INTRODUCTION

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Acute right heart syndrome (ARHS) is defined as a sudden deterioration in right ventricular (RV) function that may result in systemic hypoperfusion and can often be detected by dilation of the right ventricle by echocardiography (1, 2). In the absence of RV infarction, this syndrome is consequent to an increase in pulmonary vascular resistance and hence RV afterload, usually because of vascular obstruction, e.g., pulmonary embolus, the adult respiratory distress syndrome (ARDS), external compression of the circulation by increased alveolar pressure, e.g., positive end-expiratory pressure (PEEP) in a patient with pulmonary hypertension, or vasoconstriction, e.g., hypoxic pulmonary vasoconstriction in a patient with chronic obstructive pulmonary disease (COPD) (3). ARHS may arise de novo, e.g., pulmonary embolus, but most often it is a complication of prior pulmonary hypertension that worsens in critical illness. The acute or acute-on-chronic increase in RV afterload results in increased RV end-diastolic volume and a decreased RV ejection fraction. Ultimately, severe RV dysfunction may decrease left ventricular end-diastolic volume, thus reducing left ventricular stroke volume and cardiac output. As the RV enlarges, the paradoxical motion of the interventricular septum may further compromise left ventricular filling and stroke volume (3, 4), all resulting in systemic hypoperfusion and hypotension.

Successful treatment of ARHS requires reversal of the underlying cause(s) of increased RV afterload, e.g., thrombolytic therapy for pulmonary embolus. Until such interventions take effect, critically ill patients with ARHS usually require vasoactive drug therapy to achieve and maintain hemodynamic stability (6). Recommended drugs include inotropes, -agonists, and vasodilators (9). Even in combination, however, substantial improvements in cardiovascular function have not been uniformly demonstrated. One potential problem with the use of intravenous vasodilator therapies intended to reduce RV afterload is that their action is not limited to the pulmonary circulation and these drugs often result in systemic hypotension to an undesirable degree (6).

Nitric oxide (NO) is produced by the vascular endothelium and acts on vascular smooth muscle causing vasodilation (12, 13). Because NO is rapidly inactivated by the heme component of hemoglobin, it has a relatively short half-life and its vasodilatory effects occur regionally. When given by the inhaled route, NO preferentially vasodilates the pulmonary vasculature (14, 15). Inhaled nitric oxide (iNO) has been demonstrated to decrease pulmonary artery pressures and improve oxygenation in several pulmonary diseases, including persistent pulmonary hypertension in neonates (16, 17), congenital heart disease in children (18), ARDS (19), primary pulmonary hypertension (20), and preoperative and postoperative cardiac surgery (21, 22).

By selectively decreasing pulmonary artery pressures, it has been hypothesized that iNO can decrease RV afterload and improve RV function. The effect of iNO on right ventricular function has been evaluated in patients with ARDS (23, 24). Although RV ejection fraction increased in hemodynamically stable patients with ARDS treated with iNO, increased cardiac output and enhanced tissue perfusion have not been consistently documented (23, 24). Some investigators have suggested that higher concentrations of iNO than are typically used in the treatment of ARDS might be required to improve RV function (23). In addition, most of the patients in these studies were hemodynamically stable, suggesting that right heart dysfunction was not limiting systemic perfusion. The benefit of iNO in unstable patients with evidence of RV failure has not been extensively evaluated.

Accordingly, we sought to assess the effect of iNO in critically ill patients with ARHS, excluding patients with RV infarction. Specifically, we sought to determine: (1) the response rate to iNO in patients with ARHS; (2) the degree of improvement in cardiac output with pulmonary vasodilation; (3) patient characteristics that might predict response; and (4) the dose-response relationship for iNO.

	METHODS

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This study protocol was approved by the Institutional Review Board of the University of Chicago, and informed consent was obtained from either the patient or proxy consent was obtained from a surrogate decision maker.

Twenty-six patients in whom a diagnosis of ARHS was made were enrolled from October 1994 to June 1997. Requirements for a diagnosis of ARHS were elevation of pulmonary artery pressure (> 30 mm Hg mean pressure), with echocardiographic confirmation of RV dilation in the presence of normal left ventricular size and systolic performance. Echocardiographers were blinded to the patient's enrollment in an iNO study. All patients with echocardiographic or electrocardiographic evidence of right ventricular infarction were excluded. Other exclusion criteria were age < 18 yr and pregnancy.

All patients required mechanical ventilatory support because of underlying lung disease (COPD or ARDS) or as adjunctive management for shock. During the period of study patient effort was minimal and respiratory rates were machine-determined by the use of sedation with or without muscle relaxation. All patients were adequately fluid resuscitated as judged by the right atrial and pulmonary capillary pressures. All doses of vasoactive drug and ventilator settings were maintained constant during the trial of iNO. All patients were monitored for side effects from iNO and nitrogen dioxide and methemoglobin levels were monitored.

Of the 12 patients admitted to the study with a diagnosis of ARDS, 10 were studied within 8 d of onset of acute lung injury (mean duration of criteria for ARDS = 3 d in these patients); 22 of 26 of the patients enrolled were studied within 2 to 30 h of the initiation of vasoactive drug therapy by their clinicians to treat hypotension and/or presumed hypoperfusion, and 25 of 26 of the patients were studied within 24 h of echocardiographic demonstration of right ventricular dilation.

Monitoring included a thermodilution pulmonary artery catheter (Baxter Healthcare Corp., Irvine, CA) and a radial artery catheter (Arrow International, Inc., Reading, PA). Hemodynamic measurements included central venous pressure (CVP), pulmonary capillary wedge pressure (Ppcw), mean pulmonary artery pressure (), and cardiac output (CO), which was measured in triplicate by thermodilution technique (Spacelabs Medical Inc., Redmond, WA) and recorded as a mean of three measurements. Stroke volume (SV), systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were calculated using standard formulas for their determination. Mean systemic arterial pressure () was recorded as the electronic average reported by our monitor, and heart rate (HR) was recorded from the EKG (Spacelabs Medical Inc.). Arterial blood gas sample (ABG) and mixed venous oxygen saturation were collected anaerobically and analyzed using standard blood gas electrodes (ABL 520; Radiometer, Copenhagen, Denmark). Methemoglobin levels were measured by co-oximeter (ABL 520; Radiometer).

Our source for medical grade nitric oxide gas was H-cylinders containing 800 ppm NO in nitrogen (Ohmeda, Port Allen, LA). NO flow rate was controlled by a standard oxygen flowmeter and was delivered to the inspiratory limb of the ventilator (Siemens Servo 900c; Siemens, Elema, Sweden or Puritan Bennett 7200; Puritan Bennett, Carlsbad, CA). A mixing chamber consisting of an empty humidifying system was positioned approximately 125 cm proximal to the Y connector. NO and NO₂ levels were continuously monitored via two inline sampling ports located at the Y connector (approximately 22 mm from the mouth of the patient) connected to a chemiluminescence analyzer (Sievers NOA 270B; Sievers, Boulder, CO). Daily methemoglobin levels were measured by co-oximetry (Radiometer ABL 520). Exhaled gas was continuously scavenged from the expiratory limb of the ventilator.

iNO was increased by 10 ppm increments at 20-min intervals from 10 ppm to 80 ppm. Hemodynamic and gas exchange parameters were measured at each interval. If there was a significant improvement in the patient's hemodynamics, defined as an increase in the cardiac output greater than 20% of baseline value and/or a decrease in pulmonary vascular resistance by 20% of baseline value (patients defined as RESP), iNO was discontinued and then restarted at the dose producing this response to affirm drug effect and exclude time-related changes in hemodynamics. RESP patients had iNO concentrations increased until their hemodynamic response was maximized and were then maintained at that level. After titration to an optimal iNO concentration in RESP patients vasoactive drugs were tapered if possible. Patients without response (NRESP) up to a level of 80 ppm had iNO withdrawn. Each RESP patient had iNO titrated on subsequent days to determine whether there was continued benefit of therapy. Patients were followed until hospital discharge to determine mortality.

All values are given as mean ± standard deviation. Data between groups of patients were analyzed by Student's t test. Treatment effects are reported by Wilcoxon's test for paired data to compare values recorded during treatment with baseline values. Before and after treatment data were compared using Student's t test. If there were significant differences, treatment values were compared separately with both before and after values. All tests were two-tailed. A p value < 0.05 was considered to be significant. Patients with serial discontinuation of iNO were tested by ANOVA for the parameters of interest.

	RESULTS

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Twenty-six patients were enrolled in this study. Hemodynamic and gas exchange parameters in response to iNO in all patients is displayed in Table 1. For the group as a whole, a significant increase in CO, SV, Sv_O2, Pa_O2/FI_O2, and decrease in and PVR were observed. Baseline parameters were not significantly different from those parameters obtained when iNO was discontinued. No patient experienced worsening oxygenation requiring an increase in PEEP or FI_O2.

Fourteen of 26 patients (54%) responded to iNO with > 20% increase in CO and/or decrease in PVR. Hospital mortality was high for the study group as a whole (65%) as well as for the RESP (79%) and NRESP (50%) groups. The subsets of patients identified and their attendant hospital mortalities are displayed in Figure 1. Of the 17 patients who died, five had progressive right heart failure, seven had worsening sepsis and multisystem organ failure, three were unable to be weaned from the ventilator because of progressive hypoxemia, one died of postoperative complications, and one died from gastrointestinal hemorrhage. All patients had been weaned from iNO at the time of their deaths, except for two. In these two patients iNO was discontinued as part of a general withdrawal of care and they died shortly after discontinuation of the gas.

View larger version (17K): [in this window] [in a new window]   Figure 1.   Responses to inhaled nitric oxide.

Baseline demographic and hemodynamic data for responders (RESP) and nonresponders (NRESP) are presented in Table 2. Also listed in Table 2 is the concentration of iNO associated with optimal response in the RESP group. Although two patients appeared to benefit from concentrations of iNO as high as 70 and 80 ppm, 12 of 14 patients had their best response at a concentration of 40 ppm or less. The mean duration of iNO administration in the RESP group was 87 ± 93 h (range, 2 to 288 h).

A number of patient characteristics did not differ significantly between RESP and NRESP groups, including age, underlying cause of ARHS, ventilator parameters (PEEP, minute volume, and respiratory rate), and baseline hemodynamics (, SV, PVR) (see Table 2). There was a trend toward a higher baseline PVR and lower SV in the RESP group (p = 0.15 and 0.12, respectively). The only hemodynamic variable that was significantly different between the two groups at baseline was heart rate (116 ± 22 beats/min in the RESP group, 93 ± 25 beats/min in NRESP group; p value < 0.05).

The pattern of vasoactive drug administration at baseline did differ between RESP and NRESP groups. While both groups exhibited frequent use of dobutamine and low-dose dopamine, the use of at least one -agonist (high-dose dopamine, norepinephrine, epinephrine, or phenylephrine) was significantly more frequent in the RESP group (8 of 14) than the NRESP group (1 of 12) (p = 0.006). This difference in -agonist administration between the two groups is displayed in Table 3.

Three patients in the RESP group had hemodynamic measures taken with serial discontinuations of iNO to demonstrate the reproducibility of drug effect. The changes in SV, PVR, and for these patients are shown in Figure 2. Tested by ANOVA there was p < 0.01. 

View larger version (11K): [in this window] [in a new window]   View larger version (12K): [in this window] [in a new window]   View larger version (9K): [in this window] [in a new window]   Figure 2.   Mean arterial pressure (, mm Hg) (top), stroke volume (SV; ml/min2) (middle), and pulmonary vascular resistance (PVR, dyne · s · cm5) (bottom) of three patients with serial discontinuations of inhaled nitric oxide (p value < 0.01 by ANOVA).

The hemodynamic and gas exchange parameters for the RESP group and NRESP group are shown in Tables 4 and 5, respectively. Baseline parameters were not significantly different from parameters obtained off iNO therapy in either of the two groups. decreased significantly in both groups of patients. The RESP group also had a significant increase in , CO, SV, Sv_O2, and PVR (p value < 0.05) compared with the NRESP group. Interestingly, in the RESP group, the SVR decreased from 1,062 ± 512 to 913 ± 446 dyne · s · cm⁵ (p value < 0.05). The Pa_O2/FI_O2 increased in the NRESP group from 153 ± 100 to 198 ± 105 mm Hg (p value < 0.05), but it did not change significantly in the RESP group.

The increase in CO was statistically higher in the RESP group (5.2 ± 3 to 7.2 ± 5 L/min) compared with the NRESP group (5.9 ± 3 to 5.9 ± 3 L/min). In addition, the increase in SV in the RESP group (46 ± 28 to 65 ± 47 ml/min²) compared with the NRESP group (62 ± 24 to 65 ± 24 ml/min²) as well as the decrease in PVR between the RESP group (512 ± 240 to 330 ± 202 dyne · s · cm⁵) compared with the NRESP group (361 ± 240 to 345 ± 228 dyne · s · cm⁵) were both statistically significant.

In the RESP group, a subset of patients (5 of 14) (SRESP) were able to have their vasoactive medications decreased in the first 24 h of treatment. All five patients became hemodynamically unstable upon withdrawal of iNO in the first 24 h after initiation of therapy. All of these patients were eventually weaned from iNO therapy during the course of their ICU stay. Their initial response to iNO therapy as well as their response to iNO in comparison with the other responders (partial responders, PRESP) is presented in Table 6. At baseline, the CVP was elevated in the SRESP group (19 ± 2 mm Hg) compared with the PRESP group (12 ± 4 mm Hg) (p value < 0.05). Both groups had a significant increase in their Sv_O2 and significant reductions in both the PVR and . The degree of change in (22 ± 13% in the SRESP group compared with 1.2 ± 9.1% in the PRESP group), CVP (10 ± 6% in the SRESP group compared with 4 ± 20% in the PRESP group), and PVR (46 ± 5% in the SRESP group compared with 34 ± 9% in the PRESP group) were significantly higher in the SRESP group.

	DISCUSSION

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We have demonstrated that inhaled nitric oxide significantly increased cardiac output, stroke volume, and mixed-venous oxygen saturation in patients with right ventricular dysfunction associated with shock and respiratory failure. This evidence of improved perfusion was associated with a decrease in pulmonary vascular pressures and resistance. In a subset of approximately 50% of patients these changes were substantial (> 20%), and in approximately 25% of all patients the improvement in hemodynamic measures permitted a decrease in other vasoactive drug administration. The mean concentration of iNO required to achieve these effects was 35 ppm, and 85% of patients exhibited a substantial improvement in hemodynamics at a concentration of iNO of less than or equal to 40 ppm. Underlying causes of right heart failure and baseline hemodynamics did not predict response to iNO, but the use of -agonist catecholamines did.

Because this study was intended as a pilot investigation and we did not wish to deny patients access to a possible salvage therapy, a randomized design was not utilized. Thus, it could be argued that a major pitfall of this study is the lack of randomization and blinding, making it possible that time-related changes in hemodynamics or observer bias could undermine validity of results. We do not believe these are significant concerns, however. The protocol used provided for a discontinuation of iNO to confirm that patients returned to their baseline values, thus demonstrating consistent hemodynamics and gas exchange over the period of observation. For the group as a whole (see Table 1), for responders (see Table 4), and for nonresponders (see Table 5), there was no difference in any baseline value caused by time alone. In addition, in a subset of patients iNO was repeatedly turned on and off (see Figure 2) to demonstrate the reproducibility of drug effect. Finally, we would argue that the primary measurements made derive from thermodilution cardiac output, electronic averaging of pressure waveforms, and arterial blood gas determination and are thus not prone to large observer bias.

The improvement we observed in cardiac output after treatment with iNO is contrary to the results of many prior studies. In patients with ARDS (19, 23), stable pulmonary hypertension (20), biventricular failure (21), and stable COPD (30), iNO has been shown to reliably decrease pulmonary artery pressures and pulmonary vascular pressures. In none of these investigations, however, did stroke volume and cardiac index increase significantly. Some of these studies differ from the present investigation in terms of the concentration of iNO used, but there is significant overlap in effective iNO dosing between those studies and our own, and we do not believe that this simple difference explains the disparity in observations. Rather, it is most likely that the stable ambulatory patients or the patients with ARDS treated with iNO for severe hypoxemic respiratory failure did not have right ventricular functional impairment to the degree of our patient population. The majority of our patients had a mean systemic blood pressure < 90 mm Hg and 20 of 26 of these patients were deemed by their clinicians to require vasoactive drug support with either inotropes, vasoconstrictors, or both. Most importantly, all of the patients in our study had clear echocardiographic evidence of right ventricular dysfunction and failure. None of the studies indicating minimal effect of iNO on cardiac output or stroke volume included such assessment.

A number of studies do suggest that afterload reduction of the pulmonary circulation with iNO can significantly improve right ventricular function. When administered to hemodynamically stable patients with ARDS, iNO has been shown to reduce right ventricular end-diastolic volume and to increase right ventricular ejection fraction (23, 24). Girard and colleagues (22) demonstrated iNO increased mixed venous oxygen saturation and decreased arterial-venous oxygen content difference in patients with pulmonary hypertension after mitral valve replacement. In patients with chronic pulmonary hypertension, Sitbon and colleagues (20) identified a subset of patients with chronic pulmonary hypertension who responded to 40 ppm iNO with a small but significant increase in stroke volume. Puybasset and colleagues (31) reported that in patients with ARDS treated with ventilator strategies resulting in permissive hypercapnea, iNO increased cardiac output significantly above the level incremented by the permissive hypercapnea itself. Thus, patients can demonstrate improved right ventricular function in response to iNO. We speculate that the rather large effects of afterload reduction seen in our patients relates to the severity of baseline dysfunction.

The only patient characteristic that appeared to correlate with a substantial response to iNO in this trial was concurrent administration of vasoactive drugs with significant -agonist activity. These drugs were not administered by specific protocol and the agent(s) selected and the dose were determined by the primary care ICU team. In general, patients with right heart syndrome in our facility are managed with fluids, inotropic support, and then, if systemic hypotension persists, vasoconstrictor administration. It is possible that the administration of -agonists was simply a marker for the more compromised patients, and that right ventricular dysfunction in these patients was more amenable to treatment with iNO, explaining their greater preponderance in the response group. Alternatively, the vasoconstrictors had a significant effect on the pulmonary circulation resulting in an increase in right ventricular afterload that could be ameliorated by iNO. This is an attractive formulation for management of these patients since some investigations have shown that use of vasoconstrictors in shock caused by right ventricular failure improve right ventricular myocardial perfusion and resolve ischemia (10, 11). Combining these drugs with the selective pulmonary vasodilator iNO could represent an ideal means of improving right ventricular perfusion while maximizing stroke volume with afterload reduction.

Because our measurements of cardiac output were based on thermodilution technique from a pulmonary artery catheter, some may argue that changes in fraction or pattern of regurgitant flow across the tricuspid valve related to changes in right ventricular end-diastolic volume during iNO treatment may cause inaccuracies in the measurement of cardiac output. Although this is a legitimate concern when interpreting thermal dilution cardiac output measurements in isolation, the changes in mixed venous oxygen saturation (Sv_O2) clearly confirm the improvement in cardiac output seen in each group. The RESP group had a significant improvement in Sv_O2 (66 ± 9 to 72 ± 10%) compared with the NRESP group (72 ± 6 to 74 ± 9%). This response was even greater in the SRESP patients (64 ± 8 to 74 ± 7%) compared with the PRESP (68 ± 10 to 71 ± 12%), suggesting that patients with the least adequate perfusion had the greatest response to iNO.

Interestingly, the SVR in the RESP group was significantly reduced on iNO. This phenomenon has not been previously described. This decrease in SVR is likely a result of an increase in cardiac output that is relatively greater than the increase in systemic blood pressure, as opposed to any action of iNO on the systemic circulation. Nonetheless, we cannot exclude the latter possibility, and there have been recent reports that a form of hemoglobin, S-nitroso-hemoglobin, that could form during iNO may be a NO donor systemically (32).

The mortality of our patients was high, as expected for patients with shock and respiratory failure. Mortality was higher in the patients classified as responders, but not to a statistically significant degree. The design of the study does not permit rigorous interpretation of these findings, lacking a control arm not receiving iNO.

In summary, we report that inhaled nitric oxide causes a significant increase in stroke volume and cardiac output in patients with severe right heart dysfunction secondary to pulmonary hypertension. A majority of patients demonstrated a substantial improvement in hemodynamics that is likely of clinical significance in terms of acute management of their hypoperfused state. Echocardiography appears to be an excellent screening tool for identifying a patient group with the potential to benefit from iNO. The effect of these changes in acute physiologic derangements on long-term outcome is not clear and requires further investigation.