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J Thorac Cardiovasc Surg 2007;134:311-318
© 2007 The American Association for Thoracic Surgery

Surgery for Congenital Heart Disease

Mortality after neonatal cardiac surgery: Prediction from mean arterial pressure after rewarming in the operating room

Ari R. Joffe, MDa,*, Charlene M.T. Robertson, MDa,b, Alberto Nettel–Aguirre, PhDc,e, Ivan M. Rebeyka, MDa,d, Reginald S. Sauve, MDc,f The Western Canadian Complex Pediatric Therapies Project Follow-up Group*

a Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
d Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
b Neonatal and Infant Follow-up Clinic, Glenrose Rehabilitation Hospital, Edmonton, Alberta, Canada
c Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
f Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
e Biostatistician, Research Methods Team, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.

Received for publication October 20, 2006; revisions received January 19, 2007; accepted for publication February 1, 2007.

* Address for reprints: Ari R. Joffe, MD, FRCP(C), Department of Pediatrics, 3A3.07 Walter C Mackenzie Center, 8440 112 Street, Edmonton, Alberta, Canada, T6G 2B7. (Email: ajoffe{at}cha.ab.ca).


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Objective: To examine the predictive contribution of mean arterial pressure after rewarming to ≥34°C in the operating room to mortality after cardiac surgery in infants ≤6 weeks old.

Methods: In this prospective inception cohort study, 70 consecutive infants who had open cardiac surgery with deep hypothermic circulatory arrest when ≤6 weeks old in the years 1996 to 1999 had follow-up to 5 years of age. Demographic, preoperative, operative, and postoperative variables were recorded prospectively. The previously unexplored variables of lowest mean arterial pressure in the operating room after rewarming to 34°C were recorded retrospectively from anesthesia records. Predictor variables for death were examined using univariate and multivariate analyses.

Results: Deep hypothermic circulatory arrest time, re–cardiopulmonary bypass in the operating room, duration of mean arterial pressure below 40, 35, 30, and 25 mm Hg after rewarming in the operating room, time for lactate to return to ≤2 mmol/L postoperatively, and cardiopulmonary resuscitation were significantly associated with death at 1 and 5 years of age on univariate analysis. Multivariate stepwise forward logistic regression analysis found the duration of mean arterial pressure after rewarming below 30 mm Hg (odds ratio 1.094; 95% confidence interval 1.033–1.158) and cardiopulmonary resuscitation (odds ratio 13.800, 95% CI 3.062–62.194) were significant predictors of death by 5 years of age. Stepwise multiple regression using pre- and intraoperative variables accounted for 30.1% of the variability related to mean arterial pressure ≤30 mm Hg after rewarming.

Conclusion: In these infants, low mean arterial pressure after rewarming in the operating room, even for brief times, is significantly associated with death.

Abbreviations and Acronyms CPB = cardiopulmonary bypass; DHCA = deep hypothermic circulatory arrest; HLHS = hypoplastic left heart syndrome; MAP = mean arterial pressure; OR = operating room; PRISM = pediatric risk of mortality


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
There is a growing literature describing the outcomes of infants receiving open cardiac surgery in early infancy.1-3Go Mortality has been reduced but still remains significant, particularly in patients with some complex lesions such as hypoplastic left heart syndrome.1Go Several studies have been published regarding predictors of outcomes after congenital heart disease surgery.4-7Go Most studies find the cause of adverse outcome to be multifactorial, including preoperative, intraoperative, and postoperative conditions and events.1-8Go

Many variables that have been found to predict outcome after surgery for congenital heart disease are not modifiable. Examples include type of lesion, preoperative neurologic examination, preoperative microcephaly, chromosomal anomalies, and socioeconomic status.1-7Go Also, many postoperative variables such as severity of illness and duration of intensive care may not be modifiable and may be heavily influenced by events and conditions present prior to and during surgery. The mean arterial pressure (MAP) in the operating room (OR) after rewarming to a temperature of ≥34°C, while on or off of cardiopulmonary bypass (CPB), is a potentially modifiable variable. The MAP is a surrogate for the perfusion pressure supplying blood flow to the tissues9,10Go and may be particularly relevant on rewarming when metabolism is "reactivated."8Go

The objective of this study was to examine the predictive contribution to mortality of the potentially modifiable variable of MAP after rewarming in the OR after open cardiac surgery in infants 6 weeks old or less.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
Design
This prospective descriptive study is part of a larger interprovincial inception cohort study established to examine outcomes of infants ≤6 weeks of age who receive complex, open cardiac surgery. Ethics Boards approvals were obtained prior to onset of the study, and all patients’ parents/guardians signed informed consent forms.

Subjects
The subjects all had complex intracardiac surgery done at ≤6 weeks of age using CPB and deep hypothermic circulatory arrest (DHCA) at the Stollery Children’s Hospital, Edmonton, Alberta, through the Western Canadian Children’s Heart Network. No child was excluded for any reason.

Procedure
All infants were enrolled by a nurse research assistant. Clinical and laboratory parameters that had been agreed upon prior to data collection were recorded prospectively; these are described elsewhere11Go and listed in the results (see Table 2). A new intraoperative variable, the MAP after rewarming to a core temperature of at least 34°C in the OR (on or off of CPB and before transfer to pediatric intensive care) was obtained by one of the authors (A.J.) by retrospective review of the anesthesia record for each patient and blinded to outcome. Blood pressure was monitored continuously via arterial line in the operating room and recorded by hand by the anesthetist at 5-minute intervals onto the anesthesia record. This variable was recorded as the duration of MAP below specific thresholds (40, 35, 30, 25, and 20 mm Hg) in the operating room after rewarming. Follow-up assessments were scheduled at the Neonatal Follow-up Clinics at the tertiary site of origin in the various provinces. All patients had follow-up data for the primary outcome of mortality during hospitalization, at 1 year, and at 5 years of age.


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  		TABLE 2 Demographic, preoperative, operative, and postoperative characteristics of the 70 infants of ≤6 weeks of age with complex intracardiac surgery in relation to death at or before 5 years of age
 
During the time of this study, there was no protocol for anesthetic management or blood pressure management in the operating room. These were left to the discretion of the anesthetist. This "natural variability" in management was important for the observational design of this study. In general, maintenance anesthesia during CPB was with high-dose opioid using fentanyl or sufentanil and supplemented by volatile anesthetic including sevoflurane, desflurane, or isoflurane at the anesthetist’s discretion. When inotropes were deemed necessary, dopamine was started, and if not sufficient at a dose of 10 µg · kg–1 · min–1, an epinephrine infusion was added. Phenoxybenzamine was not used in these patients, and amrinone or milrinone usage was rare in the operating room.

Statistics
All data were transferred for entry to The Registry and Follow-up of Complex Pediatric Therapies Project at the Glenrose Rehabilitation Hospital, Edmonton, Alberta. Univariate analyses for death were done using t tests for equality of means preceded by Levene’s test for equality of variances, {chi}2 test with Yates correction or Fisher exact test (2 sided) when appropriate. Pearson product moment correlations among variables were done with 2-tailed significance. Bonferroni correction for multiple tests was applied in all cases. Multivariate stepwise forward logistic regression was used to develop prognostic indicators of death from the preoperative, intraoperative, and postoperative periods using the Wald statistic, at a significance level of .05. Stepwise multiple regression using preoperative and operative variables was used to predict the MAP after rewarming variables. SPSS (SPSS, Chicago, Ill), version 12.0 for Windows was used for analysis. The funding agency had no role in data collection, analysis, interpretation, or manuscript approval.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
Seventy consecutive subjects from September 1996 through August 1999 were identified at the time of open cardiac surgery. The primary cardiac diagnoses and surgery are shown in Table 1. Survival outcome is available for all patients. There were 51 survivors (73%): 13 deaths occurred during the initial hospitalization (19%), 2 more by 1 year of age (21%), and 4 more by 5 years of age (27%). More details of the findings in this cohort of patients have been published.11Go


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  		TABLE 1 Primary cardiac diagnoses and surgery for the cohort of 70 infants ≤6 weeks of age
 
Univariate Analyses
Potential predictors of death at age 5 years available for all 70 subjects and considered in the univariate analysis are shown in Table 2. The variables concerning MAP after rewarming to 34°C in the operating room and their relation to mortality during hospitalization and at 1 and 5 years of age are shown in Table 3.


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  		TABLE 3 Duration of mean arterial pressure below the thresholds after rewarming to at least 34°C in the operating room in relation to death at 1 and 5 years of age for 70 infants after complex intracardiac surgery done at ≤6 weeks of age
 
Multivariate Analyses
All variables that predicted death in the univariate analyses with a P < .002 (DHCA time, re-CPB in the OR, MAP after rewarming in the OR, time for plasma lactate to return to ≤2 mmol/L postoperatively, and CPR) or that were considered potentially clinically important (single-ventricle anatomy, hypoplastic left heart syndrome [HLHS], transposition of the great arteries, aortic crossclamp time, lowest arterial pH day 1 postoperatively, and use of extracorporeal membrane oxygenation) were entered in a stepwise forward logistic regression. The results for predicting death at initial hospital discharge, 1 year of age, and 5 years of age are shown in Table 4. The MAP after rewarming in the OR was the only potentially modifiable variable to be associated with mortality.


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  		TABLE 4 Multivariate stepwise forward logistic regression of significant predictor variables * for death in 70 infants of ≤6 weeks of age with complex intracardiac surgery
 
MAP on Rewarming
The significant correlations of the MAP after rewarming in the OR with selected pre- and intraoperative variables is shown in Table 5. No significant correlation of the MAP after rewarming in the OR was found with birth weight, gestational age, single-ventricle anatomy, highest dopamine dose preoperatively, highest plasma lactate preoperatively, days of ventilation preoperatively, or lowest flow on CPB. The variables from preoperative and operative periods that had a correlation with a P ≤ .1 (Table 5) were entered into a stepwise multiple regression to predict the MAP after rewarming in the OR. The multiple regression accounted for 30.1% of the variability for MAP ≤ 30 mm Hg and 38.4% of the variability for MAP ≤ 25 mm Hg (Table 6). Finally, duration of MAP ≤ 30 mm Hg and ≤ 25 mm Hg after rewarming in the OR showed no correlation with the time for plasma lactate to return to ≤5 mmol/L day 1 postoperatively, time for plasma lactate to return to ≤2 mmol/L day 1 postoperatively, highest dopamine dose day 1 postoperatively, highest epinephrine dose day 1 postoperatively, or highest plasma lactate day 2 postoperatively. There was a significant correlation with the highest plasma lactate on postoperative day 1: for duration of MAP ≤ 35 mm Hg (r = .366, P = .002) and for duration of MAP ≤25 mm Hg (r = .316, P = .009).


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  		TABLE 5 Significant correlations with duration of mean arterial pressure after rewarming in the operating room for 70 infants after complex intracardiac surgery done at ≤6 weeks of age
 

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  		TABLE 6 Stepwise multiple regressions to predict mean arterial pressure after rewarming to 34°C in the operating room of 70 infants after complex intracardiac surgery done at ≤6 weeks of age
 
The lowest values of MAP after rewarming in the OR were examined more closely to determine their timing in relation to CPB. The lowest values occurred while on CPB in 35%, while off CPB in 54%, and overlapping both times in 12%. The period on CPB after rewarming to 34°C accounted for 73% and 93% of the MAP values less than 30 mm Hg and 25 mm Hg, respectively.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
In this observational study, many variables were examined to determine their relation to mortality after complex open cardiac surgery in infants ≤6 weeks old. The study took advantage of the variability in clinical management of MAP in the OR to examine the predictive potential of this variable. The main finding of this study is that a low MAP after rewarming in the OR is a significant predictor of death at 5 years of age in both univariate and multivariate stepwise forward logistic regression analyses. Furthermore, only 30% to 38% of the variance related to MAP on rewarming in the OR could be accounted for in stepwise multiple regressions. To our knowledge, MAP after rewarming in the OR has not been previously examined in predicting outcomes after congenital heart disease surgery. Our data suggest that a MAP after rewarming in the OR of ≥35 mm Hg is desirable and that a MAP below this may be detrimental, even for brief periods of time.

There are theoretical reasons to suggest that a low MAP immediately after rewarming may be a direct cause of poor outcome. The goal in treatment of shock is to maintain perfusion pressure above the critical point below which blood flow cannot be effectively maintained in individual organs.9,10Go Below a certain threshold there will be inadequate organ and tissue perfusion, and cellular injury. This threshold may be especially important after cardiac surgery in infants in view of their significant systemic inflammatory response to CPB,12,13Go making the microcirculation particularly vulnerable to an inadequate perfusion pressure.14Go There is altered regulation of microvascular tone,8,14Go plugging of the microcirculation due to microthrombi and cellular adhesion events,8,14Go and a heterogeneous alteration of capillary density and perfusion.15Go In this study, the period of low MAP after rewarming included time on CPB when it can be argued that there is normal systemic blood flow, regardless of the patient MAP. The period on CPB after rewarming to 34°C accounted for 73% and 93% of the MAP values less than 30 mm Hg and 25 mm Hg, respectively. This suggests that it is not simply systemic blood flow that is important; rather, it may be perfusion pressure to the microcirculation of the tissues that is critical.

There is clinical evidence to support this theoretical argument for a direct adverse effect on survival of a low MAP. In the pediatric risk of mortality (PRISM) score, the low systolic blood pressure limits for predicting stepwise increased mortality rates in infants were <55 mm Hg and <40 mm Hg.16Go This was also the case for neonates in the more recent PRISM III score.17Go In the pediatric logistic organ dysfunction score, the low systolic blood pressure limits to assign stepwise increased cardiovascular organ dysfunction in term neonates are <65 mm Hg and <35 mm Hg.18Go Recent consensus guidelines on management of sepsis in adults suggest that a MAP ≥ 60 mm Hg is needed to achieve adequate tissue blood flow.10Go Similar consensus guidelines in pediatrics have recommended that the perfusion pressure (MAP minus central venous pressure) be kept ≥55 mm Hg in term newborns to maintain organ blood flow.9Go Early phases of inflammatory processes may be a particularly vulnerable time. When supraphysiologic goals of resuscitation are used in established critical illness, there is no effect on outcome19Go; however, when they are used early in severe sepsis20Go or high-risk surgical patients,21Go there is significant improvement in mortality and organ dysfunction. Comprehensive early therapy may limit the progression of the cascades leading to multiple organ dysfunction and death.19Go

The current study supports the theory that a low MAP may lead to tissue hypoxia, an exaggerated inflammatory response, multiple organ dysfunction, and death. The MAP variables on rewarming were significantly predictive of mortality in stepwise forward logistic regressions that included factors from all time periods of hospitalization. In addition, using many variables from the pre- and intraoperative time periods in a stepwise multiple regression could only explain <40% of the variability related to MAP after rewarming, suggesting that most of the predictive ability of MAP on rewarming was not due to another interrelated variable. The MAP on rewarming correlated with the lactate on the first postoperative day. This suggests that the MAP was a valid surrogate for tissue perfusion and that a threshold of perfusion had been crossed, resulting in tissue hypoxia and anaerobic metabolism. The lack of correlation to dopamine dose or epinephrine dose or the time for lactate to return to ≤5 mmol/L or ≤2 mmol/L on the first postoperative day suggests this was not due to ongoing myocardial dysfunction. It is possible that the low MAP led to the ultimate development of "cytopathic hypoxia," leading to organ dysfunction and death.19,22Go Indeed, death was associated with multiple organ dysfunction syndrome in 10/13 (77%) of the deaths during initial hospitalization, rather than sudden death. It is also plausible that initial "cytopathic hypoxia" may have caused permanent microvascular or cellular injury that resulted in the late deaths up to 5 years of age associated with subsequent illness or surgery. This hypothesis merits further investigation, as we are aware of no data to confirm or refute this possibility.

Some authors have described excellent outcomes after the Norwood procedure using phenoxybenzamine and milrinone in the operating room to lower systemic vascular resistance.23-25Go In these studies, the MAP in the first 48 hours postoperatively ranged from 44 to 62 mm Hg23-25Go and thus was much higher than that predicting mortality in the current study. In those studies epinephrine and norepinephrine were used to maintain a MAP greater than 45 mm Hg on separation from CPB.23-25Go The results of these studies suggest that vasodilation is not in itself deleterious as long as MAP is maintained in a reasonable range.

These results apply to a very select patient population, those who had neonatal cardiac surgery requiring DHCA during the period 1996 to 1999, and include a large number of HLHS and other complex lesions. The 30-day postoperative mortality during this period for this complex group of neonates was 10/70 (14.3%). Whether the results still apply in the current era of neonatal cardiac surgery cannot be proven with these data. From 2001 to 2004, our 30-day mortality for complex neonatal open cardiac surgery was 8/170 (4.7%); 30-day mortality for cardiac surgery in those <17 years was 24/2072 (1.2%).

There are limitations to this study. This was not a randomized trial and therefore the associations shown cannot be definitively identified as cause and effect. The study included a relatively small and heterogeneous group of patients having neonatal cardiac surgery and therefore there may be unaccounted for differences between patients that confound the interpretation of the results. Many of the variables were highly correlated and therefore the low MAP may be a manifestation of other underlying etiologic factors, in and of itself not harmful. For example, some specific variables such as anesthetic management and OR inotrope use were not protocolized and not recorded for this study and may confound the interpretation of why low MAP is associated with mortality. The exact cause of the low MAP in this study could not be ascertained. Theoretically, it could be due to low systemic vascular resistance, low cardiac output, or both. That most of the low MAP values occurred while on CPB may suggest that a low MAP was predominately due to low systemic vascular resistance; however, this is not certain because we were unable to record the flow on CPB after rewarming in the operating room. We were also unable to determine what therapeutic interventions were attempted for a low MAP in the operating room. Given this, we cannot determine the best therapeutic option when faced with a low MAP. Nevertheless, this observational study suggests that a novel parameter, the MAP after rewarming in the operating room, is associated with outcome and warrants further investigation.

In view of these limitations, one could argue that the MAP on rewarming variables are associated with outcome simply because they are a marker for worse cardiac function postoperatively. Whether intervention to increase the MAP will improve outcome or have its own complications can only be answered by further study.


   Conclusions
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
Despite these limitations, the main finding of the significant association of MAP after rewarming in the OR and death during hospitalization, at 1 year, and at 5 years of age is we believe, biologically plausible and likely causative. We recommend caution in accepting a low MAP in these infants after rewarming in the OR. We suggest that the time after rewarming may be a vulnerable period for the tissue microcirculation, and for this reason, the low MAP on reactivation of metabolism with rewarming may be a causative factor contributing to outcome. This observation is a novel finding, is hypothesis generating, and should lead to further investigation.


   Acknowledgments
 
We sincerely thank the parents of these very ill infants that have cooperated so positively with our follow-up programs. We thank Drs J. Dyck, J. Harder, and E. Phillipos for their support of this research. We thank the research staff that make this outcome study possible: H. Christianson and D. Anseeuw–Deeks, Calgary, Alberta, Canada; V. Debooy, Winnipeg, Manitoba, Canada; R. Kleisinger, Regina, Saskatchewan, Canada; L. Munro, Saskatoon, Saskatchewan, Canada; and G. Alton and L. Sanders, Edmonton, Alberta, Canada.


   Footnotes
 
Support was initially provided by the Glenrose Rehabilitation Hospital research trust fund, with ongoing funding from the Registry and Follow-up of Complex Pediatric Therapies Project, Alberta Health and Wellness.

* D. Moddemann, Winnipeg, Manitoba, Canada; P. Blakley, Saskatoon, Saskatchewan, Canada; A. Ninan, Regina, Saskatchewan, Canada. Back


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

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