1. TREATING HYPOTENSION IN THE PRETERM NEWBORN: « PERMISSIVE HYPOTENSION » Keith J Barrington Ste Justine Hospital, Montreal.

2. Hypotension in Preterm Infants  Common practice in the NICU, to treat preterm infants with a mean arterial blood pressure in mmHg < gestational age in weeks, regardless of clinical signs,  Many receive a fluid bolus (or 2 or 3 or 4) and then dopamine.  If the blood pressure remains « low » then dobutamine is added, and/or hydrocortisone.

3. 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.0005 238579352 24246109047 25289168434 26338188232 27429277325

4. 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) N9823116(27–504)299(65–1383) Center % Treated Lowest MAP d1 OR (95% CI) Adjusted OR (95% CI)

5. 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)

6. IVH frequency among VLBW infants, Synnes et al 2001

7. Adjusted Odds Ratios Synnes et al 2001

8. Further analysis of CNN data BP<Gestational age,  48% of <28wk “hypotensive” some time during day 1.  15.9% of “hypotensive” infants had a severe IVH.  13.3% of non-“hypotensive” babies had severe IVH.  Statistically significant (p < 0.05): but not very useful!  After correcting for use of inotropes and SNAP-PE score → no relation between “hypotension” and IVH: OR 1.19, p=NS.

10. Watkins charts  Using Watkins charts (10%les) 42,5% of the infants <28 were hypotensive  Why not 10%? Cross sectional not longitudinal data, rapidly changing variable  More strongly associated with severe IVH (16.5% vs 11.4%):  Association disappeared after correction for use of inotropes.  Normotensive infants who received inotropes, (n=150) more had severe IVH (17.9%) than hypotensive infants who did not receive inotropes (5.9%).

11. What is hypotension?  Could define  Statistically, according to a predefined percentile  Physiologically, according to a limit shown to be associated with poorer outcomes  Operationally, according to a limit below which treatment improves outcomes

12. A physiologic definition: Is hypotension related to survival or long term outcomes?  Systematic review of the literature, found 16 studies that looked carefully at this issue  The answer…  Unclear!  The majority of studies have shown some correlation between lower BP and poor outcomes BUT  Many excluded the treated infants from the cohort defining norms then included them when determining harm...  Impossible to determine a threshold for treatment AND  Systematic biases in many of them: For example: same BP used as threshold for all infants (Miall-Allen et al 30 mmHg) If you use the same threshold for everyone, the more immature babies will be more likely hypotensive, and they have the worse outcomes

13. Operational defintion: Is there evidence that treating hypotension improves outcomes?  Fluid Boluses compared to no intervention  Never studied in hypotensive preterm infants  Inotrope/Pressors compared to no intervention  Never studied in hypotensive preterm infants  Steroids compared to no intervention  Never studied in hypotensive preterm infants  No level 1 or 2 evidence of benefit, level 3 evidence of harm

14. Do we know what to treat it with?  Dopamine versus dobutamine, 5 trials  Dopamine more likely to increase BP than dobutamine  Crystalloid versus colloid, 3 trials.  FFP versus albumin, 1 trial  Dopamine versus albumin, 2 trials  Dopamine versus hydrocortisone,1 trial  All were much too small to show a clinically important difference  Commonly NO REPORT of clinically important outcomes.

15. Do we know what to treat it with?  Steroids in inotrope and fluid treated infants compared to no additional treatment  4 very small trials  Example:  Preterm infants with mean BP < GA, all receiving ≥ 10  g/kg/min of dopamine after ≥30 mL/kg of normal saline, randomized to 3 mg/kg/d of hydrocortisone for 5 days.  Hydrocortisone infants had slightly faster decrease in dopamine dose, but no clinical differences in outcomes  Conclusion giving one toxin decreases the use of another toxin!

16. Why are preterm babies ‘hypotensive’?  No association with hypovolemia  4 studies with measurements of circulating blood volume and blood pressure

17. Plots of blood volume against each of the potential explanatory variables. c-pT, Core- peripheral temperature difference; MAP, mean arterial pressure; PCV, packed cell volume. Aladangady N et al. Arch Dis Child Fetal Neonatal Ed 2004;89:F344-F347

18. 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.

19. 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?

20. LVO & RVO

21. Milrinone clinical trial Age (h)Milrinone (n = 42)Placebo (n = 48)P value SVC (mL/kg/min) 3‡3‡78 (51, 107)86 (67, 107).2 770 (48, 92)75 (51, 94).8 1067 (53, 87)81 (50, 100).5 2488 (73, 101)93 (72, 121).4 RVO (mL/kg/min) 3‡3‡182 (140, 240)189 (133, 271).9 7177 (147, 258)187 (140, 240).9 10189 (146, 258)187 (133, 243).4 24242 (194, 301)250 (207, 306).7 BP (mm Hg)3‡3‡31 ± 630 ± 3.4 728 ± 532 ± 6.001 1029 ± 432 ± 5.004 2434 ± 536 ± 6.2 HR (beats/min) 3‡3‡149 ± 16151 ± 17.6 7158 ± 15145 ± 10.001 10157 ± 13141 ± 12.001 24153 ± 13144 ± 14.003 PDA diameter3‡3‡2 ± 0.91.9 ± 0.6.5 (mm)71.9 ± 0.71.5 ± 0.6.001 101.9 ± 0.61.4 ± 0.6.001 241.7 ± 0.80.9 ± 0.7.001

22. Low dose dopamine and the kidney  No evidence from neonatal animal models that low dose dopamine increases renal blood flow  One clinical trial also showed no effect  No evidence of beneficial renal effect of low dose dopamine in critically ill older children or adults either! (several systematic reviews)

23. Pituitary effects of dopamine

24. Dopamine and thyroid suppression in the newborn Filippi L, Cecchi A, Tronchin M, Dani C, Pezzati M, Seminara S, et al. Dopamine infusion and hypothyroxinaemia in very low birth weight preterm infants. Eur J Pediatr 2004 Jan;163(1):7-13.

25. Low dose dopamine = Pituitary dose dopamine

26. Treatment of Hypotension  So why do people treat?  « Hypotension impairs cerebral perfusion »  « CBF is pressure passive… »  Of course if you go to your family Doc for a checkup you aren’t likely to be at significant risk of brain injury with life long consequences! (But you are at risk of complications from intervention)

27. Responses to Questionnaire: Canadian neonatologists  Criteria for diagnosing hypotension:  74% use both BP<GA (or another criterion) and clinical signs to define hypotension.  26% use BP alone, (most common, BP<GA)  Volume 1 st -- 97%  Dopamine is 1 st drug --92%  Three main patterns of treatment  volume, dopamine, steroid (37%)  volume, dopamine, dobutamine(28%)  volume, dopamine, epinephrine (16%)

28. Treatments  Dopamine: starting dose range 2.5-10  g/kg/min  maximum dose 10-30 The maximum dose for 7 respondents is the initial starting dose for 17 others.  Dobutamine: starting dose range 2-10  g/kg/min  maximum dose 10-20  Epinephrine: starting dose 0.01-0.1  g/kg/min  maximum dose 0.3-4.0  Usual corticosteroid = hydrocortisone (98%).  Initial doses varied 0.1–5 mg/kg/dose  Total daily doses range from 0.4-15 mg/kg/day.

29. Retrospective cohort study  118 ELBW patients admitted 2000-2003. 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.

30. Normotensive Permissive hypotension Treated Hypotension Number 523418 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)* BP @ 6hr mmHg mean (range) 32 (25-49)^26(16-62)22 (14-34)* BP @ 12hr mmHg (range) 34 (27-72)^27(17-35)22 (12-32)* BP @18hr mmHg (range) 33 (26-65)^30 (20-37)24 (13-33)* BP @ 24hr mmHg (range) 35 (25-54)^31(22-41)28 (16-36)* Antenatal steroid (%) 718265

31. Normotensive Permissive hypotension Treated Hypotension Number 523418 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%)

32. Hypotension or shock?

33. Conclusion  Very little good data to support evidence based guidelines  Do we need to treat Hypotension, or should we be treating Shock?  Hypotensive babies who are clinically well perfused may not need any treatment  Babies with poor perfusion do badly, individualizing the interventions, by measurements of relevant physiologic endpoints such as blood flow, serum lactate, brain perfusion or activity etc. may help us to improve care, but this needs to be proven.

34. Hypotension in Preterm Infants  What is hypotension?  No clear definition  Why do we worry about it?  Not clear that we should  Why are babies hypotensive?  In general because they have low vascular resistance  Is there evidence that hypotension needs treating?  Not really  Do we know what to treat it with?  No

35. 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.