Detection and quantification of left-to-right shunting using transpulmonary ultrasound dilution (TPUD): a validation study in neonatal lambs.

OBJECTIVES: We investigated the accuracy of left-to-right shunt detection using transpulmonary ultrasound dilution (TPUD) and compared the agreement between pulmonary over systemic blood flow (Qp/Qs) ratio measured by TPUD [Qp/Qs(tpud)] and ultrasonic flow probes [Qp/Qs(ufp)]. METHODS: Seven newborn lambs under general anesthesia were connected to the TPUD monitor (COstatus™) after insertion of arterial and central venous catheters. A Gore-Tex® shunt, inserted between the descending aorta and left pulmonary artery, was intermittently opened and closed while cardiac output was varied by blood withdrawals. Flow probes were placed around the main pulmonary artery (Qufp) and the descending aorta proximal (Qpre) and distal (Qpost) to the shunt insertion. Qp/Qs(ufp) was calculated as (Qufp+Qpre-Qpost)/Qufp. RESULTS: Seventy-two paired measurement sessions were analyzed. Shunts were detected by TPUD with a positive predictive value of 86%, a negative predictive value of 100%, a sensitivity of 100% and a specificity of 83%. The Bland-Altman analysis comparing Qp/Qs(tpud) and Qp/Qs(ufp) showed an overall mean bias (SD) of 0.1 (0.3), limits of agreement (LOA) of ±0.6 and a percentage error of 34.8%. CONCLUSIONS: The qualitative diagnostic accuracy of TPUD for shunt detection is high. Modification of the algorithm seems required as shunt quantification by TPUD is accurate, but not yet very precise.

The Effect of Decreasing Flow Rate on Cerebral Hemodynamics During Veno-Arterial Extracorporeal Membrane Oxygenation in Piglets.

To explore the influence of decreasing flow rate on cerebral hemodynamics during veno-arterial extracorporeal membrane oxygenation (va-ECMO), six normoxemic and six hypoxemic piglets were put on va-ECMO. The ECMO flow rate was decreased from the maximal achievable level to 50 mL min1 with steps of 50 mL min1 every 2 minutes. Changes in mean arterial blood pressure (MABP), left common carotid artery blood flow (Qcar), and other physiologic variables were continuously measured. Changes in concentrations of oxyhemoglobin and deoxyhemoglobin were measured using near infrared spectrophotometry (NIRS). Changes in difference between cerebral oxygen hemoglobin and deoxyhemoglobin concentration (ΔcHbD) and total hemoglobin concentration (ΔctHb) were calculated. ΔcHbD represents changes in cerebral blood flow (CBF), and ΔctHb reflects changes in cerebral blood volume (CBV). Data analysis was performed using mixed models and demonstrated a significant positive correlation between ECMO flow and, respectively, MABP (r = 0.7, p < 0.001), Qcar (r = 0.7, p < 0.001), cHbD (r = 0.8, p < 0.001), and ctHb (r = 0.7, p < 0.001). There was no significant relation between oxygenation state preceding ECMO and Qcar, cHbD, and ctHb during decreasing ECMO flow rate. We conclude that decreasing ECMO flow rate ultimately leads to concurrent decrease in MABP, CBF, and CBV.

Hemodynamic volumetry using transpulmonary ultrasound dilution (TPUD) technology in a neonatal animal model.

To analyze changes in cardiac output and hemodynamic volumes using transpulmonary ultrasound dilution (TPUD) in a neonatal animal model under different hemodynamic conditions. 7 lambs (3.5-8.3 kg) under general anesthesia received arterial and central venous catheters. A Gore-Tex(®) shunt was surgically inserted between the descending aorta and the left pulmonary artery to mimic a patent ductus arteriosus. After shunt opening and closure, induced hemorrhagic hypotension (by repetitive blood withdrawals) and repetitive volume challenges, the following parameters were assessed using TPUD: cardiac output, active circulating volume index (ACVI), central blood volume index (CBVI) and total end-diastolic volume index (TEDVI). 27 measurement sessions were analyzed. After shunt opening, there was a significant increase in TEDVI and a significant decrease in cardiac output with minimal change in CBVI and ACVI. With shunt closure, these results reversed. After progressive hemorrhage, cardiac output and all volumes decreased significantly, except for ACVI. Following repetitive volume resuscitation, cardiac output increased and all hemodynamic volumes increased significantly. Correlations between changes in COufp and changes in hemodynamic volumes (ACVI 0.83; CBVI 0.84 and TEDVI 0.78 respectively) were (slightly) better than between changes in COufp and changes in heart rate (0.44) and central venous pressure (0.7). Changes in hemodynamic volumes using TPUD were as expected under different conditions. Hemodynamic volumetry using TPUD might be a promising technique that has the potential to improve the assessment and interpretation of the hemodynamic status in critically ill newborns and children.

Application of ultrasound dilution technology for cardiac output measurement: Cerebral and systemic hemodynamic consequences in a juvenile animal model.

OBJECTIVE: Analysis of cerebral and systemic hemodynamic consequences of ultrasound dilution cardiac output measurements. DESIGN: : Prospective, experimental piglet study. SETTING: Animal laboratory. SUBJECTS: Nine piglets. INTERVENTIONS: Ultrasound dilution cardiac output measurements were performed in ventilated, anesthetized piglets. Interventions that are required for ultrasound dilution cardiac output measurement were evaluated for its effect on cerebral and systemic circulation and oxygenation. MEASUREMENTS AND MAIN RESULTS: DeltacHbD and DeltactHb, representing changes in cerebral blood flow and cerebral blood volume, respectively, were measured with near infrared spectrophotometry. Pulmonary artery (Q) and left carotid artery (Q) blood flow were assessed with transit time flow probes. Starting and/or stopping blood flowing through the arteriovenous loop did not cause relevant hemodynamic changes. Fast injection of isotonic saline caused a biphasic change in DeltacHbD and DeltactHb. After injection of 0.5 mL/kg, the mean (sd) increase in DeltacHbD and DeltactHb was 0.175 (0.213) micromol/L and 0.122 (0.148) micromol/L, respectively, with a subsequent mean decrease of -0.191 (0.299) micromol/L and -0.312 (0.266) micromol/L. Injection of 1.0 mL/kg caused a mean increase in DeltacHbD and DeltactHb of 0.237 (0.203) micromol/L and 0.179 (0.162) followed by a mean decrease of -0.334 (0.407) micromol/L and -0.523 (0.335) micromol/L, respectively. Q and Q changed shortly with a mean increase of 5.9 (3.0) mL/kg/min and 0.23 (0.10) mL/kg/min after injection of 0.5 mL/kg and with 12.0 (4.2) mL/kg/min and 0.44 (0.18) mL/kg/min after injection of 1.0 mL/kg, respectively. The observed changes were more profound after an injection volume of 1.0 mL/kg compared with 0.5 mL/kg for DeltacHbD (p = .06), DeltactHb (p = .09), Q, and Q (p < .01). No relevant changes in mean arterial blood pressure or heart rate were detected in response to the indicator injection. CONCLUSIONS: Cardiac output measurement by ultrasound dilution does not cause clinically relevant changes in cerebral and systemic circulation and oxygenation in a piglet model.

Cardiac output measurement using an ultrasound dilution method: a validation study in ventilated piglets.

OBJECTIVE: To assess agreement between a new method of cardiac output monitoring, using ultrasound dilution technology and ultrasound transit time-based measurement of pulmonary blood flow in a piglet model. DESIGN: Prospective, experimental juvenile animal study. SETTING: Animal laboratory of a university hospital. SUBJECTS: Nine random-bred piglets. INTERVENTIONS: After the animals received general anesthesia, we placed intravascular arterial and central venous catheters with the tip positioned in the abdominal aorta and the right atrium, respectively. The catheters were connected to the ultrasound dilution cardiac output monitor. An ultrasound transit time perivascular flow probe was positioned around the common pulmonary artery and served as the standard reference measurement. Cardiac output was manipulated during the experiment by creating hemorrhagic hypotension. Ultrasound dilution cardiac output was measured intermittently with injection volumes of 0.5 mL/kg and 1.0 mL/kg of isotonic saline at body temperature. MEASUREMENTS AND MAIN RESULTS: Ultrasound dilution cardiac output (Q) measurement was compared with pulmonary blood flow (Q). Bias, defined as Q minus Q, was calculated for each measurement. Mean bias with standard deviation was calculated for measurements with volumes of injected saline, 0.5 mL/kg and 1.0 mL/kg, and compared using the Mann-Whitney U test. Mean bias (sd) between Q and Q was 0.040 (0.132) and 0.058 (0.136) L/min for measurement with 0.5 mL/kg and 1.0 mL/kg of isotonic saline, respectively (no statistically significant difference). CONCLUSIONS: Ultrasound dilution cardiac output measurement is reliable in piglets with the use of a small volume of a nontoxic indicator (isotonic saline).

Cardiac output measurement in ventilated lambs with a significant left-to-right shunt using the modified carbon dioxide fick method.

BACKGROUND: It remains a great challenge to measure systemic blood flow in critically ill newborns. In a former study we validated the modified carbon dioxide Fick (mCO(2)F) method for measurement of cardiac output in a newborn lamb model. In this new study we studied the influence of a left-to-right shunt on the accuracy of the mCO(2)F method. OBJECTIVE: To analyze the influence of a left-to-right shunt on the agreement between cardiac output measurement with the mCO(2)F method and ultrasonic transit time pulmonary blood flow in a lamb model. METHODS: The study was approved by the Ethical Committee on Animal Research of the Radboud University Nijmegen and performed in 8 random-bred lambs. A Gore-Tex shunt was placed between the left pulmonary artery and the descending aorta. This aortopulmonary shunt was intermittently opened and closed, while cardiac output was manipulated by creating hemorrhagic hypotension. Cardiac output measurement with the mCO(2)F method (Q(mCO2F)) was compared with pulmonary blood flow obtained by a transit time ultrasonic flow probe positioned around the common pulmonary artery (Q(APC)). RESULTS: Bias, defined as Q(mCO2F) - Q(APC), was calculated for each measurement. With an open shunt there was a significant left-to-right shunt (mean Qp/Qs ratio 2.26; range 1.56-3.69). Mean bias (SD) was -12.3 (50.4) ml x kg(-1) x min(-1) and -12.3 (42.7) ml x kg(-1) x min(-1) for measurements with a closed and open shunt, respectively (no statistical significant difference). CONCLUSIONS: Cardiac output measurement with the mCO(2)F method is reliable and easily applicable in ventilated newborn lambs, also in the presence of a significant left-to-right shunt.

Changes in cerebral oxygenation and hemodynamics during cranial ultrasound in preterm infants.

OBJECTIVES: To evaluate whether application of a transducer on the anterior fontanelle during cranial ultrasound (US) examination effects cerebral hemodynamics and oxygenation in preterm infants. STUDY DESIGN*: During cranial US examination, changes in cerebral blood oxygenation (cHbD) and cerebral blood volume (CBV) were assessed using near infrared spectrophotometry (NIRS) in 76 infants (GA 30.7 (4.1)wk, BW 1423 (717)g) within two days after birth. Ten of these infants (GA 29.1 (1.6)wk, BW 1092 (455)g) were studied again at a postnatal age of one week. RESULTS*: We obtained stable and consistent NIRS registrations in 54 infants within the first two days after birth. Twenty-eight of these infants showed a decrease in cHbD (0.59 (0.54) micromol/100g) during the scanning procedure while CBV did not change. Twenty-four infants showed no changes in NIRS and 2 infants showed an atypical NIRS response during cranial US examination. At the postnatal age of one week, stable and consistent NIRS registrations were obtained in 7 infants. None of these infants showed changes in NIRS variables during cranial US examination. CONCLUSIONS: Application of an US transducer on the anterior fontanelle causes changes in cerebral oxygenation and hemodynamics in a substantial number of preterm infants. ( *values are expressed as median (interquartile range)).

Validation of transpulmonary thermodilution cardiac output measurement in a pediatric animal model.

OBJECTIVE: This study was undertaken to validate the transpulmonary thermodilution cardiac output measurement (CO(TPTD)) in a controlled newborn animal model under various hemodynamic conditions with special emphasis on low cardiac output. DESIGN: Prospective, experimental, pediatric animal study. SETTING: Animal laboratory of a university hospital. SUBJECTS: Twelve lambs. INTERVENTIONS: We studied 12 lambs under various hemodynamic conditions. Cardiac output was measured using the transpulmonary thermodilution technique with central venous injections of ice-cold saline. An ultrasound transit time perivascular flow probe around the main pulmonary artery served as the standard reference measurement (CO(UFP)). During the experiment, animals were resuscitated from hemodynamic shock using fluid boluses. Cardiac output measurements were performed throughout the experiment. MEASUREMENTS AND MAIN RESULTS: The correlation coefficient between CO(TPTD) and CO(UFP)was .97 (95% confidence interval .94-.98, p < .0001). Bland-Altman analysis showed a mean bias of 0.19 L/min with limits of agreement of -0.04 and 0.43 L/min (12.0% and +/-14.7%, respectively). The correlation coefficient between changes in CO(TPTD) and CO(UFP) during volume loading was .95 (95% confidence interval .91-.96, p < .0001). There was a significant correlation between changes in global end-diastolic volume and changes in stroke volume (r = .59) but not between changes in central venous pressure and changes in stroke volume (r = .03). CONCLUSIONS: The transpulmonary thermodilution technique is a reliable method of measuring cardiac output in newborn animals. It is also capable of tracking changes in cardiac output.

Cerebral hemodynamics and oxygenation after serial CSF drainage in infants with PHVD.

The aim of our study was to assess consecutive changes in cerebral oxygenation and hemodynamics after serial cerebrospinal fluid (CSF) drainage from a subcutaneous ventricular catheter reservoir (SVCR) in infants with PHVD. Infants with PHVD were studied during CSF drainage from a SVCR on the day of SVCR placement, half a week and one week after SVCR placement. Changes in cHbD and CBV were assessed using near infrared spectrophotometry. Time averaged peak flow velocity (TAPFV), end diastolic flow velocity (EDFV), peak systolic flow velocity (PSFV) and pulsatility index (PI) were measured before (baseline) and after CSF drainage using Doppler ultrasound. Longitudinal data analysis was performed using linear mixed models. Seven patients (GA 26.7-40.4 weeks, BW 800-4575 g) were studied. CSF drainage resulted in a statistically significant increase in CBV during each measurement. The change in CBV was maximal on the day of SVCR placement. A significant increase in cHbD and EDFV, and decrease in PI was observed after CSF drainage only on the day of SVCR placement. Baseline values of all Doppler variables improved consecutively after serial CSF removal in the first week after SVCR placement. Frequent CSF drainage results in consecutive improvement of cerebral perfusion and oxygenation in infants with PHVD.

Cardiac output measurement using a modified carbon dioxide Fick method: a validation study in ventilated lambs.

Cardiac output can be measured using a modified carbon dioxide Fick (mCO2F) method. A validation study was performed comparing mCO2F method-derived cardiac output (Q(mCO2F)) with invasively measured pulmonary blood flow. In seven randomly bred ventilated newborn lambs, cardiac output was manipulated by creating hemorrhagic hypotension. When steady state was reached, Q(mCO2F) was measured. Gas analysis was performed in simultaneously obtained arterial and venous blood samples (right atrium [RA], superior vena cava [SVC], and inferior vena cava [IVC]). Carbon dioxide exchange and pulmonary blood flow was measured continuously using a CO2SMO Plus monitor and a pulmonary ultrasonic flow probe (Q), respectively. Mean bias, defined as Q(mCO2F) - Q(ufp), was small (respectively, -0.082 L.min, -0.085 Lx min(-1) and -0.183 Lxmin(-1) for venous sampling from RA, SVC, and IVC). The limits of agreement were -0.328 to 0.164 Lxmin(-1) (RA), -0.335 to 0.165 Lxmin(-1) (SVC), and 0.415 to 0.049 Lxmin(-1) (IVC). In conclusion, measurement of cardiac output with the mCO2F method is reliable and easily applicable in ventilated newborn lambs. For clinical use, the site of venous blood sampling is of minor importance.

Effects of skin on bias and reproducibility of near-infrared spectroscopy measurement of cerebral oxygenation changes in porcine brain.

The influence of skin on the bias and reproducibility of regional cerebral oxygenation measurements is investigated using cw near-infrared spectroscopy (NIRS). Receiving optodes are placed over the left and right hemispheres of a piglet (C3, C4 EEG placement code) and one transmitting optode centrally (Cz position). Optical densities (OD) are measured during stable normo, mild, and deep hypoxemia. This is done for skin condition 1: all optodes on the skin; skin condition 2: transmitting optode on the skin and one receiving optode on the skull; and skin condition 3: all optodes on the skull. Absolute changes of oxy- (cO2Hb), deoxyhemoglobin (cHHb), and total hemoglobin (ctHb) concentrations [micromolL] are calculated from the ODs. These absolute changes are calculated for each skin condition with respect to normoxic condition. Additionally, for skin condition 2, the difference of concentration changes between receiver 1 (skull) and receiver 2 (skin) is calculated. The effect of skin removal is an average increase of attenuation changes by a factor of 1.66 (=0.51 OD) and of the concentration changes due to the arterial oxygen saturation steps by 23%. We conclude that skin significantly influences regional oxygenation measurements. Nevertheless, it is hypothesized that the estimated concentration changes are dominated by changes of the oxygenation in the brain.

Assessment of local changes of cerebral perfusion and blood concentration by near infrared spectroscopy and ultrasound contrast densitometry.

The objective of this study is to correlate regional cerebral blood concentration measurements made with near infrared spectroscopy to simultaneous local measurements of ultrasound contrast agent (CA) densitometry. Experiments were performed with piglets (7 kg) under general anesthesia. The cerebral blood flow (CBF) and volume (CBV) were changed by inducing various degrees of hypercapnia. NIRS measurements were performed with a quasi-continuous wave system, using an optode distance of 3-6 cm. The concentration changes in oxygenated and deoxygenated hemoglobin and their sum and difference (cO2Hb, cHHb, ctHb, cHbD) were continuously calculated. Ultrasound contrast agent (SF6) was administered as a short intra-venous bolus. Ultrasound equipment was used in pulse inversion second harmonic gray scale imaging mode at low transmit power setting. Three regions-of-interest (0.25 cm2) were analyzed in each image. Wash-in curves were constructed as spatial mean gray level vs. time. The variables collected with both methods changed according to the induced changes in the physiological condition. Changes in the PaCO2, pH and carotid flow induced highly correlated changes in cO2Hb, cHHb, ctHb and cHbD, and in the variables derived from CA analyses. NIRS and CA methods measure regional, respectively, local changes in CBV and CBF. Moreover, NIRS can yield complementary information about the cerebral oxygenation.

Photoacoustic determination of blood vessel diameter.

A double-ring sensor was applied in photoacoustic tomographic imaging of artificial blood vessels as well as blood vessels in a rabbit ear. The peak-to-peak time (tau(pp)) of the laser (1064 nm) induced pressure transient was used to estimate the axial vessel diameter. Comparison with the actual vessel diameter showed that the diameter could be approximated by 2ctau(pp), with c the speed of sound in blood. Using this relation, the lateral diameter could also precisely be determined. In vivo imaging and monitoring of changes in vessel diameters was feasible. Finally, acoustic time traces were recorded while flushing a vessel in the rabbit ear with saline, which proved that the main contribution to the laser-induced pressure transient is caused by blood inside the vessel and that the vessel wall gives only a minor contribution.

Ductus arteriosus with left-to-right shunt during venoarterial extracorporeal membrane oxygenation: effects on cerebral oxygenation and hemodynamics.

OBJECTIVE: To investigate the effect on cerebral oxygenation and hemodynamics of a patent ductus arteriosus with left-to-right shunt during venoarterial extracorporeal membrane oxygenation in a lamb model. DESIGN: Prospective intervention study in animals. SETTING: Animal research laboratory of a university medical center. SUBJECTS: Six anesthetized newborn lambs with patent ductus arteriosus and left-to-right shunt, installed on venoarterial extracorporeal membrane oxygenation. INTERVENTIONS: Six lambs of 140 days gestational age were prepared to keep the ductus arteriosus open by infiltration of the vessel wall with formaline 10%. The animals were installed on standard venoarterial extracorporeal membrane oxygenation. With a mechanical occluder, the ductus was closed. MEASUREMENTS AND MAIN RESULTS: Changes of mean arterial blood pressure and carotid artery blood flow were measured simultaneously. Using near infrared spectrophotometry, we calculated changes in cerebral concentration of oxyhemoglobin and deoxyhemoglobin (reflecting changes in cerebral oxygen supply) and total hemoglobin (reflecting changes in cerebral blood volume). Also, cerebral oxygen delivery before and after ductus closure was calculated. Before ductus closure there was a left-to-right shunt with a mean +/- SEM of 41 +/- 20% of total body blood flow. Closure of the ductus resulted in an immediate increase in mean arterial blood pressure and carotid artery blood flow. The concentration of oxyhemoglobin increased and the concentration of deoxyhemoglobin decreased, representing increased cerebral oxygen supply. The concentration of total hemoglobin was unchanged, representing unchanged cerebral blood volume. There was an increase in cerebral oxygen delivery. CONCLUSIONS: In this lamb model, a considerable left-to-right shunt over the ductus during venoarterial extracorporeal membrane oxygenation reduced cerebral circulation and oxygenation.