Hemodynamic effects of inhaled aerosolized iloprost and inhaled nitric oxide in heart transplant candidates with elevated pulmonary vascular resistance.

OBJECTIVE: An elevated pulmonary vascular resistance (PVR) is described as a predictor of postoperative right heart failure and increased mortality in patients undergoing orthotopic heart transplantation. The use of intravenous vasodilators is limited by their systemic effects. We evaluated the pulmonary and systemic hemodynamic effects of inhaled nitric oxide (NO) and inhaled aerosolized iloprost (IP) in heart transplant candidates with elevated PVR. METHODS: Fourteen male heart transplant candidates due to dilative or ischemic cardiomyopathia with elevated PVR (> or = 180 dyn s cm(-5)) were included in the study. Increasing concentrations of NO (5, 10 and 30 ppm) and 50 microg aerosolized IP were administered by inhalation. Hemodynamic measurements preceded and followed administration of each agent. RESULTS: Inhalation of IP, 10, and 30 ppm NO reduced PVR and mean pulmonary artery pressure (MPAP), but did not affect blood pressure or systemic vascular resistance. Comparing the effectiveness of 10 ppm NO and IP, we found a significant higher reduction of MPAP in patients treated with IP. An increase of cardiac index and stroke index could only be shown with IP-inhalation. CONCLUSIONS: Inhaled iloprost induces pulmonary vasodilation which is significantly greater than the effects of 10 and 30 ppm NO. The results of our study show, that inhaled iloprost induces a reliable hemodynamic response in the evaluation of heart transplant candidates. Further advantages of iloprost inhalation are the lack of adverse reactions and toxic side effects and an easier administration. Due to this facts we recommend iloprost as a routine screening drug for vascular reactivity in HTx-candidates. Based on our results it would be of great interest to investigate the role of iloprost in management of postoperative right heart insufficiency following cardiac transplantation.     

Pulmonary toxicity of inhaled aerosolized prostacyclin therapy--an observational study

Large white/landrace piglets (mass 11 to 21 kg) were exposed to aerosolized alkaline glycine diluent (n = 2) or inhaled aerosolized prostacyclin (n = 2) for five to eight hours. Pigs receiving these aerosols developed mild acute sterile tracheitis, involving the superficial layers of the trachea, shown histologically and ultrastructurally. Pigs receiving the diluent aerosol also showed mild inflammatory changes in the bronchioles. These findings suggest caution with the use of high volumes of aerosolized alkaline glycine diluent during inhaled aerosolized prostacyclin therapy.     

Searching the ideal inhaled vasodilator: from nitric oxide to prostacyclin

Today, the technique to directly administer vasodilators via the airway to treat pulmonary hypertension and to improve pulmonary gas exchange is widely accepted among clinicians. The flood of scientific work focussing on this new therapeutic concept had been initiated by a fundamental new observation by Pepke-Zaba [1]and Frostell in 1991 [2]: Both scientists reported, that inhalation of exogenous nitric oxide (NO) gas selectively dilates pulmonary vessels without a concomittant systemic vasodilation. No more than another decade ago NO was identified as an important endogenous vasodilator [3]while having merely been regarded an environmental pollutant before that time. Although inhaled NO proved to be efficacious, alternatives were sought-after due to NO's potential side-effects. In search for the ideal inhaled vasodilator another group of endogenous mediators -- the prostanoids -- came into the focus of interest. The evidence for safety and efficacy of inhaled prostanoids is -- among a lot of other valuable work -- based on a series of experimental and clinical investigations that have been performed or designed at the Institute for Surgical Research under the guidance and mentorship of Prof. Dr. med. Dr. h.c. mult. K. Messmer [4-19]. In the following, the current and newly emerging clinical applications of inhaled prostanoids and the experimental data which they are based on, will be reviewed.     

Hemodynamic effects of inhaled nitric oxide in four patients with severe liver disease and pulmonary hypertension

Patients with moderate and severe pulmonary hypertension have a very high mortality rate when undergoing orthotopic liver transplantation. Because nitric oxide has been successful in reducing pulmonary artery pressures in certain patients with pulmonary hypertension, the efficacy of NO inhalation (40 and 80 ppm) in 4 patients with pulmonary hypertension associated with liver disease was determined. No clinically significant changes in pulmonary artery pressures or other hemodynamic parameters were observed using either concentration of NO. In conclusion, no pulmonary vasodilatory response from inhalation of NO in 4 patients with severe liver disease and pulmonary hypertension was found. (Liver Transpl Surg 1997 Nov;3(6):594-7)     

Intravenous prostacyclin mitigates inhaled nitric oxide rebound effect: A case control study

Although extracorporeal membrane oxygenation (ECMO) improves oxygenation, pulmonary vascular resistance may be increased due to endothelial function impairment. Inhaled nitric oxide (iNO) is increasingly used for treatment of pulmonary hypertension after surgical repair of congenital heart defects, with or without ECMO. One of the main complications of its application is deterioration of oxygenation following withdrawal of iNO. To test whether intravenous prostacyclin applied prior to and during iNO withdrawal can mitigate this rebound effect, we conducted a retrospective case control study. The rebound effect was defined as a 5% decrease of oxygenation saturation within 4 h after iNO withdrawal. Twelve children suffering from pulmonary hypertension (2 after ECMO) and treated with iNO received 10 ng/kg/min prostacyclin intravenously 24 h prior to iNO withdrawal (Group 1). Twelve children treated with iNO (3 after ECMO) who received no prostacyclin prior to iNO withdrawal were matched as controls. The rebound effect occurred in 1 out of 12 children in Group 1 and in 8 out of 12 children in Group 2 (p = 0. 0039). We conclude that application of intravenous prostacyclin prior to and during iNO withdrawal may be able to mitigate the rebound effect.     

吸入一氧化氮加强牛肺表面活性剂替代治疗的疗效

目的 研究吸入一氧化氮对牛肺泡表面活性剂替代治疗肺灌洗大鼠时疗效的影响。方法 ６４只ＳＤ大鼠经气管导管反复肺灌洗至ＰａＯ２〈１３．４ｋＰａ和ＰａＣＯ２〉８．０ｋＰａ,随机分成对照组,ＢＰＳ２５ｍｇ／ｋｇ组,ＢＰＳ５０ｍｇ／ｋｇ组,ＢＰＳ１００ｍｇ／ｋｇ组,各组分ａ,ｂ,两亚组,未吸ＮＯ为ａ,ＮＯ吸入为ｂ。观察用药后ＰａＯ２,ＰａＣＯ２,肺压力－容量环及肺实质密度变化。     

Hemodynamic changes during hemodialysis: role of nitric oxide and endothelin

BACKGROUND: Etiology of dialysis induced hypotension and hypertension remains speculative. There is mounting evidence that nitric oxide (NO) and endothelin (ET-1) may play a vital role in these hemodynamic changes. We examined the intradialytic dynamic changes in NO and ET-1 levels and their role in the pathogenesis of hypotension and rebound hypertension during hemodialysis (HD). METHODS: The serum nitrate + nitrite (NT), fractional exhaled NO concentration (FENO), L-arginine (L-Arg), NGNG-dimethyl-L-arginine (ADMA) and endothelin (ET-1) profiles were studied in 27 end-stage renal disease (ESRD) patients on HD and 6 matched controls. The ESRD patients were grouped according to their hemodynamic profile; Group I patients had stable BP throughout HD, Group II had dialysis-induced hypotension, and Group III had intradialytic rebound hypertension. RESULTS: Pre-dialysis FENO was significantly lower in the dialysis patients compared to controls (19.3 +/- 6.3 vs. 28.6 +/- 3.4 ppb, P < 0.002). Between the experimental groups, pre-dialysis FENO was significantly higher in Group II (24.1 +/- 6.7 ppb) compared to Group I (17.8 +/- 5.6 ppb) and Group III (16.1 +/- 4.2 ppb; P < 0.05). Post-dialysis, FENO increased significantly from the pre-dialysis values (19.3 +/- 6.3 vs. 22.6 +/- 7.9 ppb; P=0.001). Pre-dialysis NT (34.4 +/- 28.2 micromol/L/L) level was not significantly different from that of controls (30.2 +/- 12.3 micromol/L/L). Serum NT decreased from 34.4 +/- 28.2 micromol/L/L at initiation of dialysis to 10.0 +/- 7.4 micormol/L/L at end of dialysis (P < 0.001). NT concentration was comparable in all the three groups at all time points. Pre-dialysis L-Arg (105.3 +/- 25.2 vs. 93.7 +/- 6.0 micromol/L/L; P < 0.05) and ADMA levels were significantly higher in ESRD patients (4.0 +/- 1.8 vs. 0.9 +/- 0.2 micromol/L/L; P < 0.001) compared to controls. Dialysis resulted in significant reduction in L-Arg (105.3 +/- 25.2 vs. 86.8 +/- 19.8 micromol/L/L; P < 0.005) and ADMA (4.0 +/- 1.8 vs. 1.6 +/- 0.7 micromol/L/L; P < 0.001) concentrations. Pre-dialysis ET-1 levels were significantly higher in ESRD patients compared to the controls (8.0 +/- 1.9 vs. 12.7 +/- 4.1 pg/mL; P < 0.002), but were comparable in the three study groups. Post-dialysis ET-1 levels did not change significantly in Group I compared to pre-dialysis values (14.3 +/- 4.3 vs.15.0 +/- 2.4 pg/mL, P=NS). However, while the ET-1 concentration decreased significantly in Group II (12.0 +/- 4.0 vs. 8.7 +/- 1.8 pg/mL, P < 0.05), it increased in Group III from pre-dialysis levels (12.8 +/- 3.8 vs. 16.7 +/- 4.5 pg/mL, P=0.06). CONCLUSION: Pre-dialysis FENO is elevated in patients with dialysis-induced hypotension and may be a more reliable than NT as a marker for endogenous NO activity in dialysis patients. Altered NO/ET-1 balance may be involved in the pathogenesis of rebound hypertension and hypotension during dialysis.     

Use of inhaled nitric oxide in British intensive therapy units

The use of inhaled nitric oxide in the critically ill has increased significantly over the past few years but little published information exists on standards for current practice. Sixty-four intensive therapy units in the UK were surveyed by questionnaire from which 54 (84.4%) satisfactory replies were received. We present the survey results and put forward recommendations based on current literature and our own clinical experience for the safe use of inhaled nitric oxide.      

The combination of inhaled nitric oxide and pulmonary artery balloon inflation improves oxygenation during whole-lung lavage

We present a case in which the use of inhaled nitric oxide associated with temporary partial unilateral pulmonary artery occlusion further improved oxygenation during whole-lung lavage. This is the first case in the literature describing the simultaneous use of these two modalities.     

Predictability model of the need for extracorporeal membrane oxygenation in neonates with meconium aspiration syndrome treated with inhaled nitric oxide

Background

As the use of inhaled nitric oxide (iNO) resulted in a decline in the need for extracorporeal membrane oxygenation (ECMO) in neonates with hypoxic respiratory failure, iNO has become an accepted treatment modality even in non-ECMO centers. However, because not all neonates respond to iNO, the timely identification and transfer of nonresponders to an ECMO center are important.

Objectives

The objective of this study was to identify the risk factors predictive of the need of ECMO in neonates with hypoxic respiratory failure after the first 6 hours of iNO treatment in an ECMO center.

Methods and Patient Population

Forty-nine patients with hypoxic respiratory failure transferred for iNO therapy and potential ECMO during a 2-year period were identified in this retrospective study. None of the patients had received iNO before admission. Strict clinical guidelines were used to standardize lung inflation, cardiovascular support, and iNO administration and weaning and to define treatment failure. The relationship between treatment failure (ie, the need for ECMO) and a set of suspected risk factors after 6 hours of iNO administration was examined by logistic regression analysis.

Results

Twenty-two neonates responded to iNO (non-ECMO group) whereas 27 neonates failed and met ECMO criteria (ECMO group). There was no difference between the 2 groups in demographic data, ventilatory support, air leak syndrome at 6 hours of iNO treatment, and survival to discharge. However, the dose and duration of iNO therapy were predictive of the need for ECMO with an adjusted odds ratio of 1.12 (95% CI, 1.01-1.25; P = .04) and 0.45 (95% CI, 0.27-0.65; P = .0002), respectively.

Conclusions

By the end of the first 6 hours of iNO treatment and under the specific conditions established by the use of the clinical guidelines, the dose and the duration of iNO administration were predictive of the probability for the need of ECMO in this patient population. Thus, one can establish a center-specific predictability model for the need of ECMO in neonates with hypoxic respiratory failure treated with iNO if strict clinical guidelines for iNO administration and weaning and respiratory and cardiovascular support are used in the given center.