Sergio Baldi

Inducing placebo respiratory depressant responses in humans via opioid receptors

Several lines of evidence indicate that placebos produce analgesia through the activation of endogenous opioid systems. Recently, we showed that placebos may also produce respiratory depressant responses, a typical side‐effect of narcotics, when a subject had a prior experience of respiratory depression in the course of narcotic treatment. In the present study, we report that the placebo respiratory depression can be induced after repeated administrations of the partial opioid agonist buprenorphine. The placebo respiratory depressant effect that resulted from the buprenorphine conditioning was completely blocked by a dose of 10 mg of naloxone, indicating that it was mediated by endogenous opioids. These findings show that placebos act, via the activation of opioid receptors, not only on pain mechanisms but on the respiratory centres as well, thus mimicking a typical side‐effect of narcotics. In addition, the experimental procedure we used did not produce any expectation of respiratory depression and, similarly, the subjects did not notice any sign of respiratory discomfort. Thus, the placebo respiratory depression elicited in the present study cannot be explained on the basis of cognitive or motivational mechanisms. Rather, it appears to be a sequence effect due to learning, thus suggesting a conditioning mechanism mediated by endogenous opioids.

The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression

&NA; Although in most of the cases the placebo response appears to be unpredictable, several factors have been considered in order to explain the placebo analgesic effect. For example, it is widely recognized, albeit with little empirical evidence, that placebo analgesia is more likely to occur after a successful analgesic therapy. On the basis of this assumption, we tested the placebo response in a population of patients who were treated with buprenorphine the day before for relieving postoperative pain. However, due to the high variability of opioid responsiveness, buprenorphine was effective in some patients and poorly effective in some others. Similarly, buprenorphine produced respiratory depression with a large variability, ranging from mild depression to no effect. We found that the placebo analgesic response depended on the buprenorphine analgesic effectiveness of the previous day. Analogously, we found that a placebo respiratory depressant response was more pronounced in those patients with a respiratory depressant response to buprenorphine on the day before, irrespective of the analgesic effectiveness. These specific effects suggest that (1) the placebo effect is experience‐dependent; (2) the mechanisms underlying placebo analgesia and placebo respiratory depression are independent from each other and, by considering the role of endogenous opioids in placebo analgesia, might involve different subpopulations of opioid receptors.

Videothoracoscopic lung biopsy in the diagnosis of interstitial lung disease

OBJECTIVE Interstitial lung diseases (ILD) require lung biopsy for the diagnosis in more than 30% of patients. Open lung biopsy (OLB) was generally considered the most reliable method of biopsy and tissue diagnosis. This study tests the diagnostic accuracy and safety of the videothoracoscopic lung biopsy (VTLB) in the diagnosis of ILD. METHODS During the last 5 years, 58 patients were submitted to VTLB under general anesthesia. The mean age was 49.6 +/- 12.0 years (range 21-69). All the biopsies were performed by an endostapler EndoPath 30 or 45. Conversion to minithoracotomy was necessary in only one patient because of extensive pleural sinfisis. All the specimens were sent to the microbiology and pathology department for microbiological and histopathological diagnosis. One chest-tube (28F) was positioned and connected to a drainage-system and placed on suction. RESULTS The histopathological diagnosis was obtained for all patients and therefore the diagnostic accuracy of the procedure was 100%. No postoperative haemothorax occurred and only two patients experienced a prolonged air-leakage (3.4%). The median duration of the chest-drain was 3 days (range 1-7) and the median hospital stay was 4 days (range 2-7). CONCLUSION VTLB provides adequate specimen volume for histopathologic diagnosis and achieves a very high diagnostic accuracy (100% in our series). The postoperative morbidity and mortality rates are lower than those related to OLB. We conclude that VTLB is an effective and safe procedure in the diagnosis of ILD.

Disappearance curves of tumor markers after radical surgery.

CEA serum levels were sampled from 15 patients with lung carcinoma, 12 patients with colon carcinoma, and 5 patients with gastric carcinoma before and after radical excision of the malignancy. In addition, TPA serum levels were measured in 7 patients with lung carcinoma and CA 19.9 serum levels in 9 patients with colon carcinoma, before and after curative surgery. Irrespective of the primary malignancy, a CEA half-life of approximately 3 days was calculated. The normalization time was related to the preoperative level of the marker, being longer when the preoperative CEA level was > 20 ng/ml. The TPA half-life was slightly longer than 1 day, ranging from less than 1 day to more than 3 days, with a normalization time of about 20 days. The CA 19.9 half-life was slightly longer than 1 day with variations from less than 1 day to about 3 days. Many factors, especially associated inflammatory processes and hepatic clearance imbalances, may influence marker kinetics in the postoperative period. A correct evaluation of the clinical significance of tumor marker half-life after radical surgery will require a larger number of patients as well as careful and prolonged follow-up.

Herpesviruses Detection by Quantitative Real-Time Polymerase Chain Reaction in Bronchoalveolar Lavage and Transbronchial Biopsy in Lung Transplant: Viral Infections and Histopathological Correlation

The monitoring of herpesvirus infection plays a central role in lung transplantation (LT). Herein we evaluated the prevalence of human cytomegalovirus (HCMV), human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), and Epstein-Barr Virus (EBV) DNA in bronchoalveolar lavage (BAL) and transbronchial biopsy (TBB) specimens from LT patients. We associated the findings with the occurrence of interstitial pneumonia, acute rejection, or organizing pneumonia. Viral DNA was detected using real-time polymerase chain reaction (PCR) on 76 paired samples (BAL and TBB) from 27 patients who were receiving a universal combined prophylaxis (cytomegalovirus [CMV] immunoglobulin [Ig] + gancyclovir or valgancyclovir). Histopathological analysis was performed in accordance with the International Society for Heart and Lung Transplantation (ISHLT) criteria. Overall, HCMV results were positive in 25/76 (32.9%) specimens (BAL and/or TBB); HHV-6 in 16 (21.1%); HHV-7 in 40 (52.6%); and EBV in 13 (17.1%). Interstitial pneumonia was diagnosed in 6/76 (7.9%) cases: 5 (83.3%) were positive to HCMV (combined specimens; P < .0001); 5 (83.3%) to HHV-7; and 2 (33.3%) to EBV. An acute rejection episode was diagnosed in 19/76 (25%) cases: 7 (36.8%) were positive to HCMV; 5 (26.3%) to HHV-6; 10 (52.6%) to HHV-7, and 3 (15.8%) to EBV. No significant association was observed between virus detection or load and acute rejection. Organizing pneumonia was diagnosed in 4/76 (5.3%) cases: 1 (25%) positive to HCMV; 4 (100%) to HHV-6 (P < .05); 2 (50%) to HHV-7; and none to EBV. In conclusion, the prevalence of HCMV tended to be lower than that reported in the literature, confirming the importance of universal combined prophylaxis. HCMV was a relevant agent for interstitial pneumonia; although the small numbers limit the statistical analysis, our data did not support an association between herpesviruses and acute rejection episodes, whereas the role of HHV-6 in the pathogenesis of organizing pneumonia deserves further study. Viral detection on TBB could represent an adjunctive tool to complement that on BAL.

Ex Vivo Lung Perfusion Increases the Pool of Lung Grafts: Analysis of Its Potential and Real Impact on a Lung Transplant Program

BACKGROUND Among the strategies to increase the number of lung transplants, ex vivo lung perfusion (EVLP) represents a novel technique to expand the donor pool. METHODS Data from donors referred to our center were retrospectively analyzed to identify grafts that could potentially be potentially reconditioned by EVLP and for comparison with those obtained by clinical application of EVLP program in our center. RESULTS Among 75 rejected lungs, 23 organs have been identified as potentially treatable with EVLP with a hypothetic increase of lung transplant activity of 53%. After the introduction of the EVLP program in our center, lung transplantation with reconditioned grafts was performed in 7 (23%) patients with a 30% increase in transplant procedures. CONCLUSION Although less than expected, EVLP increased the number of lungs suitable for transplantation.

Evaluation and Significance of Cytomegalovirus-Specific Cellular Immune Response in Lung Transplant Recipients

In lung transplant recipients, cytomegalovirus (CMV) has been associated with direct ie, organ and systemic infection/disease, and indirect effects, including predisposition to develop acute rejection episodes and chronic allograft dysfunction. Cellular immune responses have been demonstrated to play a role in the control of CMV replication. We evaluated CMV-specific cellular responses among lung transplant recipients associated with the onset of organ infection/disease. Cellular responses were evaluated by an Elispot assay of 48 specimens from 24 patients. All samples were evaluated beyond 1 year after transplantation; CMV DNA was concomitantly detected in bronchoalveolar lavage (BAL) and whole blood specimens. Each patient received a combined prolonged antiviral prophylaxis with CMV Ig for 12 months and gancyclovir or valgancyclovir for 3 weeks after postoperative day 21. Nine patients (37.5%) showed transient or persistent CMV nonresponses including donor-recipient negative serologic matching in 2 cases. Positive CMV DNA results were observed in 18/48 BAL specimens (37.5%) from 12 patients (50%). A viral load of >10(4) copies/mL was observed in only 3 cases, 2 of whom were positive also on whole blood. Among these 3 patients, 2 were responders and BAL (as well as whole blood) specimens collected subsequently were negative for CMV DNA; 1 nonresponder patient exhibited a viral load of 426,492 copies/mL BAL (DNAemia, <2,000 copies/mL), developed CMV pneumonia (confirmed by histopathology and immunohistochemistry) and died within 28 days. The prevalence of CMV DNA positivity on BAL did not differ in relation to the immune response; the mean viral load on BAL showed significantly higher results among nonresponders than responders, namely, 1.4 × 10(5) ± 2.4 × 10(5) copies/ml versus 7.9 × 10(3) ± 1.4 × 10(4) (P=.02). Evaluation of CMV-specific cellular immune responses by in vitro immunologic monitoring complements virologic monitoring, helping to identify lung transplant recipients at risk of developing organ infection/disease.

Combined Cytomegalovirus Prophylaxis in Lung Transplantation: Effects on Acute Rejection, Lymphocytic Bronchitis/Bronchiolitis, and Herpesvirus Infections

Lung transplantation recipients are at high risk for herpesvirus infections. We evaluated the effect of combined cytomegalovirus (CMV) prophylaxis on CMV pneumonia, acute rejection episodes (ARE), lymphocytic bronchitis/bronchiolitis (LB), and obliterans bronchiolitis (OB) diagnosed in 180 transbronchial biopsies (TBB) of lung transplant recipients. At our center, 25 patients (control group; 1999-2002) received acyclovir for 12 months and 21 recipients (study group; 2003-2007) received combined CMV prophylaxis consisting of CMV-IG (Cytotect Biotest) for 12 months and ganciclovir or valganciclovir from postoperative day 21 for 3 weeks. Among the study group (since 2005), CMV shell vial viral culture and Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), and HHV-7 DNA were determined on BAL specimens. In the study group, the number of LB was significantly lower than in the control group (2% vs 11%; P= .04). Similar results were obtained for ARE (6% vs 17%; P= .04). No difference was observed in OB (5% vs 5%; P= .53, NS). A reduction trend was found in CMV pneumonia (2% vs 7%; P= .23, NS). Logistic regression analysis showed a relationship between prophylaxis and a reduced prevalence of ARE (odds ratio [OR] 3.25, confidence interval [CI] 1.12-9.40; P= .03). Finally, in the study group, BAL EBV-DNA positivity and EBV-CMV coinfections were low (6% and 0%, respectively) compared with other herpesviruses and with the literature. Our data suggested the efficacy of combined CMV prophylaxis to prevent ARE and LB, 2 risk factors for chronic rejection, and a possible role to reduce the trend toward CMV pneumonia and EBV infections.

Closure of an iatrogenic tracheo-esophageal fistula with bronchoscopic gluing in a mechanically ventilated adult patient

Management of acquired nonmalignant tracheo-esophageal fistula (TEF) in mechanically ventilated patients is controversial. Surgical correction is often contraindicated because the high operative risk and spontaneous closure is unlikely due to the positive pressure ventilation. We present a case of successful closure of an iatrogenic TEF in a mechanically ventilated patient with bronchoscopic application of fibrin glue. The technique may be proposed in high-risk patients as either an alternative to surgery or as a first-line attempt before surgical correction.

Single Versus Double Lung Transplantation in Pulmonary Fibrosis: A Debated Topic

Idiopathic pulmonary fibrosis (IPF) represents the second most frequent indication for lung transplantation after chronic obstructive pulmonary disease. Survival rate after transplantation is poorer compared with other lung diseases for reasons that are not completely clear. Medical therapy with anti-inflammatory drugs may improve symptoms and quality of life, but it does not influence the survival rate. Lung transplantation is the best therapy for end-stage IPF. The debate regarding the superiority of double lung transplantation (DLT) compared with single lung transplantation (SLT) is still ongoing. Until some years ago, SLT was almost uniformly utilized for this indication. In the most recent years, a larger application of DLT has been observed worldwide, probably related to higher 1-year and 5-year survivals. The unanswered question is whether it is ethical to use two lungs for the same patient, considering the donor shortage, when a single lung would suffice. Many reports have demonstrated that SLT offers acceptable pulmonary function and satisfactory early and intermediate survival. Probably DLT should be reserved for younger recipients, for those with concomitant or possible chronic infection of the contralateral lung, or cases of marginal donors. Further studies will be needed to formulate recommendations regarding the preferred surgical approach in IPF.