Use of Targeted Neonatal Echocardiography to Prevent PostoperativeCardiorespiratory Instability after Patent Ductus Arteriosus Ligation

Amish Jain, MD1,2, Mohit Sahni, MD1, Afif El-Khuffash, MD1, Emad Khadawardi, MD1, Arvind Sehgal, MD1,

and Patrick J. McNamara, MD1,2,3

Objectives To investigate the value of targeted neonatal echocardiography (TnECHO) in predicting cardiorespi-ratory instability after patent ductus arteriosus (PDA) ligation, and to evaluate the impact of TnECHO-directed care.Study designWe reviewed serial echocardiography evaluations of 62 preterm infants after PDA ligation to inves-tigate the relationship between indices of myocardial performance and postoperative cardiorespiratory instability.A predictive model was developed based on TnECHO criteria, with targeted initiation of intravenous milrinone. Acomparative evaluation was performed between matched infants in the previous era (epoch 1; n = 25) and currentera (epoch 2; n = 27) of TnECHO-guided treatment.Results Left ventricular output <200 mL/kg/min at 1 hour after PDA ligation was a sensitive predictor of systemichypotension and the need for inotropes, and was used for initiation of i.v. milrinone infusion in epoch 2. Infantstreated with milrinone had a lower incidence of ventilation failure (15% vs 48%; P = .02) and less need for inotropes(19% vs 56%; P = .01), and showed a trend toward improved oxygenation (P = .08).Conclusion TnECHO facilitates early detection of infants at greatest risk for subsequent cardiorespiratory dete-rioration. Administration of milrinone to neonates with low cardiac output may lead to improved postoperativestability. (J Pediatr 2012;160:584-9).

Patent ductus arteriosus (PDA) is common in preterm infants, with a reported incidence of up to 80% in those born at<26 weeks gestation.1,2 Surgical closure of a PDA is used when medical intervention either fails or is contraindicated.This occurs in 35%-40% of cases, with the highest incidence in infants with a birth weight of <1000 g.3

The postoperative course is often complicated by acute cardiorespiratory deterioration or postligation cardiac syndrome(PLCS). The clinical components of PLCS include oxygenation failure (up to 60%), ventilatory failure (up to 45%), and sys-temic hypotension (up to 35%).4-6 Risk factors reportedly associated with PLCS include earlier age at ligation, lower birthweight, younger gestational age, large PDA, and level of preoperative cardiorespiratory support, although findings have beeninconsistent.4-7 PLCS typically occurs between 8 and 12 hours after surgery; thus, there is a temporal window for early inter-vention. The objectives of the present study were to investigate the predictive value of early postoperative echocardiographymarkers for PLCS and to evaluate the impact of targeted neonatal echocardiography (TnECHO)-directed postoperative care.

LVO Left ventricular output

PDA Patent ductus arteriosus

PLCS Postligation cardiac synd

TnECHO Targeted neonatal echoc

584

Methods

This study was conducted in 2 parts in the neonatal intensive care unit at The Hospital of Sick Children in Toronto, an outbornquaternary center providing PDA ligation services for all perinatal centers in the region. The study received Institutional Re-search Ethics Board approval. Study A was a retrospective evaluation of previously analyzed echocardiography markers to de-termine predictors of PLCS, and study B was a retrospective chart review investigating the impact of TnECHO-guidedcardiovascular intervention (epoch 2) relative to a conventional therapeutic approach (epoch 1).

Baseline neonatal demographic data, preexisting morbidities, details of preoperative inotropic support, and characteristics ofthe ductus arteriosus were recorded. Clinical and physiological indices of cardiorespiratory health were compared before and at1 hour, 8 hours, and 24 hours after surgical ligation. These indices included arterial pressure, oxygen requirement, type and

From the 1Division of Neonatology and Department ofPediatrics; 2Department of Physiology, University ofToronto; and 3Physiology and Experimental MedicineProgram, Hospital for Sick Children, Toronto, Ontario,Canada

Presented in part at the Pediatric Academic Societies’annual meeting, Denver, CO, May 2011.

details of respiratory support, and blood gas and serum lactate values. The spe-cific reasons for escalation or change in respiratory support were collected on allinfants. All infants underwent blood gas analysis immediately postligation andevery 6 hours thereafter. At our institution, infants admitted for PDA ligationare usually maintained on conventional ventilation, with high-frequencyoscillatory ventilation used as rescue therapy. The need for postoperative fluid

Winner of the Fellow Section at 23rd Annual CanadianPediatric Resident and Fellow Research National Com-petition, Winnipeg, MB, Canada, May 12, 2011.

The authors declare no conflicts of interest.

0022-3476/$ - see front matter. Copyright ª 2012 Mosby Inc.

All rights reserved. 10.1016/j.jpeds.2011.09.027

rome

ardiography

Vol. 160, No. 4 � April 2012

resuscitation, type and dose of inotropes, use of steroids, anddetails of any other procedure-related morbidity were re-corded as well. TnECHO data were collected preoperativelyand 1 hour and 8 hours postoperatively for infants in epoch1, and preoperatively and 1 hour postoperatively in epoch 2.Patient charts were screened for up to 24 hours postligationto identify prevalences of the various outcomes.

OutcomesOxygenation failure was defined as an absolute increase of atleast 20% in the fraction of inspired oxygen or mean airwaypressure compared with the preoperative value required fora minimum of 1 hour within 24 hours postligation.

Ventilatory failure was defined as the need for high-frequency oscillatory ventilation secondary to the inabilityto maintain adequate ventilation on conventional ventilatoror a 20% rise in amplitude of the preoperative value neededfor a minimum of 1 hour within 24 hours postligation. Aninfant who remained on conventional ventilation postopera-tively was not considered in ventilatory failure.

Hypotension was defined a systolic arterial blood pressurebelow the 3rd percentile for gestational age8 persisting forat least 1 hour within 24 hours postligation or for a shorterperiod if corrective intervention was provided.

Need for inotropes was defined as either an escalation ofinotropic support by >20% of the preoperative value or theneed to initiate a new inotropic agent in response to hypoten-sion within 24 hours postligation, at the discretion of theclinical team.

Low left ventricular output was defined by a left ventricularoutput (LVO) <170 mL/kg/min as measured by TnECHO at8 hours postligation.9,10

PLCS was defined as a composite outcome of the need forinotropic agents and either oxygenation failure or ventilationfailure as defined earlier in the absence of any other surgery-related etiology (eg, hypovolemia, sepsis, pneumothorax,chylothorax).

Study AA retrospective analysis was conducted on data compiledfrom serial echocardiography evaluations performed be-tween January 2005 and January 2007. Data were collectedas part of 2 previous prospective observational TnECHO-based studies of preterm infants undergoing PDA liga-tion.11,12 The relationship between TnECHO markers at 1hour postligation and clinical or echocardiography indicesof PLCS over the subsequent 24 hours were studied. SpecificTnECHO markers included LVO, fractional shortening, leftatrium/aortic root ratio, and isovolumic relaxation time.

This study included infants born at <32 weeks gestationalage previously recruited for serial TnECHO evaluations afterPDA ligation. Infants with a known chromosomal anomalyor major forms of congenital heart disease were excluded.

Specific outcomes evaluated in these analyses includedLVO <170 mL/kg/min at 8 hours postligation, hypotension,and the need for inotropic agents by 24 hours postsurgery.

Study BIn study B, the postoperative care plan was modified on thebasis of the results from study A, leading to the introductionof a TnECHO-based targeted program in January 2009. Spe-cifically, all neonates underwent a comprehensive TnECHOevaluation within 1 hour of surgical ligation. If LVO was<200 mL/kg/min, i.v. milrinone was started at a rate of0.33 mg/kg/min for 24 hours. In addition, a 10-mL/kg normalsaline bolus was coadministered during the first hour of i.v.milrinone infusion. If the infant remained clinically stable,milrinone was discontinued after 24 hours. Clinical manage-ment in the event of deterioration and subsequent care afterdiscontinuation of milrinone was at the discretion of attend-ing staff neonatologist. A comparative evaluation performedbetween neonates in the 2 distinct epochs (before and afterestablishment of the new protocol) was used to assess the im-pact of this program.We hypothesized that administration ofi.v. milrinone to high-risk infants, as identified by early TnE-CHO evaluation, would reduce the incidence of PLCS.All infants from study A with 1-hour postligation LVO

data available were considered a historical cohort (epoch 1;n = 67 infants). All infants born at <32 weeks gestationwho underwent PDA ligation in our center between January2009 and December 2010 and had LVO calculated at 1 hourpostligation were considered the treatment cohort (epoch 2).All infants in epoch 2 with LVO of <200 mL/kg/min at 1 hourwere identified and were matched with infants in epoch 1 bygestational age and 1-hour LVO using statistical software.The primary outcome was incidence of PLCS. Secondary

outcomes included oxygenation failure, ventilation failure,and need for inotropes or steroids.

StatisticsDescriptive statistics were used to analyze neonatal demo-graphic, morbidity, and echocardiographic data. In studyA, linear regression analysis was performed to characterizeassociations between early and late TnECHO markers. Re-ceiver operating characteristic curves were constructed to de-termine thresholds of early postligation TnECHO markersfor predicting subsequent development of low LVO and theneed for inotropic agents. Sensitivity and specificity were cal-culated for defined thresholds. In study B, continuous vari-ables were compared using the t test or Mann-Whitney Utest as appropriate, and categorical variables were analyzedusing Fisher exact and c

2 tests. Two-way repeat-measuresANOVA was used to investigate the effects of both epochand time interaction for each of the longitudinal cardiorespi-ratory variables. Data are presented as mean� SD or medianwith IQR. Significance was set at P < .05.

Results

Study AA total of 67 preterm infants underwent PDA ligation and re-ceived preoperative and postoperative TnECHO during thestudy period. Five infants without 8-hour postoperative

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THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 160, No. 4

TnECHO data were excluded. The included infants hadamean gestational age of 25.5� 2.0 weeks and amedian birthweight of 730 g (650-850 g) and had complete preoperativeand 1- and 8-hour postoperative TnECHO data availablefor review. The median age and weight at the time of surgerywere 26.5 days (20-35 days) and 945 g (880-1200 g), respec-tively. PDA ligation was associated with reductions in LVO(P < .001), fractional shortening (P < .001), and left ventric-ular end-diastolic diameter (P < .001) and prolongation ofisovolumetric relaxation time (P < .001) at both 1 hour and8 hours postligation compared with respective preoperativevalues. LVO at 1 hour and LVO at 8 hours had a high degreeof linear correlation (r = 0.63; P < .001; Figure 1; available atwww.jpeds.com) and was associated with low systolic arterialpressure and need for inotropic agents (P < .05). None of theother echocardiographic markers tested showed a significantcorrelation with any of the desired outcomes. Interestingly,all excluded infants had a 1-hour LVO <200 mL/kg/minand needed inotropic agents postoperatively.

Predictive Value of 1-Hour LVOEighteen infants exhibited critically low LVO (<170 mL/kg/min) at 8 hours, coinciding with the clinical deterioration.Of these infants, 15 already had critically low LVO at 1hour postligation, whereas the other 3 had an LVO of 170-200 mL/kg/min. Six infants with an LVO <200 mL/kg/minat 1 hour did not develop a critically low LVO at 8 hours. Re-ceiver operating characteristic curves were constructed to de-termine the ability for TnECHO at 1 hour postligation topredict subsequent hemodynamic deterioration. LVO at 1hour postligation yielded an area under the curve of 0.94(95% CI, 0.87-1.0; P < .001) for predicting critically lowLVO at 8 hours after surgery, with a cutoff value of 198mL/kg/min, providing a sensitivity of 1.0 and specificity of0.89 (Figure 2, A). It also yielded an area under the curveof 0.90 (95% CI, 0.82-0.98; P < .001) for predicting theneed for inotropic agents with the same cutoff provideda sensitivity of 1.0 and specificity of 0.65 (Figure 2, B).

Figure 2. Receiver operator characteristic curve for LVO at 1 hodicting A, LVO <170 mL/kg/min at 8 hours postligation and B, th

586

A threshold of a 1-hour postligation LVO <200 mL/kg/min would have identified all infants with critically lowLVO at 8 hours postligation (positive likelihood ratio, 7.3;95% CI, 3.5-15.4), 83% (10 of 12) of infants who subse-quently developed systolic hypotension (sensitivity, 0.83[95% CI, 0.55-0.95]; specificity, 0.72 [95% CI, 0.58-0.82];positive likelihood ratio, 3 [95% CI, 1.8-5.0]; negative likeli-hood ratio, 0.23 [95% CI, 0.06-0.83]; OR, 12.9 [95% CI,2.5-66.2]), and all infants (n = 9) who required inotropictreatment (positive likelihood ratio, 3.5; 95% CI, 2.3-5.4).

Study BFifty-seven preterm infants underwent PDA ligation in epoch2, all of whom underwent TnECHO evaluation within 1 hourof ligation. Of these, 27 infants had an LVO <200 mL/kg/minand received i.v. milrinone infusion. After matching, 25 in-fants who had an LVO <200 mL/kg/min at 1 hour postliga-tion were selected from epoch 1. There were no differencesin baseline demographic data, comorbidities, preoperativeclinical status, and preoperative and 1-hour postoperativeTnECHO measures between the 2 epochs (Table I). Allinfants treated with inotropic agents had documentedhypotension and received at least 20 mL/kg of fluidresuscitation before initiation of inotropic therapy.Treatment was initiated with either dobutamine ordopamine, at the discretion of the attending staffneonatologist. No other inotropic agent was used. Allneonates treated with steroids had hypotensionunresponsive to simultaneous infusion of both agents(minimum infusion rate, 10 mg/kg/min of each). Neonatesin epoch 2 demonstrated a significant improvement inclinical indices of postoperative cardiorespiratory stability(Table II). Diastolic arterial pressure increased over time inboth epochs, with no intergroup difference. Treatment withprophylactic milrinone infusion was associated with loweroccurrences of both the primary and all secondaryoutcomes (Table III). The absolute risk reduction in PLCSbetween epochs was 0.31 (95% CI, 0.06-0.52), leading to

ur after PDA ligation. Sensitivity versus false-positive in pre-e need for inotropes within 24 hours postligation.

Jain et al

Table I. Neonatal demographic data, preoperative comorbidities, and clinical status and preoperative and 1-hourpostoperative TnECHO variables in epochs 1 and 2

Characteristic Epoch 1 (n = 25)* Epoch 2 (n = 27)† P value

Gestational age at birth, weeks, median (IQR) 25 (24-26) 25.1 (24.2-26.5) .60Birth weight, g, median (IQR) 690 (656-794) 660 (584-851) .64Male sex, n (%) 13 (52) 15 (55) .98Age at surgery, days, mean� SD 23.1� 8.2 23.7� 7.0 .78Weight at surgery, g, median (IQR) 880 (797-942) 890 (714-1033) .85Necrotizing enterocolitis, n (%) 11 (44) 5 (11.5) .09Intraventricular hemorrhage, n (%) 13 (52) 15 (55) .98Systolic arterial pressure, mm Hg, median (IQR) 49 (47-56) 54 (48-60) .35Diastolic arterial pressure, mm Hg, median (IQR) 26 (23-31) 24 (21-32) .58Fraction of inspired O2, %, median (IQR) 30 (28-42) 29 (25-35) .18Mean airway pressure, cm H2O, median (IQR) 9.0 (7.7-11.0) 8.6 (7.6-10.0) .62PDA diameter, mm, mean� SD 2.8� 0.3 2.6� 0.5 .22Left atrium-to-aortic annulus ratio, mean� SD 1.9� 0.3 2.0� 0.3 .15LVO, mL/kg/min, mean� SD 422� 159 453� 158 .58Fractional shortening, %, mean� SD 40� 8 42� 7 .39IVRT, msec, mean� SD 31� 8 33� 10 .72LVO-1, mL/kg/min, median (IQR)z 170 (140-190) 168 (141-185) .60Fractional shortening-1, %, mean� SDz 34� 8 34� 10 .99IVRT-1, msec, mean� SDz 68� 20 68� 20 .94

IVRT, isovolumetric relaxation time.*All matched infants in epoch 1 with 1-hour postligation LVO <200 mL/kg/min were managed conventionally.†All infants in epoch 2 with 1-hour postligation LVO <200 mL/kg/min received milrinone prophylactic therapy.zAt 1 hour postligation.

April 2012 ORIGINAL ARTICLES

a number needed to treat of 3 (95% CI, 2-16). There was nomortality in either epoch. None of the treated infantsdeveloped rebound hypotension or needed inotropicsupport after discontinuation of milrinone infusion.

Discussion

We report on a targeted cardiovascular intervention, basedon echocardiography, in neonates after PDA ligation surgery.Our main findings were that (1) an LVO of <200 mL/kg/minwithin 1 hour of PDA ligation in preterm infants may predict

Table II. Postligation clinical indices of cardiorespiratory sta

Baseline

Systolic arterial pressure, mm HgEpoch 1 49 (47.5-55.7)Epoch 2 46 (45-59.7)

Diastolic arterial pressure, mm HgEpoch 1 26 (23-31.2)Epoch 2 24 (21-32.2)

Mean arterial pressure, mm HgEpoch 1 38.0� 6.1Epoch 2 41.5� 2.7

Heart rate, bpmEpoch 1 153.6� 13.9Epoch 2 157.0� 919

Fraction of inspired O2 (%)Epoch 1 30 (28-42)Epoch 2 29 (25-34.7)

Mean airway pressure (cm H2O)Epoch 1 9.0 (7.7-11)Epoch 2 9.2 (8-10)

Oxygenation indexEpoch 1 8.4 (5.8-14)Epoch 2 12 (3.7-16)

*P < .05 versus epoch 1.†P < .05 versus baseline (2-way repeat-measures ANOVA).

Use of Targeted Neonatal Echocardiography to Prevent PostopePatent Ductus Arteriosus Ligation

subsequent cardiorespiratory compromise and the need forinotropic agents, and (2) administration of i.v. milrinoneto neonates with an LVO <200 mL/kg/min after the 1-hourpostligation TnECHO evaluation was associated with im-proved postoperative stability.The pathophysiology of PLCS is incompletely understood.

The inability of an immature myocardium to adapt to sud-den changes in loading conditions is thought to be contribu-tory. The physiological consequences include an acute rise insystemic vascular resistance (left ventricular afterload) anda drop in pulmonary venous return (left ventricular preload).

bility in epochs 1 and 2

1 hour 8 hours P value

56.2� 13.2 47 (40.5-51.7) .00757.6� 12.5 56 (44-65.5)*,†

34.1� 9.9† 30.4� 7.1 <.00133.3� 10† 31.3� 9.7

41.9� 6.5† 33.7� 5.4 .0142.9� 3.9 42.5� 2.4*

148.6� 17.5† 150.9� 14.5† <.001143.9� 16.1† 149.6� 12.8

35 (27-50) 39 (23.5-50) .1928 (25-42.2) 32 (25-39.5)

9.0 (7.9-11.0) 9.0 (7.9-11.0) .818.3 (7.3-10) 9.0 (7.5-34.7)

5.8 (5.2-16.5) 6.6 (5.6-16.4) .0026.2 (3.6-10.7) 3.1 (2.0-9.0)*

rative Cardiorespiratory Instability after 587

Table III. Primary and secondary outcomes in epochs 1 and 2

PLCS Need for inotropes Ventilation failure Oxygenation failure Need for steroids

Epoch 1 (n = 25), n (%) 11 (44) 14 (56) 12 (48) 13 (52) 4 (16)Epoch 2 (n = 27), n (%) 3 (11) 5 (19) 4 (15) 7 (26) 0P value .01 .01 .02 .08 .03

PLCS is defined as a composite outcome of the need for inotropic agents and either oxygenation or ventilation failure in the absence of any other identifiable etiology.

THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 160, No. 4

Studies in an immature primate model13 and in human pre-term infants11 demonstrated that ligation was followed byimpaired left ventricular systolic function and reduced car-diac output, which coincided with increased systemic vascu-lar resistance. Systolic myocardial function was moresensitive to afterload in neonates compared with older chil-dren.14 This sensitivity likely is even greater in preterm in-fants. The association of PDA ligation with impaired leftventricular performance and low LVO has been welldescribed.5,11,15,16

Study A is a large echocardiography-based analysis of thispopulation, which increases the validity of our findings. Al-though the data were analyzed retrospectively, all measure-ments were collected prospectively. We believe that thedata are representative, given that the overall incidence ofPLCS and its components observed in epoch 1 were similarto those reported previously.4-6 LVOwas the sole marker cor-related with subsequent clinical deterioration. This may beexplained by the fact that LVO is influenced by both preloadand afterload, both of which change very rapidly after PDAligation. We found no correlation between indices of systolicfunction and subsequent PLCS. This may be related to thedifferential responsiveness of the myocardium to alteredloading conditions, with early impairment in systolic perfor-mance in some patients but compensatory increases in con-tractility in others. The correlation between the thresholdvalue of LVO <200 mL/kg/min at 1 hour and critically lowLVO at the time of clinical deterioration was high. In addi-tion, the sensitivity of this threshold for other indices ofPLCS was high, suggesting that it may be a reliable screeningtool. The magnitude of this association led to modification ofthe postoperative clinical care pathway to incorporate TnE-CHO in refining clinical decision making.

Milrinone is a selective phosphodiesterase III inhibitorthat acts by increasing intracellular levels of cyclic adenosinemonophosphate. Established pharmacologic effects includepositive inotropy, lusitropy, and pulmonary and peripheralvasodilation.17,18 Milrinone improves mortality by prevent-ing low cardiac output in neonates and young children aftercardiac surgery.19 Given the known pathophysiology ofPLCS, milrinone is considered a biologically plausible agentfor targeted intervention, by virtue of its vasodilator andinotropic properties. One of our a priori concerns with mil-rinone is the effect of excessive vasodilation on a preload-compromised myocardium. Other theoretical adverse effectsof milrinone in preterm infants include bleeding from plate-let dysfunction. Neither complication was observed in any ofthe treated infants in our study.

588

In study B, we chose to match patients in both epochs ac-cording to gestational age at birth and LVO at 1 hour postli-gation. This was considered important because both epochswere inherently different. In addition, matching ensuredcomparable illness severity between groups. It should benoted that the predictive value of the 1-hour LVO evaluationwas further confirmed in epoch 2. All but 1 infant with anLVO >200 mL/kg/min remained hemodynamically stable.That infant had an LVO of 236 mL/kg/min with no evidenceof myocardial dysfunction at 1 hour postligation, but devel-oped systolic and diastolic hypotension with severe oxygena-tion failure by 8 hours. The hypotension was refractory tovolume and inotropic agents but responded well to hydro-cortisone, suggesting an alternative physiological process,such as vasodilation.Along with the well-recognized challenges of functional

echocardiography measurements, this study had other limi-tations. First, there might have been patient selection bias.Epoch 1 included only those patients who consented for 2previous echocardiography studies in this population,whereas epoch 2 was all-inclusive. In addition, there maybe other important unaccounted differences between groups.Second, postoperative outcomes might have been affected byclinical practice differences among neonatologists, evolutionof the PDA ligation team, or other unaccounted-for practicechanges. Nevertheless, the preoperative care of infants under-going PDA ligation is highly standardized at our center sincethe creation of a dedicated PDA ligation team under leader-ship of a single staff neonatologist (P.M.) in 2005. Preopera-tive stabilization and surgical and anesthetic managementdid not differ between the 2 epochs; details have been re-ported previously.11 Third, the dosing of milrinone was ex-trapolated from pharmacokinetic data for infants andchildren undergoing cardiac surgery.20 Mindful of the theo-retical risk of increased side effects in preterm infants, wechoose not to give a loading dose and added a slow bolusof 10 mL/kg of normal saline solution to the milrinone infu-sion. Whether the lack of side effects seen in the present studywas related to these interventions cannot be established. A re-cent pharmacokinetic study of milrinone in preterm infantsused a dose similar to that used in the present study.21

Fourth, given the design of our study, we can only hypothe-size as to themechanism of action of milrinone leading to im-proved stability. However, a recently published case reportprovided detailed pretreatment and posttreatment TnECHOindices in a preterm infant treated with milrinone after PDAligation.22 TnECHO performed 6 hours after initiation ofmilrinone infusion demonstrated improved indices of left

Jain et al

April 2012 ORIGINAL ARTICLES

ventricular diastolic function, LVO, and right ventricularoutput that coincided with clinical improvement, suggestingpositive lusitropic and vasodilatory effects. Nonetheless,a larger sample size is needed to establish the pharmacologicaction of milrinone in this population. Finally, the impact ofmilrinone on intermediate and long-term morbidity andmortality remains unknown.

Studies have shown an association between PDA ligationand many short-term morbidities, as well as long-term neu-rosensory impairment.23 One study reported a 3-fold in-crease in mortality before discharge in infants who becameunstable after ligation despite adjusting for other variables.24

We have demonstrated the successful use of a predictive andpreventative strategy for improving post-PDA ligationcare. Data from our study could be used in planning a ran-domized control trial using TnECHO for targeted milrinoneprophylaxis.

We conclude that the postoperative course after PDA liga-tion may be modifiable. TnECHO facilitates early identifica-tion of PLCS and a targeted interventional approach, whichmay improve short-term outcomes. Specifically, LVO <200mL/kg/min at 1 hour postligation may identify most infantsat risk for subsequent deterioration. The administration oftargeted milrinone therapy, using this cutoff, appears to besafe and may significantly improve the immediate postoper-ative course in preterm infants. An echocardiography-basedrandomized controlled trial is needed to test this hypothesisand establish the mechanisms of action of milrinone in thispopulation. n

Submitted for publication May 27, 2011; last revision received Aug 6, 2011;

accepted Sep 6, 2011.

Reprint requests: Dr Patrick J. McNamara, MB, MSc, MRCP, MRCPCH,

University of Toronto, Department of Neonatology, Hospital for Sick Children,

555 University Avenue, Toronto, Ontario, Canada, M5G1X8. E-mail: patrick.

mcnamara@sickkids.ca

References

1. Wyllie J. Treatment of patent ductus arteriosus. Semin Neonatol 2003;8:

425-32.

2. Alexander F, Chiu L, Kroh M, Hammel J, Moore J. Analysis of outcome

in 298 extremely low-birth-weight infants with patent ductus arteriosus.

J Pediatr Surg 2009;44:112-7.

3. Koehne PS, Bein G, Alexi-Meskhishvili V, Weng Y, B€uhrer C,

Obladen M. Patent ductus arteriosus in very low birthweight infants:

complications of pharmacological and surgical treatment. J Perinat

Med 2001;29:327-34.

4. Teixeira LS, Shivananda SP, Stephens D, Van Arsdell G, McNamara PJ.

Postoperative cardiorespiratory instability following ligation of the pre-

term ductus arteriosus is related to early need for intervention. J Perina-

tol 2008;28:803-10.

5. Noori S, Friedlich P, Seri I,Wong P. Changes inmyocardial function and

hemodynamics after ligation of the ductus arteriosus in preterm infants.

J Pediatr 2007;150:597-602.

Use of Targeted Neonatal Echocardiography to Prevent PostopePatent Ductus Arteriosus Ligation

6. Harting MT, Blakely ML, Cox CS Jr., Lantin-Hermoso R, Andrassy RJ,

Lally KP. Acute hemodynamic decompensation following patent duc-

tus arteriosus ligation in premature infants. J Invest Surg 2008;21:

133-8.

7. Moin F, Kennedy KA, Moya FR. Risk factors predicting vasopressor use

after patent ductus arteriosus ligation. Am J Perinatol 2003;20:313-20.

8. Northern Neonatal Nursing Initiative. Systolic blood pressure in babies

of less than 32 weeks gestation in the first year of life. ArchDis Child Fetal

Neonatal Ed 1999;80:F38-42.

9. Gill AB, Weindling AM. Echocardiographic assessment of cardiac func-

tion in shocked very low birthweight infants. Arch Dis Child 1993;68:17-

21.

10. Pladys P, Wodey E, Beuch�ee A, Branger B, B�etr�emieux P. Left ventricle

output and mean arterial blood pressure in preterm infants during the

1st day of life. Eur J Pediatr 1999;158:817-24.

11. McNamara PJ, Stewart L, Shivananda SP, Stephens D, Sehgal A. Patent

ductus arteriosus ligation is associated with impaired left ventricular sys-

tolic performance in premature infants weighing less than 1000 g. J

Thorac Cardiovasc Surg 2010;140:150-7.

12. Sehgal AS, McNamara PJ. Coronary artery hypo-perfusion is associated

with impaired diastolic dysfunction in preterm infants after patent duc-

tus arteriosus ligation (abstract). Pediatric Academic Societies Annual

Meeting: Toronto E-PAS2007:615896.15.

13. Taylor AF, Morrow WR, Lally KP, Kinsella JP, Gerstmann DR,

deLemos RA. Left ventricular dysfunction following ligation of the duc-

tus arteriosus in the preterm baboon. J Surg Res 1990;48:590-6.

14. Rowland DG, Gutgesell HP. Noninvasive assessment of myocardial con-

tractility, preload and afterload in healthy newborn infants. Am J Cardiol

1995;75:818-21.

15. Kimball TR, Ralston MA, Khoury P, Crump RG, Cho FS, Reuter JH. Ef-

fect of ligation of patent ductus arteriosus on left ventricular perfor-

mance and its determinants in premature neonates. J Am Coll Cardiol

1996;27:193-7.

16. Lindner W, Seidel M, Versmold HT, Dohlemann C, Riegel KP. Stroke

volume and left ventricular output in preterm infants with patent ductus

arteriosus. Pediatr Res 1990;27:278-81.

17. Silver PJ, Harris AL, Canniff PC, Lepore RE, Bentley RG, Hamel LT, et al.

Phosphodiesterase isozyme inhibition, activation of the cAMP system,

and positive inotropy mediated by milrinone in isolated guinea pig car-

diac muscle. J Cardiovasc Pharmacol 1989;13:530-40.

18. Wynands JE. Amrinone: is it the inotrope of choice? J Cardiothorac

Anesth 1989;3(Suppl 2):45-57.

19. Hoffman TM, Wernovsky G, Atz AM, Kulik TJ, Nelson DP, Chang AC,

et al. Efficacy and safety of milrinone in preventing low cardiac output

syndrome in infants and children after corrective surgery for congenital

heart disease. Circulation 2003;107:996-1002.

20. Bailey JM, Levy JH, Kikura M, Szlam F, Hug CC Jr. Pharmacokinetics of

intravenous milrinone in patients undergoing cardiac surgery. Anesthe-

siology 1994;81:616-22.

21. Paradisis M, Jiang X, McLachlan AJ, Evans N, Kluckow M, Osborn D.

Population pharmacokinetics and dosing regimen design of milrinone

in preterm infants. Arch Dis Child Fetal Neonatal Ed 2007;92:F204-9.

22. Sehgal A, Francis JV, Lewis AI. Use of milrinone in the management of

haemodynamic instability following duct ligation. Eur J Pediatr 2011;

170:115-9.

23. Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A. Neu-

rosensory impairment after surgical closure of patent ductus arteriosus

in extremely low birth weight infants: results from the Trial of Indo-

methacin Prophylaxis in Preterms. J Pediatr 2007;150:229-34.

24. Natarajan G, Chawla S, Aggarwal S. Short-term outcomes of patent duc-

tus arteriosus ligation in preterm infants: reason for concern? Am J Peri-

natol 2010;27:431-7.

rative Cardiorespiratory Instability after 589

Figure 1. Relationship of LVO at 1 hour (on the y-axis) and 8hours (on the x-axis) postligation demonstrating a high degreeof correlation (r = 0.63).

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