Hypotension and assessment of adequate tissue oxygen delivery in the Preterm Newborn: Keith J Barrington CHU Ste Justine Montréal

Laughon et al: the ELGAN study Total n No Treatment n=249 Any Treatment n = 1138 Vasopressor Treatment n = 470 Gestnl age, wk Proportion of Infants, % P =.001P

Variability in « any » Rx A292811c B46272(1–4)3(1–6) C61204(2–7)5(2–10) D69245(3–9)9(5–18) E80259(5–20)33(14–80) F852413(6–27)25(11–56) G912324(11–50)44(19–102) H922326(13–52)54(25–118) I932332(7–145)84(17–404) J932534(15–78)80(32–203) K942237(16–82)58(24–140) L942339(14–106)92(31–275) M962665(19–225)105(29–385) N (27–504)299(65–1383) Center % Treated Lowest MAP d1 OR (95% CI) Adjusted OR (95% CI)

Variability in inotrope Rx A61911c N12202(1–6)3(1–9) F15213(1–7)3(1–10) M18253(1–9)4(2–12) D20224(1–10)5(2–14) B27376(2–15)8(3–22) H32217(3–17)12(5–30) K38219(4–22)11(4–27) C441912(4–30)19(7–52) J462313(5–31)25(10–65) I482514(5–42)34(11–107) E522416(6–42)48(17–132) G602322(9–54)35(14–91) L642426(10–67)61(23–165) Center % Treated Lowest MAP d1 OR (95% CI) Adjusted OR (95% CI)

Logan JW, et al, ELGAN Investigators: Early postnatal hypotension and developmental delay at 24 months of age among extremely low gestational age newborns. Archives of Disease in Childhood - Fetal and Neonatal Edition 2011, 96(5):F321-F328.

Copyright ©2004 BMJ Publishing Group Ltd. Osborn, D A et al. Arch. Dis. Child. Fetal Neonatal Ed. 2004;89:F168-F173 Figure 3 Scatter plot of mean blood pressure (BP) against superior vena cava (SVC) flow for all observations. Reference lines represent SVC flow of 41 ml/kg/min and mean BP of 30 mm Hg.

Physiological responses to current common treatments? Fluid boluses – appear to increase left ventricular output but not RVO – Increase ductal shunt: don’t improve systemic perfusion – Small transient increase in blood pressure Dopamine – Increases BP, almost entirely by vasoconstriction, decreasing systemic flow Steroids – Increase pressure slowly, by what hemodynamic mechanism?

LVO & RVO

Retrospective cohort study 118 ELBW patients admitted BP data were available on 107, 53% of patients had BP < GA. 18/118 ELBW infants received treatment for Hypotension: – 11 received only an epinephrine infusion, – 4 had only a single fluid bolus (saline 10 ml/kg), and – 3 had a fluid bolus followed by epinephrine infusion. 4 other Hypotensive infants received only a blood transfusion, over 2 hr, as therapy.

Normotensive Permissive hypotension Treated Hypotension Number Birth weight grams, mean (SD) 828 (144)^742 (131)728 (149) Gestation weeks, mean (SD) 26.6 (1.6)26.1 (1.6)25.2 (1.6)* Crib II score, median (range) 11 (7-18)11 (8-16)15 (9-16)* 6hr mmHg mean (range) 32 (25-49)^26(16-62)22 (14-34)* 12hr mmHg (range) 34 (27-72)^27(17-35)22 (12-32)* mmHg (range) 33 (26-65)^30 (20-37)24 (13-33)* 24hr mmHg (range) 35 (25-54)^31(22-41)28 (16-36)* Antenatal steroid (%)

Normotensive Permissive hypotension Treated Hypotension Number Necrotizing enterocolitis, n (%) 4 (8%)3 (9%)2 (11%) Surgical NEC, n 111 Isolated GI perforation, n 201 IVH 3 or 4, n 245 Cystic PVL, n 100 Mortality, n 10413* Survival without severe IVH, cystic PVL, surgical NEC, or GI perforation, n (%) 40 (77%)26 (76%)4* (22%)

Evaluation of perfusion Clinical exam Lab/blood testing Ancillary methods – Accuracy in determining adequacy of O2 delivery – Accuracy in predicting outcome – Applicability in day-to-day With thanks to de Boode Early Hum Develop 2010

Clinical examination Capillary refill Warmth of toes Colour of skin Urine output Activity level

Capillary refill Osborn Dempsey Others in term infants – Significant inter-individual variation in the measurement, except when measured on the chest.

Scatter plot of capillary refill time against superior vena cava (SVC) flow for all observations. Osborn D A et al. Arch Dis Child Fetal Neonatal Ed 2004;89:F168-F173 ©2004 by BMJ Publishing Group Ltd and Royal College of Paediatrics and Child Health

Normal flowLow flowTotal *Mean blood pressure ≤ gestation in weeks. CPTd < 2°C ≥ 2°C Total CRT < 3 seconds –3.9 sec ≥ 4 seconds Total Systolic BP ≥ 48 mm Hg – < 40 mm Hg Total Mean BP ≥ 30 mm Hg < 30 mm Hg Total > Gestation ≤ Gestation* Total

Clinical examination Capillary refill +/- Warmth of toes Colour of skin Urine output ? Activity level ?

Lab/blood tests Base Excess – Poor indicator of tissue O2 delivery – Poorly correlated with lactate Lactate – Absolute values – Direction of change

Serum Lactate Several studies show that infants with high lactates in early life have an increased mortality, but the PPV is not high, e.g. 47% – Groenendaal F, Lindemans C, Uiterwaal CSPM, de Vries LS: Early Arterial Lactate and Prediction of Outcome in Preterm Neonates Admitted to a Neonatal Intensive Care Unit. Neonatology 2003, 83(3): Others have shown that the progression of lactates is more useful – Deshpande SA, Platt MP: Association between blood lactate and acid-base status and mortality in ventilated babies. Arch Dis Child Fetal Neonatal Ed 1997, 76(1):F15-20.

Miletin Pichova and Dempsey A capillary refill time of >4 s combined with serum lactate concentrations >4 mmol/l had a sensitivity of 50%, a specificity of 97%, a PPV of 80% and an NPV of 88% for predicting low flow states.

Ancillary methods Functional Echo NIRS Mixed venous O2 Indirect – EEG – aEEG Masimo Perfusion Index

Functional Echocardiography Threshold of 40 mL/kg/min well-supported but a bit simplistic – Ignores HgB, SpO2, VO2 Not simple to measure SVC flow Inter-observer variability Intermittent

NIRS Gold Standard? Tissue oxygenation is what we are really concerned about Some analyses suggest +/- 17% accuracy Are low results correlated with long term outcomes? How low is too low?

NIRS and Echo, Moran, Miletin, Pichova and Dempsey 2009

Kissack et al Cerebral FOE during the first 3 d after birth in nine infants with IVH, including two with HPI.

Figure 1. The course of rcSO2 (A), FTOE (B), and tcSaO2 (C) in preterm infants with GMH-IVH or PVHI versus a preterm control group. Verhagen E A et al. Stroke 2010;41:

The course of the values for rsco2 (A), FTOE (B), and tcSao2 (C) during the first 2 weeks after birth in infants with and without TPE. a Differences between the 2 groups (P <.05, TPE versus no TPE). Verhagen E A et al. Pediatrics 2009;124: ©2009 by American Academy of Pediatrics

Takahashi et al, J Perinatol 2010 Perfusion Index, Masimo pulse oximeter

Cresi et al Ital J Ped 2010

Summary An SVC flow below 40 mL/kg/min is associated with poorer outcomes – Using the same limit for everyone is a bit simplistic, it ignores variations in HgB, Saturation and O2 demand: but it is by far the best evaluated and supported measure we have SVC <40 has become relatively uncommon in the small preterms (<20%) Other measures have often been evaluated for their correlation with SVC flow – They should also be evaluated independently for their association with clinical outcomes

Summary (2) Capillary filling has some correlation with SVC flow Overall clinical estimation of poor perfusion is associated with poor outcomes Cap filling 4 associated with low SVC flow

Summary (3) NIRS of brain and other regions – Methods of analysis, best parameter to use, uncertain – Is there a single cutoff that predicts poorer outcome, therefore could be used to investigate therapy? Perfusion Index from the pulse oximeter? Other invasive methods

What do we need to do Prospective cohort studies analyzing all of these factors in a group of preterm infants Comparison with echo indices of flow Comparison with short and long term complications. Research question to be asked: Does this measure correspond with outcomes? Does it correlate with flow Is it an appropriate measure to guide treatment?

The HIP trial  Succesful FP7 application, PI Gene Dempsey,  RCT of 800 infants less than 28 weeks  Masked trial, dopamine or placebo  If max study drug dose reached further treatment only if signs of poor perfusion  If signs of poor perfusion during treatment, rescue  Primary outcome survival without serious brain injury  Co-primary outcome: survival without neurodevelopmental impairment to 2 years CA.  Survey for completion, please.