K.D. Liem

Changes in cerebral, renal and mesenteric blood flow velocity during continuous and bolus infusion of indomethacin.

Vasoconstriction induced by bolus injection of indomethacin reduces organ perfusion and has been related to the well‐known side effects of indomethacin given for closure of the patent ductus arteriosus (PDA). The aim of the study was to compare the changes in cerebral, renal and mesenteric blood flow velocities after continuous infusion versus bolus injection of indomethacin for closure of the PDA. Thirty‐two preterm infants (range 26–35 wk gestational age) with PDA were randomly assigned to receive the same amount of indomethacin either as three bolus injections (n= 14) or as a continuous infusion (n= 18) over 36 h. Blood flow velocities were measured in the internal carotid, right renal and superior mesenteric arteries at baseline and serially at 10, 30, 60 and 120 min and 12, 24, 36 and 48 h after the start of indomethacin treatment. There were no differences in blood flow velocities between both groups at baseline. During continuous infusion of indomethacin there was no significant change in the cerebral, renal and mesenteric blood flow velocities, whereas the flow velocities in the infants receiving bolus injections decreased significantly during the first 2 h after indomethacin administration in all arteries measured. There was a transient, but significant reduction in urine output after bolus injection of indomethacin.

The effect of blood transfusion and haemodilution on cerebral oxygenation and haemodynamics in newborn infants investigated by near infrared spectrophotometry

Abstract The objective of this study was to investigate the influence of blood transfusion and haemodilution on cerebral oxygenation and haemodynamics in relation to changes in cerebral blood flow velocity (CBFV) and other relevant physiological variables in newborn infants. Thirteen preterm infants with anaemia (haematocrit < 0.33) and ten infants with polycythaemia (haematocrit > 0.65) were studied during blood transfusion and haemodilution respectively using adult red blood cells and partial plasma exchange transfusion. Changes in cerebral concentrations of oxyhaemoglobin (cO2Hb), deoxyhaemoglobin (cHHb), total haemoglobin (ctHb), (oxidized - reduced) cytochrome aa3 (cCyt.- aa3) were continuously measured using near infrared spectrophotometry throughout the whole procedure. Simultaneously, changes of mean CBFV in the internal carotid artery were continuously measured using pulsed Doppler ultrasound. Heart rate, transcutaneous partial pressure of oxygen and carbon dioxide, and arterial O2 saturation were continuously and simultaneously measured. Blood transfusion resulted in increase of cO2Hb, cHHb, ctHb and red cell transport (product of CBFV and haematocrit), whereas CBFV decreased. The increase of cO2Hb exceeded that of cHHb, reflecting improvement of cerebral O2 supply. Haemodilution resulted in a decrease of cO2Hb, cHHb and ctHb, whereas CBFV increased. Red cell transport was unchanged. The decrease of cO2Hb exceeded that of cHHb, reflecting decreased cerebral O2 supply. cCyt.aa3 decreased after blood transfusion and remained unchanged after haemodilution, but the reliability of these results is uncertain. With the exception of a small, but significant increase in transcutaneous partial pressure of oxygen after blood transfusion, the other variables showed no changes. Each blood withdrawal during exchange transfusion resulted in only a significant increase in heart rate without changes in the other variables measured, suggesting unchanged cerebral perfusion. Conclusion In newborn infants blood transfusion in anaemia results in improvement of cerebral oxygenation, but haemodilution in polycythaemia does not improve cerebral oxygenation despite possible improvement of cerebral perfusion.

Effects of midazolam and morphine on cerebral oxygenation and hemodynamics in ventilated premature infants

Background: Midazolam sedation and morphine analgesia are commonly used in ventilated premature infants. Objectives: To evaluate the effects of midazolam versus morphine infusion on cerebral oxygenation and hemodynamics in ventilated premature infants. Methods: 11 patients (GA 26.6–33.0 weeks, BW 780–2,335 g) were sedated with midazolam (loading dose 0.2 mg/kg, maintenance 0.2 mg/kg/h) and 10 patients (GA 26.4–33.3 weeks, BW 842–1,955 g) were sedated with morphine (loading dose 0.05 mg/kg, maintenance 0.01 mg/kg/h). Changes in oxyhemoglobin (ΔcO2Hb) and deoxyhemoglobin (ΔcHHb) were assessed using near infrared spectrophotometry. Changes in cHbD (= ΔcO2Hb – ΔcHHb) reflect changes in cerebral blood oxygenation and changes in concentration of total hemoglobin (ΔctHb = ΔcO2Hb + ΔcHHb) represent changes in cerebral blood volume (ΔCBV). Changes in cerebral blood flow velocity (ΔCBFV) were intermittently measured using Doppler ultrasound. Heart rate (HR), mean arterial blood pressure (MABP), arterial oxygen saturation (saO2) and transcutaneous measured pO2 (tcpO2) and pCO2 (tcpCO2) were continuously registered. Statistical analyses were carried out using linear mixed models to account for the longitudinal character study design. Results: Within 15 min after the loading dose of midazolam, a decrease in saO2, tcpO2 and cHbD was observed in 5/11 infants. In addition, a fall in MABP and CBFV was observed 15 min after midazolam administration. Immediately after morphine infusion a decrease in saO2, tcpO2 and cHbD was observed in 6/10 infants. Furthermore, morphine infusion resulted in a persistent increase in CBV. Conclusions: Administration of midazolam and morphine in ventilated premature infants causes significant changes in cerebral oxygenation and hemodynamics, which might be harmful.

Effects of Rapid versus Slow Infusion of Sodium Bicarbonate on Cerebral Hemodynamics and Oxygenation in Preterm Infants

Background: Sodium bicarbonate (NaHCO3) is often used for correction of metabolic acidosis in preterm infants. The effects of NaHCO3 administration on cerebral hemodynamics and oxygenation are not well known. Furthermore, there is no consensus on infusion rate of NaHCO3. Objectives: To evaluate the effects of rapid versus slow infusion of NaHCO3 on cerebral hemodynamics and oxygenation in preterm infants. Methods: Twenty-nine preterm infants with metabolic acidosis were randomized into two groups (values are mean ±SD): In group A (GA 30.5 ± 1.7 weeks, b.w. 1,254 ± 425 g) NaHCO3 4.2% was injected as a bolus. In group B (GA 30.3 ± 1.8 weeks, b.w. 1,179 ± 318 g) NaHCO3 4.2% was administered over a 30-min period. Concentration changes of oxyhemoglobin (cO2Hb) and deoxyhemoglobin (cHHb) were assessed using near infrared spectrophotometry. Changes in HbD (= cO2Hb – cHHb) represent changes in cerebral blood oxygenation and changes in ctHb (= cO2Hb + cHHb) reflect changes in cerebral blood volume. Cerebral blood flow velocity was intermittently measured using Doppler ultrasound. Longitudinal data analysis was performed using linear mixed models (SAS procedure MIXED), to account for the fact that the repeated observations in each individual were correlated. Results: Administration of NaHCO3 resulted in an increase of cerebral blood volume which was more evident if NaHCO3 was injected rapidly than when infused slowly. HbD and cerebral blood flow velocity did not show significant changes in either group. Conclusion: To minimize fluctuations in cerebral hemodynamics, slow infusion of sodium bicarbonate is preferable to rapid injection.

Recirculation in double lumen catheter veno-venous extracorporeal membrane oxygenation measured by an ultrasound dilution technique.

Recirculation is a limiting factor for oxygen delivery in double lumen catheter veno-venous extracorporeal membrane oxygenation (DLVV-ECMO). This study compares three different methods for the determination of the recirculation fraction during double lumen catheter veno-venous ECMO at ECMO flow rates of 150, 125, 100, 75, and 50 ml/kg.min in nine lambs: (1) an ultrasound dilution method, in which the change in ultrasound velocity in blood after injection of a saline bolus as a marker is used for determination of recirculation; (2) an SvO2 method using real mixed venous blood oxygen saturation, the gold standard, for determination of recirculation fraction; and (3) the CVL method, in which oxygen saturation of a blood sample of the inferior vena cava is considered to represent mixed venous oxygen saturation. In all methods, the recirculation fraction increased with increasing ECMO flow rate. The correlation coefficient between the ultrasound dilution method and the SvO2 method was 0.68 (p < 0.01); mean difference was -2.4% (p = 0.6). Correlation coefficient between the ultrasound dilution method and the CVL method was 0.48 (p < 0.01); mean difference was -18.1% (p < 0.01). The correlation coefficient between the SvO2 method and the CVL method was 0.51 (p < 0.01); mean difference was -15.7% (p < 0.01). The ultrasound dilution method is a useful method for measurement of the recirculation fraction in DLVV-ECMO and is easier to use than the other methods.

Disturbance of cerebral oxygenation and hemodynamics related to the opening of the bypass bridge during Veno-arterial extracorporeal membrane oxygenation

ABSTRACT: The objective of this study was to investigate changes of cerebral oxygenation and hemodynamics related to opening of the bypass bridge during veno-arterial extracorporeal membrane oxygenation (ECMO). Ten newborn infants and 12 piglets were studied during opening of the bridge for 10 and 1 s, respectively. Changes in cerebral concentration of oxyhemoglobin (c O2Hb), deoxyhemoglobin (c HHb), (oxidized-reduced) cytochrome aa3 (c Cyt.aa3), and blood volume (CBV) were continuously measured by near infrared spectropbotometry. Heart rate, arterial O2 saturation (s aO2), and mean arterial blood pressure (MABP) were measured simultaneously. In the piglets, central venous pressure (CVP), intracranial pressure (ICP), and left common carotid artery blood flow (CaBF) were also measured. Opening of the bridge for 10 s in the infants resulted in a significant decrease in MABP, s aO2, and c O2Hb, whereas c HHb increased. CBV did not change significantly. In piglets biphasic changes were observed for MABP, CaBF, c O2Hb, and CBV, showing an initial decrease followed by a smaller increase. c HHb and CVP showed reverse biphasic changes. ICP increased but s aO2 was unchanged. In all cases heart rate and c Cyt.aa3 did not change significantly. Opening of the bridge for 1 s resulted in minor changes in only a few variables. In conclusion, opening of the bridge resulted in a decrease of CBV and cerebral O2 supply due to a decrease of cerebral blood flow, followed by a compensatory increase of cerebral O2 extraction and vasodilatation. The return of oxygenated blood after reclosing resulted in an increase of CBV with overcompensation of cerebral O2 supply.

Early life intervention with glucocorticoids has negative effects on motor development and neuropsychological function in 14-17 year-old adolescents.

OBJECTIVE To reduce the risk of bronchopulmonary dysplasia, preterm infants receive neonatal treatment with glucocorticoids, mostly dexamethasone (DEX). Compared to current protocols, treatment regimens of the late 1980s - early 1990s prescribed high doses of DEX for an extensive period up to 6 weeks. Worldwide at least one million children have been treated with this dose regimen. Previous studies have shown adverse effects of neonatal treatment with the glucocorticoid dexamethasone (DEX) on outcome in children aged 7-10 years. On the other hand, treatment with another glucocorticoid, hydrocortisone (HC), was not related to adverse effects in childhood. In the current study we determined the consequences of early life intervention with DEX or HC in adolescents (age 14-17 years). Besides motor function and intellectual capacities, we also examined fundamental neuropsychological functions which have so far received little attention. METHODS In an observational cohort study we compared 14-17 year-old adolescents who received DEX (.5 mg/kg/day tapering off to .1 mg/kg/day over 21 days, n=63), or HC (5 mg/kg/day tapering off to 1 mg/kg/day over 22 days, n=67), or did not receive neonatal glucocorticoids (untreated, n=71) after premature birth (gestational age<32 weeks). Because gestational age was shorter and duration of ventilation was longer in the DEX-treated group, all analyses were corrected for these potential confounders. Motor function, IQ, and neuropsychological functions were assessed. RESULTS DEX-treated group participants scored lower on gross motor skill tasks than their HC-treated and untreated counterparts. A higher proportion of DEX-treated girls needed special education compared to the other groups. DEX-treated adolescents performed poorer on neuropsychological tasks measuring alertness, visuomotor coordination, and emotion recognition. The HC-treated group did not differ from the untreated group. CONCLUSIONS Even after 14-17 years, neonatal treatment with .5 mg/kg/day DEX was associated with adverse effects on motor function, school level, and neuropsychological functions, whereas treatment with the clinically equally effective dose of 5 mg/kg/day HC was not. Potential physiological mechanisms underlying the differences in dexamethasone and hydrocortisone effects are discussed. Based on the current findings, we recommend early identification of neuropsychological deficits after DEX treatment in order to specify extra educational needs.

Hemodynamic changes during opening of the bridge in venoarterial extracorporeal membrane oxygenation

Objective To investigate the cause of the hemodynamic changes occurring during opening of the bridge in venoarterial (VA) extracorporeal membrane oxygenation (ECMO). Design Prospective intervention study in animals. Setting Animal research laboratory of a university medical center. Subjects Eight anesthetized lambs installed on VA-ECMO. Interventions During VA-ECMO the bridge was randomly opened during 1, 2.5, 5, 7.5, 10, and 15 secs at ECMO flow rates of 500, 400, 300, 200, 100, and 50 mL/min. Flows in the ECMO circuit between venous cannula and bridge and bridge and arterial cannula, mean arterial blood pressure, mean left carotid artery blood flow, central venous pressure, superior sagittal sinus pressure, inline mixed venous oxygen saturation, heart rate, and arterial oxygen saturation were measured continuously. Using near infrared spectrophotometry, changes in concentrations of cerebral oxygenated and deoxygenated hemoglobin and cerebral blood volume were also measured. Values during bridge opening were compared with values before opening. The same variables were determined with a roller pump on the bridge with a flow over the bridge at various flow rates. Measurements and Main Results Bridge opening resulted in a change of flow direction between venous cannula and bridge and bridge and arterial cannula. A biphasic response with initial decrease and secondary increase occurred in mean arterial blood pressure and mean left carotid artery blood flow. Central venous pressure, superior sagittal sinus pressure, deoxygenated hemoglobin, and cerebral blood volume increased, whereas cerebral oxygenated hemoglobin decreased. These effects occurred in each combination of ECMO flow rate and opening time. These effects could be abolished by installing a roller pump on the bridge. Conclusions Bridge opening in VA-ECMO resulted in significant cerebral hemodynamic changes caused by an arteriovenous shunt over the bridge. The decreased cerebral perfusion pressure may contribute to the occurrence of cerebral ischemia, and the venous congestion may result in intracranial hemorrhages. These could be prevented by installing a roller pump on the bridge.

Cerebral Aspects of Neonatal Extracorporeal Membrane Oxygenation: A Review

Background: Neonatal extracorporeal membrane oxygenation (ECMO) is a lifesaving therapeutic approach in newborns suffering from severe, but potentially reversible, respiratory insufficiency, mostly complicated by neonatal persistent pulmonary hypertension. However, cerebral damage, intracerebral hemorrhage as well as ischemia belong to the most devastating complications of ECMO. Objectives: The objectives are to give insights into what is known from the literature concerning cerebral damage related to neonatal ECMO treatment for pulmonary reasons. Methods: A short introduction to ECMO indications and technical aspects of ECMO are provided for a better understanding of the process. The remainder of this review focuses on outcome and especially on (potential) risk factors for cerebral hemorrhage and ischemia during ECMO treatment. Results: Although neonatal ECMO treatment shows improved outcome compared to conservative treatment in cases of severe respiratory insufficiency, it is related to disturbances in various aspects of neurodevelopmental outcome. Risk factors for cerebral damage are either related to the patients disease, EMCO treatment itself, or a combination of both. Conclusion: It is of ongoing importance to further understand pathophysiological mechanisms resulting in cerebral hemorrhage and ischemia due to ECMO and to develop neuroprotective strategies and approaches.

Influence of lung injury on cardiac output measurement using transpulmonary ultrasound dilution: a validation study in neonatal lambs

BACKGROUND Transpulmonary ultrasound dilution (TPUD) is a promising method for cardiac output (CO) measurement in severely ill neonates. The incidence of lung injury in this population is high, which might influence CO measurement using TPUD because of altered lung perfusion. We evaluated the influence of lung injury on the accuracy and precision of CO measurement using TPUD in an animal model. METHODS In nine neonatal lambs, central venous and arterial catheters were inserted and connected to the TPUD monitor. Repeated lavages with warmed isotonic saline were performed to gradually induce lung injury. CO measurements with TPUD (COtpud) were compared with those obtained by an ultrasonic transit-time flow probe around the main pulmonary artery (COufp). An increase in oxygenation index was used as an indicator of induced lung injury during the experiment. Post-mortem lung injury was confirmed by histopathological examination. RESULTS Fifty-five sessions of three paired CO measurements were analysed. The mean COufp was 1.53 litre min(-1) (range 0.66-2.35 litre min(-1)), and the mean COtpud was 1.65 litre min(-1) (range 0.78-2.91 litre min(-1)). The mean bias (standard deviation) between the two methods was 0.13 (0.15) litre min(-1) with limits of agreement of ±0.29 litre min(-1). The overall percentage error was 19.1%. The accuracy and precision did not change significantly during progressive lung injury. Histopathological severity scores were consistent with heterogeneous lung injury. The capability to track changes in CO using TPUD was moderate to good. CONCLUSIONS The accuracy and precision of CO measurement using TPUD is not influenced in the presence of heterogeneous lung injury in an animal model.