phenomenon, characterized as vasoplegia, which appears with an incidence ranging between 5Y0 and 15%. The etiology is not completely elucidated and the clinical importance remains speculative. Methods: In this prospective clinical trial, w e assessed the incidence of postoperative low systemic vascular resistance in 800 consecutive patients undergoing elective coronary artery bypass grafting and/or valve replacement. We have attempted to identify the predictive factors responsible for the presence of l o w systemic vascular resistance and w e have examined the subsequent postoperative outcome of those patients w h o developed early postoperative vasoplegia. The severity of vasoplegia was divided into three groups according either t o the value of systemic resistance and/or the dose of vasoconstrictive agents necessary t o correct the hemodynamic. Results: Six hundred twenty-five patients (78.1 %) did n o t develop vasoplegia, 115 patients (14.4%) developed a mild vasoplegia, and 60 patients (7.5%) suffered from severe vasoplegia. Low systemic vascular resistance did not affect hospital mortality but was the cause for delayed extubation and prolonged stay on the intensive care unit (ICU). Logistic regression analysis identified temperature and duration of cardiopulmonary bypass, total cardioplegic volume infused, reduced left ventricular function, and preoperative treatment with angiotensin-converting enzyme (ACE)-inhibitors, out of 25 parameters, as predictive factors for early postoperative vasoplegia. Conclusion. The occurrence of l o w systemic vascular resistance following cardiopulmonary bypass is as high as 21.8%. The etiology of this clinical condition is most probably multifactorial. Mortality is n o t affected b y vasoplegia, b u t there is a trend t o higher morbidity and prolonged stay in the ICU. fJ Card surg 2000; 7 5:34 7-353)

Low systemic vascular resistance (SVR) developing during and immediately after cardiopulAddress for correspondence: T. Carrel, M.D.. Clinic for Cardiovascular Surgery, University Hospital, CH-3010 Berne. Switzerland. Fax: (41) 31-382-02-79: e-mail: thierrv,par. [email protected]

monary bypass (CPB) is a well-known phenomenon observed in patients undergoing cardiac surgery. It is characterized by hypotension with normal or elevated cardiac output and usually normal or decreased filling pressures despite adeqUate Volume This clinical syndrome known as vasoplegia has been attributed

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to hemodilution, hyperkalemia after infusion of large volume of cardioplegia, temperature of the patient, flow rate and character during CPB, baroceptor reflexes, complement activation, and the inflammatory response to the synthetic surfaces of the CPB circuit; and perhaps also to vasodilators that have been administered preoperat i ~ e l y . ~Furthermore, -I~ a host of vasoactive substances, which may interfere with the SVR, are produced, released, or altered during or immediately after CPB.18*19 Despite all these theoretical considerations, there are only a few series published with special attention to the outcome of these patients. Recent trials have reported incidence of low SVR after CPB between 5% and 15%, depending on the definition criteria applied. This prospective study had the following three goals: (1) to define the incidence of low SVR after isolated coronary artery bypass grafting (CABG) and aortic valve surgery, (2) to determine potential pre- and intraoperative factors that may predict the occurrence of low SVR, and (3)to analyze the clinical consequences of vasoplegia in terms of mortality, morbidity, and hospital stay. METHODS The peri-, intra-, and postoperative data of 800 consecutive patients who underwent either isolated CABG or aortic valve replacement at our institution during a 1-year period were collected prospectively. Patients were divided into three groups according to the severity of vasoplegia, (see Table 1) defined either on the basis of calculation of SVR, the evaluation of the hemodynamics, or the requirement vasoconstrictor to agents establish adequate mean arterial pressure > 65 m m Hg. The "vasoplegia" syndrome was defined when two of the following four conditions were met: (1) mean arterial pressure < 60 mmHg despite normal left ventricular contractility (verified by transesophageal ehocardiography) and normal filling conditions (left atrial pressure and central venous pressure > 12-15 mmHg, (2) cardiac index (when pulmonary artery catheter available) over 3.5 Vm2, (3) immediate and sustained increase of the mean blood pressure after administration of 510 pg norepinephrine, and (4) calculated SVR < 500 dynes per sec/cm5. This somewhat extended definition of low SVR (see Table 2) was necessary because pulmonary artery catheter was available in only 68% of the patients.

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TABLE 1 Three Groups of SVR Depending on the Dose of Catecholamines Used for Successful Treatment Vasoplegia Absent (n = 625)

SVR, dyn/sec/cm5 > 800 Hemodynamicsl Cardiac index, < 3.5 liters per minlm2 LAP, m m Hg > 12-14 < 5 kg/kg Postoperative norepinephrine per minute

Severe

Moderate (n = 115)

(n = 60)

600-800

< 600

3.5-4.5

> 4.5

8-1 2 5-1 0 pg/kg per minute

< 6-8 > 10 kg/kg minute Per

'Patients with a normal left ventricular function predominantly concerned. SVR = systemic vascular resistance; LAP = left arterial pressure.

Demographic factors are summarized in Table 3. We analyzed 25 demographic factors and perioperative parameters (see Table 4) registered during the peri- and postoperative period and focused also on preoperative medication: the goal was to identify important independent risk factors for the development of low SVR. Anesthesia, extracoporeal perfusion, and surgical technique The usual cardiac medications, including nitrates, p-blockers, calcium-channel blockers, and angiotensin-converting enzyme (ACE)-inhibitors were administered until the morning of surgery. Premedication consisted of 7.5 mg intramuscular morphine and 5-10 mg diazepam orally 1 hour be-

TABLE 2 Definition of Low SVR Mean arterial pressure < 60 mmHg Left ventricular ejection fraction > 55% in echocardiography Adequate preload (CVP and/or LAD 1 12-1 5 ) Cardiac index > 3.5 liters per rn2/rnin SVR < 500 dynes/sec/cm Immediate and durable response to norepinephrine SvO, > 70% (facultative) -.

SVR = systemic vascular resistance; CVP = central venous pressure; LAD = left anterior descending.

CARREL, ET AL. LOW SYSTEMIC VASCULAR RESISTANCE

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~~

~

~~

TABLE 3 Main Demographic ~~

~

-~

~~

Postoperative Vasoplegia ~__ Absent Moderate Severe ~

Age (y -t SD) Female gender, % Preoperative myocardial infarction, % Unstable angina, % Left main disease, 'YO Three-vessel disease, 'YO LV ejection fraction

62 -t 7 16 '1.5

63+9 13 13

55 22.5 84 9

47 17 86.5 13

56 25

64%6 12 17

5.5 39.9 16.6 15 8 11.5

9 43.4 19.6 18.3 16.3

10.5 46.2 15.4 23.5 8

17 5.5

2.1 7.0

0.8 8.2

90

16

< 0.4, ?O Redosurgery, % Arterial hypertension. % Active nicotine, % Diabetes, 'YO Peripheral vascular disease, 'YO Renal failure. YO Chronic pulmonary disease, 'Y LV = left ventricle

fore induction of anesthesia. General anesthesia was induced according to standard practice and consisted of fentanyl (1 0-25 pg/kg), diazepam (0.05-0.10mg/kgf, and pancuronium (0.15 mg/kgf together with halothane or isoflurane (0.5% to 2 % ) . Fentanyl and midazolam were usually administered in increasing dosages to produce un-

consciousness while maintaining hernodynamic stability. Mechanical ventilation was adjusted to maintain normocapnia and normoxemia with an inspired oxygen concentration of 50% before CPB and 100% immediately after weaning from CPB. Bovine heparin was administered before CPB (300 U/kg) and when necessary during CPB to maintain activated clotting time of around 400 seconds. Cannulation was performed in a conventional fashion and CPB was conducted a t moderate hypothermia (32'-34"C). Mild hemodilution, achieving a hematocrit value 0.20-0.30 was tolerated in all patients. Myocardial protection included repetitive doses of antegrade or retrograde cold blood (4:l) cardioplegia at 20 minute intervals. (Composition of blood cardioplegia 4:l -pH 7.7-7.8, Ca2+ 0.5-0.6 mmol/L, K+ 18-20 mmol/L, THAM 0.3 M, citrate phosphate dextrose, glucose 5%, and Kcl 2 mmol/mL. Osmolarity = 340-360 mOsm/L.) A nonpulsatile flow-rate greater than 2.0-2.2 L/m2 was maintained during the hypothermic phase of the operation. After arrival in the intensive care unit (ICU), morphine and/or diazepam were repeatedly administered to keep the patient pain-free and comfortable. Weaning from mechanical ventilation was started as soon as the patient emerged from anesthesia and when the hemodynamic was stable and normothermia had been maintained for at least 1 hour.

~~

TABLE 4 Perioperative Parameters According to the Groups of Patients Without or With Mild or Severe Vasoplegia Postoperative Vasoplegia

Body surface area, m2 Perfusion rate, Umin Lowest temperature, C Total pump time, min Cross-clamp time, min Cardioplegia volume, L Warm blood cardioplegia, % Cold blood cardioplegia, % Postoperative hematocrit Highest K during CPB, mmol/L Blood Droducts after CPB. mL

349

Absent (n = 625)

Moderate (n = 115)

Severe (n 60)

1.82 ? 0.1 5 4.7 t 0.4 32 Z 0.5 61 % 16 4 8 t 12 2.1 ? 0.55 9

1 79 2 0.18

1.85 ? 0.25 4.9 ? 0.7 30.2 t 0.5" 83 % 14* 67 ? 9 2 9 Z 0.75" 7 93 0 26 ? 0.07 5.5 5 0.6 320 ? 50

91

0.25 -t 0.04 5.3 ? 0.6 250 ? 150

4 4 t 0 5 33.5 t 1 5 7 4 ? 11 53 2 18 23 t 06 11

89 0 27 t 0 06 5.1 2 0.7 220 2 100

*When p < 0 2 is univariate analysis, the variables were entered into the multivariate regression analysis CPB = cardiopulmonary bypass

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CARREL, ETAL. LOW SYSTEMIC VASCULAR RESISTANCE

Time to extubation, total fluid requirements, and the need for any vasopressor or inotropic substance were recorded during and after the operation. Statistical analysis Statistical analysis was performed with the SPSS (Statistical package, Los Angeles, Calif, USA). Differences among the three groups were analyzed with the chi-square analysis and when appropriate, the two-tailed Fisher's exact test when discrete data were employed. Parametric date were expressed as means f SEM and analyzed using the two-way analysis of variance with Dunnett's test for within group changes with respect to baseline. Differences were considered to be important when p < 0.05. A stepwise logistic regression analysis was used to assess the determinants of high vasopressor requirements versus those without or with only mild vasopressor requirements. All variables with p values < 0.2 shown by univariate analysis were entered into the multivariate analysis by the stepwise logistic regression technique. The variables were then removed from the model if the improvement x 2 value was > 0.1. With the chi-test, differences among groups were analyzed. The predictive factors for low SVR were assessed by univariate analysis and important predictors were identified by stepwise logistic regression technique. RESULTS Demographic characteristics among the patients of the different gorups were similar with regard to gender, age, incidence and distribution of

J CARD SURG 2000;15:347-353

cardiovascular risk factors, and extent of coronary artery disease. Preoperative functional class for angina and/or dyspnea as well as hemodynamic variables in patients with aortic valve disease did not reveal any difference among the groups. Six hundred twenty-five patients (78.1 YO)did not develop vasoplegia, 1 15 patients (14.4%) developed a mild vasoplegia, and 60 patients (7.5%) suffered from severe vasoplegia. Low SVR did not affect hospital mortality, which was similar in all three groups of patients (1.7% in Group 1, 0.9% in Group 2, and 1.9% in Group 3).However, delayed extubation and prolonged stay in the ICU was more frequently observed in Group 3 than in Group 2 and Group 1 patients (see Table 5). Logistic regression analysis identified the lowest temperature during extracorporeal perfusion, the total duration of CPB, the total cardioplegic volume infused, reduced left ventricular function, and preoperative treatment with ACE-inhibitors as predictive factors for early postoperative vasoplegia after weaning from CPB. lntraoperative hernodilution could not be correlated with low SVR incidence (Table 6). Preoperative ACE-inhibitor administration (average dosage of Enalapril 12.5 mg daily, Captopril 75-100 mg daily) was found to be a predictor for the development of low SVR. All other vasodilator drugs (including p-blockers, calcium-antagonists, and nitroderivates) did not show any persistent vasodilatory effects in the early postoperative course (Table 7). The following interesting observations were made in the majority of patients of Group 3 with severe vasoplegia: notable pyrexia occurred in 85%, metabolic acidosis at any early postoperative time in 72% and leucocytosis > 12 000 in 60%.

TABLE 5 Relationship Between Low SVR and Clinical Outcome

Mortality Low cardiac output Myocardial infarction Cerebrovascular accident Time ventilated, h Time in ICU. d Time in hospital, d

Group 1 (n = 625) No Low SVR

Group 2 (n = 115) Moderate Low SVR

Group 3 (n = 60) Severe Low SVR

1.7% 4.9% 3.9%

0.9% 3.7% 1.1% 1.6% 7.2 I 4.1 1.7 2 0.9 9.4 2 2.1

2.1% 4.1 % 2.7%

0.9% 8 I' 2.9 1.6 5 0.6 8.9 i 1.7

SVR = systemic vascular resistance; ICU = intensive care unit.

0.7% 11.4 5 2.3 2.9 2 1.3 11.5 2 1.9

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2000;15:347-353

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transient decrease in SVR occurring immediately after separation from CPB; these include a recruitment of peripheral capillaries during the switch from nonpulsatile to pulsatile blood flow and release of numerous vasodilators that have Odds Ratio accurnulated in the pulmonary vascular bed when (95% CI) p Value the lungs are reperfused.8.’ ’,18 However, the majority of reports available conLowest temperature 2 26 (1 58-3 85) 0 0065 clude that a multifactorial etiology is responsible Duration of CPB 2 55 (1 33-340) 0030 Total cardioplegic volume 3 13 (2 5-4 15) 0 001 for the development of low SVR. A low SVR state Systolic LV-function < 0 4 2 85 (205-4 15) 0 0778 would be more likely to occur in patients who Preoperative ACE inhibitors 3 75 (2 9-5 0) 0 0001 have sustained an extensive perioperative myNumbers within parentheses represent ranges ocardial infarction, who have peripheral vascular CPB = cardiopulmonary bypass, CABG coronary artery disease, or who suffer from septicemia in the bypass grafting CI = confidence interval, LV = left ventricle, ACE = angiotensin-converting enzyme early postoperative course. We could not confirm these observations in the present trial; also, diabetes was not found to be a predictive factor for postoperative low SVR in our study. TABLE 7 Logistic regression analysis identified temperaPreoperative Drug Regimen and the ture and duration of CPB, total cardioplegic volOccurrence of Low SVR ume infused, reduced left ventricular function, Group 1 Group 2 Group 3 and preoperative treatment with ACE-inhibitors (n = 625) (n = 115) (n = 60) as predictive factors for early postoperative vasoNo Low Moderate Severe plegia. Low SVR did not affect hospital mortality SVR Low SVR Low SVR but was the cause for delayed extubation and proACE-inhibitors 254 (39%) 49 (42%) 42 (70%)” longed stay in the ICU. P-blockers 470 (75) 90 (78%) 40 (67%) Ca-antagonists 206 (33%) 42 (36%) Arterial hypotension after cardiac surgery with 2 3 (39%) Nitro-derivates 478 (76%) 84 (73%) 39 (65%) the aid of extracorporeal circulation may precipi~tate cerebrovascular accidents and visceral is“p < 0 01 SVR = systemic vascular resistance, ACE = angiotensinchemia, especially in patients with occlusive arconverting enzymes terial disease. Therefore the majority of authors who have studied the problem of low SVR after CPB recommended adequate treatment to reCOMMENTS store acceptable hemodynamics as soon as possible. Many pharmacologic interventions have It is well established that perioperative hemobeen proposed to deal with decreased SVR. Use dynamic control is principally determined by the of vasoconstrictors is not free from adverse sysinterplay among the sympathetic nervous systemic effects such as malperfusion in areas of tem, the renin-angiotensin system, the hypothalcompensatory vasocontriction (e.g., in the splanamic release of vasopressive mediators, and, fichnic territory).22Since nitric oxide (NO) has been nally, the end-organ responsiveness within the described as an endothelium-derived relaxing faccardiovascular system.’3 CPB exposes blood to tor, use of NO-synthase inhibitors might provide large areas of foreign materials and induces the a better management of vasoplegic phenomenon production and release of several vasoactive subafter CPB.23-25 stances that may affect vascular permeability, More recently, several publications from the SVR, overall perioperative fluid balance, and myColumbia University have focused on the subject ocardial contractility. These substances conof postoperative vasodilatory shock in different tribute to the systemic inflammatory response syndrome (SIRS) associated with CPB.5,15.20,71 subsets of patients: left ventricular assist device (LVAD) recipients as well as children and adult paThe real incidence of low SVR after moderate hytients who had undergone cardiac surgery with pothermic CPB is not well known as are the facthe aid of CPB. The incidence of this clinical contors associated with this condition. Various mechdition was very similar to our findings (8% vs anisms have been suggested to explain the

TABLE 6 Multivariate Predictors of Severe Vasoplegia After CPB Following Isolated CABG or Aortic Valve Replacement

~~

~

~~~

~

~~~

~~

~

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CARREL, ET AL. LOW SYSTEMIC VASCULAR RESISTANCE

7.5%). In a collective of 145 adult patients undergoing open heart surgery, they found that low ejection fraction and ACE-inhibitor use before surgery wer e risk factors for postbypass vasodila-

tory shock. This clinical condition was associated with inappropriately low serum arginine vasopressine concentrations; low-dose vasopressine infusions resulted in normalization of the arterial pressure and decrease of norepinephrine requirements in a majority of patients.26-28

CONCLUSION W h e n registered prospectively, th e occurrence

of low SVR after CPB is as high as 22%. The etiology of this clinical condition is m o s t probably multifactorial. Mortality is not affected by vasoplegia, but there is a trend to higher morbidity and delayed recovery with prolonged stay in the ICU and total hospitalization time.

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