Intra-Aortic Balloon Pump Effects on Macrocirculation and Microcirculation in Cardiogenic Shock Patients Supported by Venoarterial Extracorporeal Membrane Oxygenation* Thibaut Petroni, MD1; Anatole Harrois, MD, PhD2; Julien Amour, MD, PhD3; Guillaume Lebreton, MD4; Nicolas Brechot, MD, PhD1; Sébastien Tanaka, MD2; Charles-Edouard Luyt, MD, PhD1; Jean-Louis Trouillet, MD1; Jean Chastre, MD1; Pascal Leprince, MD, PhD4; Jacques Duranteau, MD, PhD2; Alain Combes, MD, PhD1
Objectives: This study was designed to assess the effects on macrocirculation and microcirculation of adding an intra-aortic balloon pump to peripheral venoarterial extracorporeal membrane oxygenation in patients with severe cardiogenic shock and little/ no residual left ventricular ejection. Design: A prospective, single-center, observational study where macrocirculation and microcirculation were assessed with clinical-, Doppler echocardiography–, and pulmonary artery–derived hemodynamic variables and also cerebral and thenar eminence tissue oxygenation and side-stream dark-field imaging of sublingual microcirculation. Setting: A 26-bed tertiary ICU in a university hospital.
*See also p. 2143. 1 Medical-Surgical Intensive Care Unit, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, Assistance Publique– Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France. 2 Department of Anesthesiology and Critical Care Medicine, Hôpital Bicêtre, Assistance Publique–Hôpitaux de Paris, Université Paris Sud, Le Kremlin-Bicêtre, France. 3 Department of Anesthesiology and Critical Care Medicine, UMRS INSERM 956, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France. 4 Department of Cardiac Surgery, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France. Dr. Petroni received a grant support for article research and an educational grant from Assistance Publique–Hôpitaux de Paris. Dr. Luyt served as a board member for Bayer Healthcare and lectured for Novartis, MSD, and ThermoFischer Brahms. His institution received grant support from Janssen and Bayer. Dr. Combes served as board member for GAMBRO and lectured for MAQUET. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected] Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000410
Critical Care Medicine
Patients: We evaluated 12 consecutive patients before and 30 minutes after interrupting and restarting intra-aortic balloon pump. Interventions: Measurements were performed before, and 30 minutes after interrupting and restarting intra-aortic balloon pump. Measurements and Main Results: Stopping intra-aortic balloon pump was associated with higher pulmonary artery-occlusion pressure (19 ± 10 vs 15 ± 8 mm Hg, p = 0.01), increased left ventricular end-systolic (51 ± 13 vs 50 ± 14 mm, p = 0.05) and end-diastolic (55 ± 13 vs 52 ± 14 mm, p = 0.003) dimensions, and decreased pulse pressure (15 ± 13 vs 29 ± 22 mm Hg, p = 0.02). Maximum pulmonary artery-occlusion pressure reduction when the intra-aortic balloon pump was restarted was observed in the seven patients whose pulmonary artery-occlusion pressure was more than 15 mm Hg when intra-aortic balloon pump was off (–6.6 ± 4.3 vs –0.6 ± 3.4 mm Hg, respectively). Thenar eminence and brain tissue oxygenation and side-stream dark-field–assessed sublingual microcirculation were unchanged by stopping and restarting intra-aortic balloon pump. Conclusions: Restoring pulsatility and decreasing left ventricular afterload with intra-aortic balloon pump was associated with smaller left ventricular dimensions and lower pulmonary artery pressures but did not affect microcirculation variables in cardiogenic shock patients with little/no residual left ventricular ejection while on peripheral venoarterial extracorporeal membrane oxygenation. (Crit Care Med 2014; 42:2075–2082) Key Words: cardiogenic shock; extracorporeal membrane oxygenation; macrocirculation; microcirculation; pulmonary edema
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in patients with overt cardiac failure of various etiologies, for example, acute myocardial infarction (AMI) (1, 2), end-stage dilated cardiomyopathy (3), viral or toxic myocarditis (4), complications of cardiac surgery (5), or cardiac arrest (6). Because the ECMO system reinjects oxygenated blood countercurrent into the descending aorta, it increases in left ventricular (LV) afterload and, in 15–20% of the patients, is associated with severe hydrostatic pulmonary edema, one of the most feared ECMO complications (1). The latter is even more frequent in patients with little/no residual LV ejection on ECMO. In this context, hydrostatic pulmonary edema is further aggravated by mitral regurgitation induced by LV dilation and increased LV end-diastolic pressure, resulting from poor LV unloading. The intra-aortic balloon pump (IABP), which inflates during diastole and actively deflates during systole, increases coronary artery blood flow and reduces LV afterload (7). Some ECMO centers systematically combine IABP and ECMO to prevent pulmonary edema. Creating such a pseudopulsatile blood flow might improve regional microcirculation, as recently suggested (8). However, to date, no study has carefully evaluated IABP impact on general and regional hemodynamics of patients with severe cardiogenic shock on ECMO. This study was undertaken to assess IABP effects on clinical-, Doppler echocardiography–, and pulmonary artery–derived hemodynamic variables and also cerebral and thenar eminence tissue oxygenation (Sto2) and side-stream dark-field (SDF) imaging–evaluated intravital sublingual microcirculation.
METHODS Setting This study, conducted between November 2010 and October 2011 in our tertiary ICU, was approved by our hospital’s institutional review board. Informed consent was obtained from all patients or their surrogates. Patients Before installing ECMO, every patient had the following signs of acute refractory cardiogenic shock (1, 4): evidence of tissue hypoxia concomitant with adequate intravascular volume, sustained hypotension, and low cardiac index (< 2.2 L/min/m2), despite infusion of high-dose catecholamines (epinephrine > 0.2 μg/kg/min or dobutamine > 20 μg/kg/min with/without norepinephrine > 0.2 μg/kg/min). Femorofemoral venoarterial extracorporeal membrane oxygenation (VA-ECMO) was initiated because of acute refractory cardiogenic shock complicating AMI, end-stage dilated cardiomyopathy, heart surgery for acute valvular dysfunction (aortic endocarditis and aortic mechanical valve thrombosis), or fulminant myocarditis. IABP (CS100, Datascope, Maquet; Getinge Group, Lübeck, Germany) was inserted in all patients in the contralateral femoral artery. Hemodynamics was monitored via a right arterial catheter for continuous blood pressure (BP) monitoring and a pulmonary artery catheter inserted into the internal jugular vein. Only patients with no/very low (i.e., velocity-time integral [VTI] < 5 cm) residual LV ejection were included. Exclusion criteria were age less than 18 years, 2076
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intrabuccal bleeding making it impossible to acquire SDF images, and IABP or ECMO implantation contraindicated. ECMO Circuit Settings and Patients Management Under ECMO ECMO (1, 4, 9) consisted of polyvinyl chloride tubing, a membrane oxygenator (Quadrox Bioline; Jostra-Maquet, Orléans, France), a centrifugal pump (Rotaflow; Jostra-Maquet), and either percutaneous arterial and venous femoral or central right atrial and aortic cannulae (Biomedicus Carmeda; Medtronic, Boulogne-Billancourt, France). An oxygen-air blender (Sechrist Industries, Anaheim, CA) ventilated the membrane oxygenator. When percutaneous femoral ECMO was instituted, an additional 7F cannula was inserted distally into the femoral artery to prevent severe leg ischemia. Vasopressors were down-titrated to obtain a systolic BP (SBP) of 100–110 mm Hg or a mean arterial BP of 70–90 mm Hg. Unfractionated-heparin anticoagulation was used to obtain anti-factor-Xa activity of 0.2–0.4 IU/mL or activated partial thromboplastin time of 45–65 seconds. Experienced perfusionists checked the circuit daily. Study Protocol IABP impact on general and regional hemodynamic variables was assessed in three stages. IABP was set at 100% inflation and 1/1 frequency in automatic mode based on surface electrocardiogram recording. A first sequence of measurements was obtained; IABP was interrupted for 30 minutes and another sequence was obtained; and IABP was restarted for another 30 minutes prior to obtaining the third sequence. During the procedure, patients received midazolam, propofol, and fentanyl sedation and were paralyzed with pancuronium. Catecholamine infusion, ECMO, and mechanical ventilation (MV) settings were kept constant during all protocol stages, with no fluid loading. Variables Studied The following data were recorded at ECMO onset: age, sex, indication for ECMO support, initiation under cardiopulmonary resuscitation, Simplified Acute Physiology Score-2 (SAPS-2) (range, 0–174) (10), the Sepsis-Related Organ Failure Assessment (SOFA) score (11), MV status, IV inotrope use, or requiring renal replacement therapy. Hemodynamic status was assessed by measuring SBP, diastolic BP (DBP), mean arterial BP, pulse pressure (SBP – DBP), and heart rate. The pulmonary artery catheter provided pulmonary artery systolic pressure, pulmonary artery diastolic pressure, mean pulmonary artery pressures, and pulmonary artery-occlusion pressure (PAOP) (12). Patients were studied while in the supine position, zero pressure was taken as atmospheric pressure at the midaxillary line and zone of West assessed as previously described (13). All values were measured at end expiration. Blood gases were analyzed in right atrium, pulmonary artery, and peripheral artery samples. Transthoracic echocardiography was performed with an Acuson Sequoia (Siemens, Malvern, PA) and the following variables were recorded: LV end-systolic dimension (LVESD), LV end-diastolic dimension (LVEDD), LV ejection fraction September 2014 • Volume 42 • Number 9
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(LVEF), aortic VTI, cardiac output and cardiac index, transmitral early peak (E) and late (A) diastolic velocities, and spectral tissue Doppler lateral mitral annulus peak systolic (TDSa) and early diastolic (Ea) velocities (14), with E/Ea estimating LV-filling pressures (15, 16). The InSpectra Tissue oxygenation monitor (model 650; Hutchinson Technology, Hutchinson, MN) measured thenar Sto2. The near-infrared spectroscopy (NIRS) probe, with 15 mm between illumination and detection optical fibers, was placed on the thenar eminence and transferred continuously read measurements to a computer. After assuring stabilized baseline Sto2, a vascular occlusion test (VOT) was run as previously described (17). Tissue desaturation and resaturation slopes were calculated automatically with the InSpectra Analysis Program V4.00 (Hutchinson Technology), as previously described (17, 18). Although visible light penetrates tissue only short distances, near infra-red spectrum (ranging from 700 to 1,100 nm) photons are capable of deeper penetration of several centimeters or more and can also go through bones. NIRS Equanox cerebral sensors (Equanox; Nonin Medical, Plymouth, MN), each with two emitters (light-emitting diodes [LEDs] with three wavelengths in the 700–900 nm range) and two detectors to cancel out surface and shallow tissue variations to improve accuracy and repeatability of measurements, were placed on the left and right forehead to measure left and right cerebral hemisphere oxygen saturation (left and right So2) (19). SDF imaging obtained microcirculation videos of the sublingual mucosa with a video microscope (Microscan; Microvision Medical, Amsterdam, the Netherlands) containing a ring of stroboscopic LEDs (20). The SDF-imaging device is noninvasive, can be used at bedside, and yields reproducible results, with intra- and interobserver variabilities less than 10%. Images were acquired and analyzed according to international recommendations (20) with dedicated software analysis (Automated Vascular Analysis v1.0; Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands). Microscan stability was enhanced with a multiperforated sterile metal ring adapted to the tip of the probe for acquisition. Every patient had video sequences lasting more than or equal to 20 seconds obtained on five different tongue fields, avoiding pressure artifacts, using a portable computer and analog-digital video converter. Those sequences were analyzed blindly and randomly. First, a semiquantitative score, the microvascular flow index (MFI) using an ordinal scale (absent, 0; intermittent, 1; sluggish, 2; normal, 3), quantified flow in each of the four quadrants on the screen. The global MFI score is the sum of the four quadrant scores divided by the number of quadrants in which the vessel type is seen (20, 21). Second, we calculated the percentage of perfused vessels (PPV) (20, 21). Flow was categorized as present (continuous for ≥ 20 s), absent (no flow for ≥ 20 s), or intermittent (no flow for ≥ 50% of the time). PPV was calculated as follows: 100 × (total number of vessels – [no + intermittent flows])/total number of vessels. The same software measured functional capillary density (FCD) and determined the flow heterogeneity index. To determine heterogeneity of perfusion between different sublingual sites, we calculated the heterogeneity MFI index as the highest MFI of the five Critical Care Medicine
sites minus the lowest MFI of the five sites divided by the mean of the MFI of all sublingual sites. For each patient and each dataset, values obtained from the five tongue fields were averaged. Table 1. Main Characteristics of the 12 Patients Variable
Value
Range
Age, yr
57 ± 14
28–75
Men, n (%)
9 (75)
Body mass index
26.9 ± 4.6
18.3–33.8
Simplified Acute Physiology Score-2
79 ± 16
65–106
Sepsis-Related Organ Failure Assessment
16 ± 5
8–21
Days of ECMO
6.3 ± 5.9
1–21
Days of intra-aortic balloon pump
4.7 ± 4.4
1–17
At ECMO initiation
Before inclusion
Diagnosis, n (%) Acute myocardial infarction
8 (67)
Acute valvular dysfunction
2 (17)
Dilated cardiomyopathy
1 (8)
Fulminant myocarditis
1 (8)
ECMO under cardiopulmonary resuscitation
3 (25)
During study protocol ECMO flow, L/min
4.3 ± 0.9
ECMO rpm during study protocol, /min
3–5.5
3,480 ± 740 2,200–4,580
Catecholamines 7.5 ± 3.0
Dobutamine (n = 4), μg/kg/min
0.6
Norepinephrine (n = 1), mg/hr
3.0 ± 4.0
Epinephrine (n = 5), mg/hr Patients on mechanical ventilation, n (%)
0.35–10
12 (100) 5 (42)
Renal replacement therapy, n (%) ICU length of stay, d
5–10
24.9 ± 7.5
3–69
Outcomes, n (%) Recovery
3 (25)
Heart-Mate II
2 (17)
CardioWest
1 (8)
Death
6 (50)
ECMO = extracorporeal membrane oxygenation. Data are mean ± sd or number (%). www.ccmjournal.org
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Statistical Analyses Hemodynamic, Doppler echocardiography, tissue oxygenation, and SDF variable changes during the three protocol stages were compared with the Friedman statistic using StatView v5.0 software (SAS Institute, Cary, NC). p value of less than 0.05 was defined as significance.
RESULTS Study Population Clinical characteristics of the 12 patients (age 57 ± 14 yr, nine male patients) evaluated are summarized in Table 1. Mean SAPS-2 (69 ± 21, predicting death of > 62%) and SOFA score (14 ± 5) were high, reflecting disease severity at ICU admission. Among the 12 patients studied, only six were on Table 2.
vasopressors and three of them were receiving low-dose epinephrine or norepinephrine (≤ 0.7 mg/hr). When the protocol was run, all were in sinus rhythm and mechanically ventilated. They had been on ECMO for 6.3 ± 5.9 days and had an IABP inserted for 4.7 ± 4.4 days. Mean ECMO flow was 4.3 ± 0.9 L/min. Their in-ICU stays were prolonged. Three recovered normal LVEF and were weaned off ECMO, three received a long-term VAD (Heart-Mate II; Thoratec Corporation, Pleasanton, CA; for two and CardioWest [Syn Cardia systems, Tucson, AZ], for one), and six died of multiple organ failure. IABP Impact on General Hemodynamic Variables When the IABP was interrupted (Table 2), DBP and mean BP (MBP) increased, pulse pressure decreased, while heart
General Hemodynamic Variables IABP On
Heart rate
99 ± 21
101 ± 17
103 ± 20
0.07
103 ± 20
102 ± 20
100 ± 22
0.75
74 ± 17
88 ± 16
72 ± 16
0.002
87 ± 14
92 ± 16
84 ± 16
0.06
Pulse pressure (mm Hg)
29 ± 22
15 ± 13
29 ± 24
0.02
DBP increase (mm Hg)
134 ± 40
—
125 ± 26
—
LV end-diastolic dimension (mm)
52 ± 14
55 ± 13
47 ± 13c
0.003d
LV end-systolic dimension (mm)
50 ± 14
51 ± 13
42 ± 13c
0.05d
Velocity-time integral (mm)
25 ± 13
25 ± 14
26 ± 15
0.85
0.79 ± 0.46
0.77 ± 0.78
0.81 ± 0.74
0.85
Transmitral early peak (cm/s)
49 ± 19
61 ± 25
51 ± 26
0.07
Transmitral late peak (A) (cm/s)
32 ± 13
31 ± 9
31 ± 12
0.10
Systolic BP (mm Hg) DBP (mm Hg) Mean BP (mm Hg)
b
IABP Off
IABP Restart
pa
Variable
Echocardiographic data
Cardiac output (L/min) Diastolic velocity
Transmitral early/late peak
1.26 ± 0.38
1.95 ± 0.66
1.33 ± 0.36
0.003
Lateral mitral early annular (cm/s)
6.4 ± 2.8
6.4 ± 2.5
5.8 ± 1.9
0.44
Transmitral early peak/lateral mitral early annular
8.6 ± 4.0
9.8 ± 2.6
9.2 ± 4.3
0.31
Systolic mitral annulus velocity (cm/s)
4.9 ± 2.5
5.0 ± 2.9
4.9 ± 2.3
0.90
Pulmonary artery systolic pressure, mm Hg
24 ± 9
29 ± 11
23 ± 10
0.01
Pulmonary artery diastolic pressure, mm Hg
16 ± 7
19 ± 10
16 ± 9
0.04
Mean pulmonary artery pressures, mm Hg
19 ± 8
24 ± 10
19 ± 9
0.02
Pulmonary artery-occlusion pressure, mm Hg
15 ± 8
19 ± 10
15 ± 8
0.01
Central venous oxygen saturation, %
73 ± 11
73 ± 15
75 ± 12
0.43
Pulmonary artery catheter
IABP = intra-aortic balloon pump, BP = blood pressure, DBP = diastolic BP, LV = left ventricle. Dash indicates that this variable does not exist when IABP is off. a Friedman test for the comparisons of the mean ranks between the three study stages. b Mean arterial BP was calculated by the ICU bedside monitor from assisted systolic and diastolic pressures. c Data available for seven of 12 patients. d p for the comparison between IABP on and IABP off stages. Data are mean ± sd.
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healthy volunteers and comparable to those of septic shock or trauma patients (17, 18, 22–24). SDF microvascular variables (FCD, MFI, PPV, and heterogeneity MFI index) did not differ significantly among the three protocol stages (Fig. 2).
DISCUSSION The results of this pilot physiological study demonstrated that for patients on femorofemoral VA-ECMO for refractory cardiogenic shock and whose native cardiac function was almost completely abolished, IABP Figure 1. Pulmonary artery-occlusion pressure before and 30 min after interrupting and restarting intra-aortic addition to ECMO was associballoon pump (IABP) in the 12 patients on extracorporeal membrane oxygenation. The three squares represent the mean ± sd. ated with reduced LVEDD and decreased pulmonary artery BPs, rate and SBP were unchanged. Mean pulmonary SBP, DBP, without modifying microcirculation variables evaluated with and MBP and PAOP were significantly higher when IABP thenar eminence and brain NIRS and sublingual SDF imaging. was interrupted and returned to baseline values when it IABP use has been proposed for more than four decades was restarted (Fig. 1). For the seven patients whose PAOP to treat patients with severe cardiac failure by increasing diawere more than 15 mm Hg with IABP off, maximum PAOP stolic blood flow in the coronary and systemic circulations and reduction was observed when it was restarted (–6.6 ± 4.3 vs lowering cardiac afterload by the brief vacuum created by the –0.6 ± 3.4 mm Hg for the others, respectively). Furthermore, rapid end-diastolic balloon deflation (7). However, its use has with IABP off, Doppler echocardiography variables indicated a been questioned in recent years (25–27) and a large randommodest LVEDD rise and significant mitral inflow E/A increase, ized trial showed that IABP did not significantly reduce 30-day whereas the E/Ea ratio was not markedly modified, and TDSa mortality in patients with cardiogenic shock complicating AMI and Ea velocities, aortic VTI, mean Svo2, and other blood gas for whom an early revascularization strategy was planned (28). variables including lactate (not shown) were unaffected. Conversely, cardiac index is not or only mildly affected (7) and only ECMO can improve failing systemic perfusion in patients Regional Hemodynamics Variables with very low cardiac output (1, 6). However, the continuous Like right and left cerebral hemisphere rSo2 values, thenar emiflow created by the centrifugal pump increases LV afterload nence Sto2 values were within the normal range (Table 3) and and may sharply increase left ventricular end-diastolic pressure unchanged by IABP. Although unaffected by IABP, thenar tissue and induce severe pulmonary edema (1, 29), especially when desaturation and resaturation slopes were lower than those of LV ejection is null or residual, as for our patients. Table 3.
Regional Hemodynamic Variables: Tissue Oxygenation IABP On
IABP Off
IABP Restart
p
82 ± 6
79 ± 8
82 ± 6
0.41
–0.13 ± 0.06
–0.13 ± 0.06
–0.14 ± 0.08
0.56
–0.04 to –0.23
–0.02 to –0.24
–0.03 to –0.28
1.26 ± 0.76
1.28 ± 0.70
1.28 ± 0.58
0.56 to –3.20
0.67–2.55
0.57–2.95
Right, %
69.1 ± 5.3
69.4 ± 5.1
69.9 ± 5.3
0.76
Left, %
67.4 ± 5.5
68.6 ± 4.0
68.9 ± 5.3
0.24
Near-Infrared Spectroscopy
Thenar Baseline tissue oxygenation, % Tissue desaturation during VOT, %/s Range Tissue resaturation after VOT, %/s Range
0.21
Cerebral hemisphere rSo2
IABP = intra-aortic balloon pump, VOT = vascular occlusion test. Data are mean ± sd.
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Figure 2. Side-stream dark-field imaging of sublingual microcirculation: sublingual functional capillary density (FCD, cm/cm2), microcirculatory flow index (MFI), percentage of perfused vessels (PPV, %), and flow heterogeneity index before and 30 min after interrupting and restarting intra-aortic balloon pump (IABP) in the 12 patients on extracorporeal membrane oxygenation. Box plots: horizontal line inside the box is the median; lower and upper box limits are the 25th and 75th percentiles; T-bars represent the 10th and 90th percentiles.
In animal models of cardiogenic shock, IABP restoration of pulsatility improved hemodynamic variables (increased MBP, pulse pressure, cardiac output, and interventricular coronary artery flow) (30) and that pulsatility was converted into surplus hemodynamic energy (31) in swine models of profound cardiogenic shock. Combining IABP with peripherally inserted ECMO also reduced LV afterload and volume in a sheep model of acute LV ischemia (32). Our findings confirmed, in the context of patients with profound cardiogenic shock supported by peripheral VA-ECMO, that IABP adjunction increases pulsatility and reduces LVEDD and PAOP. Its effect was even more pronounced for the patient subgroup with higher (> 15 mm Hg) baseline PAOP and, 2080
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hence, might prevent severe hydrostatic pulmonary edema in this context. In patients with AMI complicated by cardiogenic shock, decreased perfused sublingual capillary density was associated with worse outcomes (33), whereas ECMO achieved three-fold increased tissue perfusion in a heterogeneous series of 10 patients with severe heart failure or cardiogenic shock (34). However, nonpulsatile continuous flow might induce microcirculatory dysfunction (35–39), perhaps by decreasing hemodynamic energy, thereby resulting in capillary collapse, microvascular shunting, and activation of inflammatory mediators in patients undergoing cardiopulmonary bypass (36). Recent observations also suggested that restoring pulsatile flow can preserve microcirculatory perfusion during extracorporeal circulation for cardiac surgery and throughout the early postoperative period, regardless of systemic hemodynamics as assessed by SDF imaging of the sublingual microcirculation (38, 39). The specific IABP impact on the microcirculation has rarely been tested. In 13 patients with severe cardiogenic shock, microflow in vessels 10–50 μm in diameter was significantly improved during IABP support (40), whereas IABP interruption did not impact on heterogeneity MFI index but paradoxically increased small vessels (< 20 μm) perfusion density independently of global hemodynamic variables and oxygenderived variables in another series of 15 patients, who had recovered from severe cardiogenic shock (41). To date, the only described flow-index improvement in 10–50-μm vessels concerned a patient evaluated during an AMI phase complicated by refractory ventricular fibrillation and receiving ECMO-IABP support (8). Our findings did not confirm that observation in 12 patients whose baseline microvascular indexes (vessel density, vessel perfusion, and microvascular heterogeneity) were already in the normal range. Possible explanations for this difference are higher ECMO blood flows in our study (unfortunately not reported for the former case) and that our patients were evaluated after a mean of 6 days on ECMO support, which may have achieved microcirculation improvement following restoration of adequate blood flow. Whether more prolonged interruption of IABP-induced pseudopulsatile flow might have resulted in sublingual microcirculation alterations will remain speculative. Parenthetically, although it had been hypothesized that long-term continuous blood flow would be associated with organ dysfunction or damage, this was not confirmed in patients who received long-term support with the newest generation continuous flow left ventricular assist devices (34, 42). Thenar eminence NIRS Sto2 measurement during a dynamic VOT can detect functional alterations in the peripheral microcirculation (17, 18, 43). The Sto2 desaturation slope and the Sto2 resaturation slope have been proposed as markers of tissue oxygen consumption and postischemic vasodilatation and capillary recruitment, respectively (17, 18, 43). Sto2 desaturation and resaturation slopes were flatter for patients with septic shock, trauma, and end-stage heart failure than for healthy controls (17, 18, 22–24), and with increasing disease severity (24, 44–46), they improved during recovery from sepsis (24) or after cardiac patients received IV inotropes (23). Sto2 September 2014 • Volume 42 • Number 9
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desaturation and resaturation rates during dynamic VOT in our patients with severe cardiogenic shock on VA-ECMO were comparable to those of patients with septic shock and trauma (17, 18, 22–24) and were unaffected by IABP interruption, suggesting persistently decreased thenar eminence oxygen consumption and vascular reserves, despite a mean of 6 days on ECMO. Furthermore, their baseline thenar eminence Sto2 and brain rSo2 were within normal ranges and unaffected by IABP, indicating adequate global tissue oxygenation on high-flow ECMO in a context of little/no residual heart function. Our pilot study has limitations. First, it was monocentric and included only 12 patients. Second, those patients had been stabilized on ECMO-IABP for several days, and therefore, macrocirculation and microcirculation variables after ECMO initiation and the impact of adding IABP for patients on ECMO alone were not evaluated. Third, IABP was interrupted for only 30 minutes, and results might be different after a longer time without it. Fourth, changes in LVEDD and LVESD during IABP on and IABP off stages were small, no interobserver variability in measurements was performed, and due to a computer technical problem, echocardiographic measurements of LVEDD and LVESD after IABP restart were only available for seven of 12 patients. Finally, only half of our patients had elevated baseline PAOP when the IABP was interrupted, indicating that not every patient with little/no residual LV function is at risk of severe hydrostatic pulmonary edema under peripheral VA-ECMO. In conclusion, restoring pulsatility and decreasing cardiac afterload with IABP in patients receiving peripheral VA-ECMO were associated with lower LVEDD and pulmonary artery pressures, without affecting microcirculation variables in cardiogenic shock patients with little/no residual LV ejection. Future randomized studies should prospectively evaluate the impact of early IABP adjunction to ECMO on short- and long-term outcomes of severe cardiogenic shock patients in this context.
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1. Combes A, Leprince P, Luyt CE, et al: Outcomes and long-term quality-of-life of patients supported by extracorporeal membrane oxygenation for refractory cardiogenic shock. Crit Care Med 2008; 36:1404–1411 2. Sheu JJ, Tsai TH, Lee FY, et al: Early extracorporeal membrane oxygenator-assisted primary percutaneous coronary intervention improved 30-day clinical outcomes in patients with ST-segment elevation myocardial infarction complicated with profound cardiogenic shock. Crit Care Med 2010; 38:1810–1817 3. Schwarz B, Mair P, Margreiter J, et al: Experience with percutaneous venoarterial cardiopulmonary bypass for emergency circulatory support. Crit Care Med 2003; 31:758–764 4. Mirabel M, Luyt CE, Leprince P, et al: Outcomes, long-term quality of life, and psychologic assessment of fulminant myocarditis patients rescued by mechanical circulatory support. Crit Care Med 2011; 39:1029–1035 5. Rastan AJ, Dege A, Mohr M, et al: Early and late outcomes of 517 consecutive adult patients treated with extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock. J Thorac Cardiovasc Surg 2010; 139:302–311, 311.e1 6. Chen YS, Lin JW, Yu HY, et al: Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: An observational study and propensity analysis. Lancet 2008; 372:554–561
Critical Care Medicine
7. Dunkman WB, Leinbach RC, Buckley MJ, et al: Clinical and hemodynamic results of intraaortic balloon pumping and surgery for cardiogenic shock. Circulation 1972; 46:465–477 8. Jung C, Lauten A, Roediger C, et al: In vivo evaluation of tissue microflow under combined therapy with extracorporeal life support and intra-aortic balloon counterpulsation. Anaesth Intensive Care 2009; 37:833–835 9. Bréchot N, Luyt CE, Schmidt M, et al: Venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock. Crit Care Med 2013; 41:1616–1626 10. Le Gall JR, Lemeshow S, Saulnier F: A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993; 270:2957–2963 11. Vincent JL, Moreno R, Takala J, et al: The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22:707–710 12. O’Quin R, Marini JJ: Pulmonary artery occlusion pressure: Clinical physiology, measurement, and interpretation. Am Rev Respir Dis 1983; 128:319–326 13. West J: Respiratory Physiology: The Essentials. Baltimore, MD, Waverly Press, 1979 14. Aissaoui N, Luyt CE, Leprince P, et al: Predictors of successful extracorporeal membrane oxygenation (ECMO) weaning after assistance for refractory cardiogenic shock. Intensive Care Med 2011; 37:1738–1745 15. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997; 30:1527–1533 16. Combes A, Arnoult F, Trouillet JL: Tissue Doppler imaging estimation of pulmonary artery occlusion pressure in ICU patients. Intensive Care Med 2004; 30:75–81 17. Mayeur C, Campard S, Richard C, et al: Comparison of four different vascular occlusion tests for assessing reactive hyperemia using nearinfrared spectroscopy. Crit Care Med 2011; 39:695–701 18. Gómez H, Torres A, Polanco P, et al: Use of non-invasive NIRS during a vascular occlusion test to assess dynamic tissue O(2) saturation response. Intensive Care Med 2008; 34:1600–1607 19. Fellahi JL, Fischer MO, Rebet O, et al: Cerebral and somatic nearinfrared spectroscopy measurements during fluid challenge in cardiac surgery patients: A descriptive pilot study. J Cardiothorac Vasc Anesth 2013; 27:266–272 20. Pottecher J, Deruddre S, Teboul JL, et al: Both passive leg raising and intravascular volume expansion improve sublingual microcirculatory perfusion in severe sepsis and septic shock patients. Intensive Care Med 2010; 36:1867–1874 21. De Backer D, Creteur J, Dubois MJ, et al: Microvascular alterations in patients with acute severe heart failure and cardiogenic shock. Am Heart J 2004; 147:91–99 22. Lima A, van Bommel J, Sikorska K, et al: The relation of near-infrared spectroscopy with changes in peripheral circulation in critically ill patients. Crit Care Med 2011; 39:1649–1654 23. Nanas S, Gerovasili V, Dimopoulos S, et al: Inotropic agents improve the peripheral microcirculation of patients with end-stage chronic heart failure. J Card Fail 2008; 14:400–406 24. Pareznik R, Knezevic R, Voga G, et al: Changes in muscle tissue oxygenation during stagnant ischemia in septic patients. Intensive Care Med 2006; 32:87–92 25. Prondzinsky R, Lemm H, Swyter M, et al: Intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: The prospective, randomized IABP SHOCK Trial for attenuation of multiorgan dysfunction syndrome. Crit Care Med 2010; 38:152–160 26. Sjauw KD, Engström AE, Vis MM, et al: A systematic review and meta-analysis of intra-aortic balloon pump therapy in ST-elevation myocardial infarction: Should we change the guidelines? Eur Heart J 2009; 30:459–468 www.ccmjournal.org
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37. Koning NJ, Atasever B, Vonk AB, et al: The effects of pulsatile cardiopulmonary bypass on microcirculatory perfusion: Perspectives from a null-result study. J Cardiothorac Vasc Anesth 2011; 25:e24; author reply e25 38. Koning NJ, Vonk AB, van Barneveld LJ, et al: Pulsatile flow during cardiopulmonary bypass preserves postoperative microcirculatory perfusion irrespective of systemic hemodynamics. J Appl Physiol (1985) 2012; 112:1727–1734 39. O’Neil MP, Fleming JC, Badhwar A, et al: Pulsatile versus nonpulsatile flow during cardiopulmonary bypass: Microcirculatory and systemic effects. Ann Thorac Surg 2012; 94:2046–2053 40. Jung C, Rödiger C, Fritzenwanger M, et al: Acute microflow changes after stop and restart of intra-aortic balloon pump in cardiogenic shock. Clin Res Cardiol 2009; 98:469–475 41. Munsterman LD, Elbers PW, Ozdemir A, et al: Withdrawing intra-aortic balloon pump support paradoxically improves microvascular flow. Crit Care 2010; 14:R161 42. Radovancevic B, Vrtovec B, de Kort E, et al: End-organ function in patients on long-term circulatory support with continuous- or pulsatile-flow assist devices. J Heart Lung Transplant 2007; 26:815–818 43. De Backer D, Hollenberg S, Boerma C, et al: How to evaluate the microcirculation: Report of a round table conference. Crit Care 2007; 11:R101 44. Mozina H, Podbregar M: Near-infrared spectroscopy during stagnant ischemia estimates central venous oxygen saturation and mixed venous oxygen saturation discrepancy in patients with severe left heart failure and additional sepsis/septic shock. Crit Care 2010; 14:R42 45. Payen D, Luengo C, Heyer L, et al: Is thenar tissue hemoglobin oxygen saturation in septic shock related to macrohemodynamic variables and outcome? Crit Care 2009; 13(Suppl 5):S6 46. Thooft A, Favory R, Salgado DR, et al: Effects of changes in arterial pressure on organ perfusion during septic shock. Crit Care 2011; 15:R222
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Objectives: This study was designed to assess the effects on macrocirculation and microcirculation of adding an intra-aortic balloon pump to peripheral venoarterial extracorporeal membrane oxygenation in patients with severe cardiogenic shock and little/ no residual left ventricular ejection. Design: A prospective, single-center, observational study where macrocirculation and microcirculation were assessed with clinical-, Doppler echocardiography–, and pulmonary artery–derived hemodynamic variables and also cerebral and thenar eminence tissue oxygenation and side-stream dark-field imaging of sublingual microcirculation. Setting: A 26-bed tertiary ICU in a university hospital.
*See also p. 2143. 1 Medical-Surgical Intensive Care Unit, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, Assistance Publique– Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France. 2 Department of Anesthesiology and Critical Care Medicine, Hôpital Bicêtre, Assistance Publique–Hôpitaux de Paris, Université Paris Sud, Le Kremlin-Bicêtre, France. 3 Department of Anesthesiology and Critical Care Medicine, UMRS INSERM 956, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France. 4 Department of Cardiac Surgery, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France. Dr. Petroni received a grant support for article research and an educational grant from Assistance Publique–Hôpitaux de Paris. Dr. Luyt served as a board member for Bayer Healthcare and lectured for Novartis, MSD, and ThermoFischer Brahms. His institution received grant support from Janssen and Bayer. Dr. Combes served as board member for GAMBRO and lectured for MAQUET. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected] Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000410
Critical Care Medicine
Patients: We evaluated 12 consecutive patients before and 30 minutes after interrupting and restarting intra-aortic balloon pump. Interventions: Measurements were performed before, and 30 minutes after interrupting and restarting intra-aortic balloon pump. Measurements and Main Results: Stopping intra-aortic balloon pump was associated with higher pulmonary artery-occlusion pressure (19 ± 10 vs 15 ± 8 mm Hg, p = 0.01), increased left ventricular end-systolic (51 ± 13 vs 50 ± 14 mm, p = 0.05) and end-diastolic (55 ± 13 vs 52 ± 14 mm, p = 0.003) dimensions, and decreased pulse pressure (15 ± 13 vs 29 ± 22 mm Hg, p = 0.02). Maximum pulmonary artery-occlusion pressure reduction when the intra-aortic balloon pump was restarted was observed in the seven patients whose pulmonary artery-occlusion pressure was more than 15 mm Hg when intra-aortic balloon pump was off (–6.6 ± 4.3 vs –0.6 ± 3.4 mm Hg, respectively). Thenar eminence and brain tissue oxygenation and side-stream dark-field–assessed sublingual microcirculation were unchanged by stopping and restarting intra-aortic balloon pump. Conclusions: Restoring pulsatility and decreasing left ventricular afterload with intra-aortic balloon pump was associated with smaller left ventricular dimensions and lower pulmonary artery pressures but did not affect microcirculation variables in cardiogenic shock patients with little/no residual left ventricular ejection while on peripheral venoarterial extracorporeal membrane oxygenation. (Crit Care Med 2014; 42:2075–2082) Key Words: cardiogenic shock; extracorporeal membrane oxygenation; macrocirculation; microcirculation; pulmonary edema
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in patients with overt cardiac failure of various etiologies, for example, acute myocardial infarction (AMI) (1, 2), end-stage dilated cardiomyopathy (3), viral or toxic myocarditis (4), complications of cardiac surgery (5), or cardiac arrest (6). Because the ECMO system reinjects oxygenated blood countercurrent into the descending aorta, it increases in left ventricular (LV) afterload and, in 15–20% of the patients, is associated with severe hydrostatic pulmonary edema, one of the most feared ECMO complications (1). The latter is even more frequent in patients with little/no residual LV ejection on ECMO. In this context, hydrostatic pulmonary edema is further aggravated by mitral regurgitation induced by LV dilation and increased LV end-diastolic pressure, resulting from poor LV unloading. The intra-aortic balloon pump (IABP), which inflates during diastole and actively deflates during systole, increases coronary artery blood flow and reduces LV afterload (7). Some ECMO centers systematically combine IABP and ECMO to prevent pulmonary edema. Creating such a pseudopulsatile blood flow might improve regional microcirculation, as recently suggested (8). However, to date, no study has carefully evaluated IABP impact on general and regional hemodynamics of patients with severe cardiogenic shock on ECMO. This study was undertaken to assess IABP effects on clinical-, Doppler echocardiography–, and pulmonary artery–derived hemodynamic variables and also cerebral and thenar eminence tissue oxygenation (Sto2) and side-stream dark-field (SDF) imaging–evaluated intravital sublingual microcirculation.
METHODS Setting This study, conducted between November 2010 and October 2011 in our tertiary ICU, was approved by our hospital’s institutional review board. Informed consent was obtained from all patients or their surrogates. Patients Before installing ECMO, every patient had the following signs of acute refractory cardiogenic shock (1, 4): evidence of tissue hypoxia concomitant with adequate intravascular volume, sustained hypotension, and low cardiac index (< 2.2 L/min/m2), despite infusion of high-dose catecholamines (epinephrine > 0.2 μg/kg/min or dobutamine > 20 μg/kg/min with/without norepinephrine > 0.2 μg/kg/min). Femorofemoral venoarterial extracorporeal membrane oxygenation (VA-ECMO) was initiated because of acute refractory cardiogenic shock complicating AMI, end-stage dilated cardiomyopathy, heart surgery for acute valvular dysfunction (aortic endocarditis and aortic mechanical valve thrombosis), or fulminant myocarditis. IABP (CS100, Datascope, Maquet; Getinge Group, Lübeck, Germany) was inserted in all patients in the contralateral femoral artery. Hemodynamics was monitored via a right arterial catheter for continuous blood pressure (BP) monitoring and a pulmonary artery catheter inserted into the internal jugular vein. Only patients with no/very low (i.e., velocity-time integral [VTI] < 5 cm) residual LV ejection were included. Exclusion criteria were age less than 18 years, 2076
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intrabuccal bleeding making it impossible to acquire SDF images, and IABP or ECMO implantation contraindicated. ECMO Circuit Settings and Patients Management Under ECMO ECMO (1, 4, 9) consisted of polyvinyl chloride tubing, a membrane oxygenator (Quadrox Bioline; Jostra-Maquet, Orléans, France), a centrifugal pump (Rotaflow; Jostra-Maquet), and either percutaneous arterial and venous femoral or central right atrial and aortic cannulae (Biomedicus Carmeda; Medtronic, Boulogne-Billancourt, France). An oxygen-air blender (Sechrist Industries, Anaheim, CA) ventilated the membrane oxygenator. When percutaneous femoral ECMO was instituted, an additional 7F cannula was inserted distally into the femoral artery to prevent severe leg ischemia. Vasopressors were down-titrated to obtain a systolic BP (SBP) of 100–110 mm Hg or a mean arterial BP of 70–90 mm Hg. Unfractionated-heparin anticoagulation was used to obtain anti-factor-Xa activity of 0.2–0.4 IU/mL or activated partial thromboplastin time of 45–65 seconds. Experienced perfusionists checked the circuit daily. Study Protocol IABP impact on general and regional hemodynamic variables was assessed in three stages. IABP was set at 100% inflation and 1/1 frequency in automatic mode based on surface electrocardiogram recording. A first sequence of measurements was obtained; IABP was interrupted for 30 minutes and another sequence was obtained; and IABP was restarted for another 30 minutes prior to obtaining the third sequence. During the procedure, patients received midazolam, propofol, and fentanyl sedation and were paralyzed with pancuronium. Catecholamine infusion, ECMO, and mechanical ventilation (MV) settings were kept constant during all protocol stages, with no fluid loading. Variables Studied The following data were recorded at ECMO onset: age, sex, indication for ECMO support, initiation under cardiopulmonary resuscitation, Simplified Acute Physiology Score-2 (SAPS-2) (range, 0–174) (10), the Sepsis-Related Organ Failure Assessment (SOFA) score (11), MV status, IV inotrope use, or requiring renal replacement therapy. Hemodynamic status was assessed by measuring SBP, diastolic BP (DBP), mean arterial BP, pulse pressure (SBP – DBP), and heart rate. The pulmonary artery catheter provided pulmonary artery systolic pressure, pulmonary artery diastolic pressure, mean pulmonary artery pressures, and pulmonary artery-occlusion pressure (PAOP) (12). Patients were studied while in the supine position, zero pressure was taken as atmospheric pressure at the midaxillary line and zone of West assessed as previously described (13). All values were measured at end expiration. Blood gases were analyzed in right atrium, pulmonary artery, and peripheral artery samples. Transthoracic echocardiography was performed with an Acuson Sequoia (Siemens, Malvern, PA) and the following variables were recorded: LV end-systolic dimension (LVESD), LV end-diastolic dimension (LVEDD), LV ejection fraction September 2014 • Volume 42 • Number 9
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(LVEF), aortic VTI, cardiac output and cardiac index, transmitral early peak (E) and late (A) diastolic velocities, and spectral tissue Doppler lateral mitral annulus peak systolic (TDSa) and early diastolic (Ea) velocities (14), with E/Ea estimating LV-filling pressures (15, 16). The InSpectra Tissue oxygenation monitor (model 650; Hutchinson Technology, Hutchinson, MN) measured thenar Sto2. The near-infrared spectroscopy (NIRS) probe, with 15 mm between illumination and detection optical fibers, was placed on the thenar eminence and transferred continuously read measurements to a computer. After assuring stabilized baseline Sto2, a vascular occlusion test (VOT) was run as previously described (17). Tissue desaturation and resaturation slopes were calculated automatically with the InSpectra Analysis Program V4.00 (Hutchinson Technology), as previously described (17, 18). Although visible light penetrates tissue only short distances, near infra-red spectrum (ranging from 700 to 1,100 nm) photons are capable of deeper penetration of several centimeters or more and can also go through bones. NIRS Equanox cerebral sensors (Equanox; Nonin Medical, Plymouth, MN), each with two emitters (light-emitting diodes [LEDs] with three wavelengths in the 700–900 nm range) and two detectors to cancel out surface and shallow tissue variations to improve accuracy and repeatability of measurements, were placed on the left and right forehead to measure left and right cerebral hemisphere oxygen saturation (left and right So2) (19). SDF imaging obtained microcirculation videos of the sublingual mucosa with a video microscope (Microscan; Microvision Medical, Amsterdam, the Netherlands) containing a ring of stroboscopic LEDs (20). The SDF-imaging device is noninvasive, can be used at bedside, and yields reproducible results, with intra- and interobserver variabilities less than 10%. Images were acquired and analyzed according to international recommendations (20) with dedicated software analysis (Automated Vascular Analysis v1.0; Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands). Microscan stability was enhanced with a multiperforated sterile metal ring adapted to the tip of the probe for acquisition. Every patient had video sequences lasting more than or equal to 20 seconds obtained on five different tongue fields, avoiding pressure artifacts, using a portable computer and analog-digital video converter. Those sequences were analyzed blindly and randomly. First, a semiquantitative score, the microvascular flow index (MFI) using an ordinal scale (absent, 0; intermittent, 1; sluggish, 2; normal, 3), quantified flow in each of the four quadrants on the screen. The global MFI score is the sum of the four quadrant scores divided by the number of quadrants in which the vessel type is seen (20, 21). Second, we calculated the percentage of perfused vessels (PPV) (20, 21). Flow was categorized as present (continuous for ≥ 20 s), absent (no flow for ≥ 20 s), or intermittent (no flow for ≥ 50% of the time). PPV was calculated as follows: 100 × (total number of vessels – [no + intermittent flows])/total number of vessels. The same software measured functional capillary density (FCD) and determined the flow heterogeneity index. To determine heterogeneity of perfusion between different sublingual sites, we calculated the heterogeneity MFI index as the highest MFI of the five Critical Care Medicine
sites minus the lowest MFI of the five sites divided by the mean of the MFI of all sublingual sites. For each patient and each dataset, values obtained from the five tongue fields were averaged. Table 1. Main Characteristics of the 12 Patients Variable
Value
Range
Age, yr
57 ± 14
28–75
Men, n (%)
9 (75)
Body mass index
26.9 ± 4.6
18.3–33.8
Simplified Acute Physiology Score-2
79 ± 16
65–106
Sepsis-Related Organ Failure Assessment
16 ± 5
8–21
Days of ECMO
6.3 ± 5.9
1–21
Days of intra-aortic balloon pump
4.7 ± 4.4
1–17
At ECMO initiation
Before inclusion
Diagnosis, n (%) Acute myocardial infarction
8 (67)
Acute valvular dysfunction
2 (17)
Dilated cardiomyopathy
1 (8)
Fulminant myocarditis
1 (8)
ECMO under cardiopulmonary resuscitation
3 (25)
During study protocol ECMO flow, L/min
4.3 ± 0.9
ECMO rpm during study protocol, /min
3–5.5
3,480 ± 740 2,200–4,580
Catecholamines 7.5 ± 3.0
Dobutamine (n = 4), μg/kg/min
0.6
Norepinephrine (n = 1), mg/hr
3.0 ± 4.0
Epinephrine (n = 5), mg/hr Patients on mechanical ventilation, n (%)
0.35–10
12 (100) 5 (42)
Renal replacement therapy, n (%) ICU length of stay, d
5–10
24.9 ± 7.5
3–69
Outcomes, n (%) Recovery
3 (25)
Heart-Mate II
2 (17)
CardioWest
1 (8)
Death
6 (50)
ECMO = extracorporeal membrane oxygenation. Data are mean ± sd or number (%). www.ccmjournal.org
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Statistical Analyses Hemodynamic, Doppler echocardiography, tissue oxygenation, and SDF variable changes during the three protocol stages were compared with the Friedman statistic using StatView v5.0 software (SAS Institute, Cary, NC). p value of less than 0.05 was defined as significance.
RESULTS Study Population Clinical characteristics of the 12 patients (age 57 ± 14 yr, nine male patients) evaluated are summarized in Table 1. Mean SAPS-2 (69 ± 21, predicting death of > 62%) and SOFA score (14 ± 5) were high, reflecting disease severity at ICU admission. Among the 12 patients studied, only six were on Table 2.
vasopressors and three of them were receiving low-dose epinephrine or norepinephrine (≤ 0.7 mg/hr). When the protocol was run, all were in sinus rhythm and mechanically ventilated. They had been on ECMO for 6.3 ± 5.9 days and had an IABP inserted for 4.7 ± 4.4 days. Mean ECMO flow was 4.3 ± 0.9 L/min. Their in-ICU stays were prolonged. Three recovered normal LVEF and were weaned off ECMO, three received a long-term VAD (Heart-Mate II; Thoratec Corporation, Pleasanton, CA; for two and CardioWest [Syn Cardia systems, Tucson, AZ], for one), and six died of multiple organ failure. IABP Impact on General Hemodynamic Variables When the IABP was interrupted (Table 2), DBP and mean BP (MBP) increased, pulse pressure decreased, while heart
General Hemodynamic Variables IABP On
Heart rate
99 ± 21
101 ± 17
103 ± 20
0.07
103 ± 20
102 ± 20
100 ± 22
0.75
74 ± 17
88 ± 16
72 ± 16
0.002
87 ± 14
92 ± 16
84 ± 16
0.06
Pulse pressure (mm Hg)
29 ± 22
15 ± 13
29 ± 24
0.02
DBP increase (mm Hg)
134 ± 40
—
125 ± 26
—
LV end-diastolic dimension (mm)
52 ± 14
55 ± 13
47 ± 13c
0.003d
LV end-systolic dimension (mm)
50 ± 14
51 ± 13
42 ± 13c
0.05d
Velocity-time integral (mm)
25 ± 13
25 ± 14
26 ± 15
0.85
0.79 ± 0.46
0.77 ± 0.78
0.81 ± 0.74
0.85
Transmitral early peak (cm/s)
49 ± 19
61 ± 25
51 ± 26
0.07
Transmitral late peak (A) (cm/s)
32 ± 13
31 ± 9
31 ± 12
0.10
Systolic BP (mm Hg) DBP (mm Hg) Mean BP (mm Hg)
b
IABP Off
IABP Restart
pa
Variable
Echocardiographic data
Cardiac output (L/min) Diastolic velocity
Transmitral early/late peak
1.26 ± 0.38
1.95 ± 0.66
1.33 ± 0.36
0.003
Lateral mitral early annular (cm/s)
6.4 ± 2.8
6.4 ± 2.5
5.8 ± 1.9
0.44
Transmitral early peak/lateral mitral early annular
8.6 ± 4.0
9.8 ± 2.6
9.2 ± 4.3
0.31
Systolic mitral annulus velocity (cm/s)
4.9 ± 2.5
5.0 ± 2.9
4.9 ± 2.3
0.90
Pulmonary artery systolic pressure, mm Hg
24 ± 9
29 ± 11
23 ± 10
0.01
Pulmonary artery diastolic pressure, mm Hg
16 ± 7
19 ± 10
16 ± 9
0.04
Mean pulmonary artery pressures, mm Hg
19 ± 8
24 ± 10
19 ± 9
0.02
Pulmonary artery-occlusion pressure, mm Hg
15 ± 8
19 ± 10
15 ± 8
0.01
Central venous oxygen saturation, %
73 ± 11
73 ± 15
75 ± 12
0.43
Pulmonary artery catheter
IABP = intra-aortic balloon pump, BP = blood pressure, DBP = diastolic BP, LV = left ventricle. Dash indicates that this variable does not exist when IABP is off. a Friedman test for the comparisons of the mean ranks between the three study stages. b Mean arterial BP was calculated by the ICU bedside monitor from assisted systolic and diastolic pressures. c Data available for seven of 12 patients. d p for the comparison between IABP on and IABP off stages. Data are mean ± sd.
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healthy volunteers and comparable to those of septic shock or trauma patients (17, 18, 22–24). SDF microvascular variables (FCD, MFI, PPV, and heterogeneity MFI index) did not differ significantly among the three protocol stages (Fig. 2).
DISCUSSION The results of this pilot physiological study demonstrated that for patients on femorofemoral VA-ECMO for refractory cardiogenic shock and whose native cardiac function was almost completely abolished, IABP Figure 1. Pulmonary artery-occlusion pressure before and 30 min after interrupting and restarting intra-aortic addition to ECMO was associballoon pump (IABP) in the 12 patients on extracorporeal membrane oxygenation. The three squares represent the mean ± sd. ated with reduced LVEDD and decreased pulmonary artery BPs, rate and SBP were unchanged. Mean pulmonary SBP, DBP, without modifying microcirculation variables evaluated with and MBP and PAOP were significantly higher when IABP thenar eminence and brain NIRS and sublingual SDF imaging. was interrupted and returned to baseline values when it IABP use has been proposed for more than four decades was restarted (Fig. 1). For the seven patients whose PAOP to treat patients with severe cardiac failure by increasing diawere more than 15 mm Hg with IABP off, maximum PAOP stolic blood flow in the coronary and systemic circulations and reduction was observed when it was restarted (–6.6 ± 4.3 vs lowering cardiac afterload by the brief vacuum created by the –0.6 ± 3.4 mm Hg for the others, respectively). Furthermore, rapid end-diastolic balloon deflation (7). However, its use has with IABP off, Doppler echocardiography variables indicated a been questioned in recent years (25–27) and a large randommodest LVEDD rise and significant mitral inflow E/A increase, ized trial showed that IABP did not significantly reduce 30-day whereas the E/Ea ratio was not markedly modified, and TDSa mortality in patients with cardiogenic shock complicating AMI and Ea velocities, aortic VTI, mean Svo2, and other blood gas for whom an early revascularization strategy was planned (28). variables including lactate (not shown) were unaffected. Conversely, cardiac index is not or only mildly affected (7) and only ECMO can improve failing systemic perfusion in patients Regional Hemodynamics Variables with very low cardiac output (1, 6). However, the continuous Like right and left cerebral hemisphere rSo2 values, thenar emiflow created by the centrifugal pump increases LV afterload nence Sto2 values were within the normal range (Table 3) and and may sharply increase left ventricular end-diastolic pressure unchanged by IABP. Although unaffected by IABP, thenar tissue and induce severe pulmonary edema (1, 29), especially when desaturation and resaturation slopes were lower than those of LV ejection is null or residual, as for our patients. Table 3.
Regional Hemodynamic Variables: Tissue Oxygenation IABP On
IABP Off
IABP Restart
p
82 ± 6
79 ± 8
82 ± 6
0.41
–0.13 ± 0.06
–0.13 ± 0.06
–0.14 ± 0.08
0.56
–0.04 to –0.23
–0.02 to –0.24
–0.03 to –0.28
1.26 ± 0.76
1.28 ± 0.70
1.28 ± 0.58
0.56 to –3.20
0.67–2.55
0.57–2.95
Right, %
69.1 ± 5.3
69.4 ± 5.1
69.9 ± 5.3
0.76
Left, %
67.4 ± 5.5
68.6 ± 4.0
68.9 ± 5.3
0.24
Near-Infrared Spectroscopy
Thenar Baseline tissue oxygenation, % Tissue desaturation during VOT, %/s Range Tissue resaturation after VOT, %/s Range
0.21
Cerebral hemisphere rSo2
IABP = intra-aortic balloon pump, VOT = vascular occlusion test. Data are mean ± sd.
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Figure 2. Side-stream dark-field imaging of sublingual microcirculation: sublingual functional capillary density (FCD, cm/cm2), microcirculatory flow index (MFI), percentage of perfused vessels (PPV, %), and flow heterogeneity index before and 30 min after interrupting and restarting intra-aortic balloon pump (IABP) in the 12 patients on extracorporeal membrane oxygenation. Box plots: horizontal line inside the box is the median; lower and upper box limits are the 25th and 75th percentiles; T-bars represent the 10th and 90th percentiles.
In animal models of cardiogenic shock, IABP restoration of pulsatility improved hemodynamic variables (increased MBP, pulse pressure, cardiac output, and interventricular coronary artery flow) (30) and that pulsatility was converted into surplus hemodynamic energy (31) in swine models of profound cardiogenic shock. Combining IABP with peripherally inserted ECMO also reduced LV afterload and volume in a sheep model of acute LV ischemia (32). Our findings confirmed, in the context of patients with profound cardiogenic shock supported by peripheral VA-ECMO, that IABP adjunction increases pulsatility and reduces LVEDD and PAOP. Its effect was even more pronounced for the patient subgroup with higher (> 15 mm Hg) baseline PAOP and, 2080
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hence, might prevent severe hydrostatic pulmonary edema in this context. In patients with AMI complicated by cardiogenic shock, decreased perfused sublingual capillary density was associated with worse outcomes (33), whereas ECMO achieved three-fold increased tissue perfusion in a heterogeneous series of 10 patients with severe heart failure or cardiogenic shock (34). However, nonpulsatile continuous flow might induce microcirculatory dysfunction (35–39), perhaps by decreasing hemodynamic energy, thereby resulting in capillary collapse, microvascular shunting, and activation of inflammatory mediators in patients undergoing cardiopulmonary bypass (36). Recent observations also suggested that restoring pulsatile flow can preserve microcirculatory perfusion during extracorporeal circulation for cardiac surgery and throughout the early postoperative period, regardless of systemic hemodynamics as assessed by SDF imaging of the sublingual microcirculation (38, 39). The specific IABP impact on the microcirculation has rarely been tested. In 13 patients with severe cardiogenic shock, microflow in vessels 10–50 μm in diameter was significantly improved during IABP support (40), whereas IABP interruption did not impact on heterogeneity MFI index but paradoxically increased small vessels (< 20 μm) perfusion density independently of global hemodynamic variables and oxygenderived variables in another series of 15 patients, who had recovered from severe cardiogenic shock (41). To date, the only described flow-index improvement in 10–50-μm vessels concerned a patient evaluated during an AMI phase complicated by refractory ventricular fibrillation and receiving ECMO-IABP support (8). Our findings did not confirm that observation in 12 patients whose baseline microvascular indexes (vessel density, vessel perfusion, and microvascular heterogeneity) were already in the normal range. Possible explanations for this difference are higher ECMO blood flows in our study (unfortunately not reported for the former case) and that our patients were evaluated after a mean of 6 days on ECMO support, which may have achieved microcirculation improvement following restoration of adequate blood flow. Whether more prolonged interruption of IABP-induced pseudopulsatile flow might have resulted in sublingual microcirculation alterations will remain speculative. Parenthetically, although it had been hypothesized that long-term continuous blood flow would be associated with organ dysfunction or damage, this was not confirmed in patients who received long-term support with the newest generation continuous flow left ventricular assist devices (34, 42). Thenar eminence NIRS Sto2 measurement during a dynamic VOT can detect functional alterations in the peripheral microcirculation (17, 18, 43). The Sto2 desaturation slope and the Sto2 resaturation slope have been proposed as markers of tissue oxygen consumption and postischemic vasodilatation and capillary recruitment, respectively (17, 18, 43). Sto2 desaturation and resaturation slopes were flatter for patients with septic shock, trauma, and end-stage heart failure than for healthy controls (17, 18, 22–24), and with increasing disease severity (24, 44–46), they improved during recovery from sepsis (24) or after cardiac patients received IV inotropes (23). Sto2 September 2014 • Volume 42 • Number 9
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desaturation and resaturation rates during dynamic VOT in our patients with severe cardiogenic shock on VA-ECMO were comparable to those of patients with septic shock and trauma (17, 18, 22–24) and were unaffected by IABP interruption, suggesting persistently decreased thenar eminence oxygen consumption and vascular reserves, despite a mean of 6 days on ECMO. Furthermore, their baseline thenar eminence Sto2 and brain rSo2 were within normal ranges and unaffected by IABP, indicating adequate global tissue oxygenation on high-flow ECMO in a context of little/no residual heart function. Our pilot study has limitations. First, it was monocentric and included only 12 patients. Second, those patients had been stabilized on ECMO-IABP for several days, and therefore, macrocirculation and microcirculation variables after ECMO initiation and the impact of adding IABP for patients on ECMO alone were not evaluated. Third, IABP was interrupted for only 30 minutes, and results might be different after a longer time without it. Fourth, changes in LVEDD and LVESD during IABP on and IABP off stages were small, no interobserver variability in measurements was performed, and due to a computer technical problem, echocardiographic measurements of LVEDD and LVESD after IABP restart were only available for seven of 12 patients. Finally, only half of our patients had elevated baseline PAOP when the IABP was interrupted, indicating that not every patient with little/no residual LV function is at risk of severe hydrostatic pulmonary edema under peripheral VA-ECMO. In conclusion, restoring pulsatility and decreasing cardiac afterload with IABP in patients receiving peripheral VA-ECMO were associated with lower LVEDD and pulmonary artery pressures, without affecting microcirculation variables in cardiogenic shock patients with little/no residual LV ejection. Future randomized studies should prospectively evaluate the impact of early IABP adjunction to ECMO on short- and long-term outcomes of severe cardiogenic shock patients in this context.
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