Koen J. Hartemink

Immunoparalysis as a cause for invasive aspergillosis

Aspergillus infections are among the most feared opportunistic infections in humans. These organisms are ubiquitous in nature; protection against infection is usually provided by anatomical barriers and by the immune system. Tissue invasion by Aspergillus is uncommon, occurring primarily in the setting of immunosuppression. The prognosis of invasive aspergillosis is very poor. Although it is widely recognised that critically ill patients in the Intensive Care Unit (ICU) are at risk for nosocomial infections, it is not generally appreciated that such patients may also be at risk for opportunistic infections usually seen only in immunocompromised patients. This might be explained by a biphasic immunological pattern during sepsis: an early hyperinflammatory phase followed by an anti-inflammatory response, leading to a hypo-inflammatory state, the so-called compensatory anti-inflammatory response syndrome (CARS or immunoparalysis). We describe four patients admitted to our ICU for various reasons, without a history of abnormal immune function, who developed invasive pulmonary aspergillosis. We hypothesise that the occurrence of these opportunistic infections in our patients may have been due to immunoparalysis, and that perhaps all ICU patients with sepsis and multiple organ dysfunction syndrome (MODS) may be at risk for opportunistic infections such as aspergillosis as a result of this syndrome. Physicians treating critically ill patients in the ICU should be aware of the CARS/immunoparalysis syndrome and its potential to cause opportunistic infections, even in patients with normal immune function prior to ICU admission.

Diaphragm Muscle Fiber Weakness and Ubiquitin–Proteasome Activation in Critically Ill Patients

RATIONALE The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood. OBJECTIVES We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm. METHODS We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation. MEASUREMENTS AND MAIN RESULTS Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation. CONCLUSIONS These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.

α-atrial natriuretic peptide, cyclic guanosine monophosphate, and endothelin in plasma as markers of myocardial depression in human septic shock

OBJECTIVE To assess the value of alpha-atrial natriuretic peptide (alpha-ANP), second messenger cyclic guanosine monophosphate (cGMP,) and endothelin as markers of myocardial depression in septic shock. DESIGN Prospective observational study. SETTING Medical intensive care unit (ICU) of a university hospital. PATIENTS Fourteen consecutive patients with septic shock and arterial and pulmonary artery catheters in place. MEASUREMENTS AND MAIN RESULTS Hemodynamic variables and plasma levels of alpha-ANP, cGMP, and endothelin were measured every 6 hrs for 3 days after admission. Eight patients died from shock in the ICU. The nadir left ventricular stroke work index (LVSWI) was below 35 g/m2 in all patients, and the median peak circulating alpha-ANP (n < 68 pg/mL) was 276 pg/mL (range, 79-1056), the median peak cGMP (n < 2.1 ng/mL) was 8.1 ng/mL (range, 3.2-29.7), and the median peak endothelin (n < 5.3 pg/mL) was 15.5 pg/mL (range, 8.5-33.9), supranormal in all patients. Outcome groups differed in the course of cardiac index and LVSWI, which were lower in nonsurvivors despite similar filling pressures and more intensive inotropic treatment (p < .01). The course of alpha-ANP, cGMP, and endothelin plasma levels also differed between groups, with higher levels in nonsurvivors (p < .05). As for pooled data, the mean daily or nadir LVSWI inversely related to mean daily or peak alpha-ANP, cGMP, and endothelin levels, respectively (p < .05). The area under the receiver operating characteristic curve for myocardial depression (LVSWI < 35 g/m2) was for alpha-ANP and endothelin 0.77, and for cGMP 0.85 (p < .01). The optimum cutoff values for alpha-ANP, cGMP, and endothelin were 172 pg/mL, 4.5 ng/mL, and 10.0 pg/mL, respectively. The sensitivity for myocardial depression of alpha-ANP, cGMP, and endothelin was 68%, 77%, and 72%, and the specificity was 82%, 93%, and 69%, respectively. CONCLUSIONS Circulating alpha-ANP, endothelin, and, particularly, cGMP may be markers of the myocardial depression of human septic shock, which is associated with mortality.

Diaphragm fiber strength is reduced in critically ill patients and restored by a troponin activator

To the Editor: Diaphragm weakness in the intensive care unit (ICU) plays an important role in difficult weaning from mechanical ventilation. Diaphragm strength in mechanically ventilated (MV) critically ill patients has been assessed indirectly using phrenic nerve stimulation, which demonstrated that the pressure-generating capacity of the diaphragm was reduced in these patients (1–3). However, this technique cannot distinguish between impaired phrenic nerve function, abnormal neuromuscular transmission, and intrinsic abnormalities in the diaphragm muscle itself. Consequently, it is unknown whether intrinsic contractile weakness of diaphragm muscle fibers occurs in MV critically ill patients. If so, targeted treatment strategies that enhance contractility may improve the success of weaning. Such treatment strategies may include the administration of a novel class of small-molecule drugs, named fast skeletal troponin activators, which improve the contractile strength of skeletal muscle fibers (4). In this study, we obtained diaphragm biopsy specimens from critically ill patients (n = 10; MV for 28–603 h) undergoing laparotomy or thoracotomy, and compared them with control patients undergoing elective lung surgery (n = 10; MV 1–2 h, see Table E1 in the online supplement). The size and the contractile performance of isolated diaphragm muscle fibers were determined. In addition, we tested the ability of the fast skeletal troponin activator, CK-2066260, to improve contractile strength. Diaphragm fiber cross-sectional area (CSA) was determined by means of immunohistochemical analyses with myosin heavy chain antibodies performed on cryosections of the biopsy specimens (5, 6). Figure 1A demonstrates atrophy of slow- and fast-twitch diaphragm fibers in critically ill patients (CSA slow-twitch fibers: control patients, 3,284 ± 793 μm2 vs. critically ill patients, 2,328 ± 763 μm2, P = 0.004; fast-twitch fibers: control patients, 2,766 ± 606 μm2 vs. critically ill patients, 1,819 ± 527 μm2, P < 0.0001). Figure 1. (A) Severe diaphragm muscle fiber atrophy in mechanically ventilated (MV) critically ill patients. Typical examples of serial diaphragm cross-sections stained with antibodies against slow-twitch myosin heavy chain (green). Wheat germ agglutinin (WGA) ... We measured the contractile performance of permeabilized single diaphragm fibers isolated from the biopsy specimens. Fibers were mounted between a force transducer and a length motor, and exposed to activating calcium solutions. Maximal contractile strength was markedly lower in critically ill patients (absolute force slow-twitch fibers: control patients, 0.44 ± 0.16 mN vs. critically ill patients, 0.19 ± 0·07 mN, P < 0.0001; fast-twitch fibers: control patients, 0.49 ± 0.21 mN vs. critically ill patients, 0.24 ± 0.09 mN, P = 0.0002; Figure 1B). After normalization of force to the CSA of these fibers (i.e., specific force), a deficit remained in diaphragm fibers of critically ill patients (see Figure E1). This suggests that, in these critically ill patients, there is not only a loss of contractile proteins, but also dysfunction of the remaining ones. In addition, we measured the sensitivity of force to calcium. The negative logarithm of the calcium concentration needed to obtain 50% of maximal force (pCa50) was unaffected in slow-twitch fibers (control patients, 5.64 ± 0.03 vs. critically ill patients, 5.61 ± 0.08, P = 0.30), whereas, in fast-twitch fibers, the pCa50 was significantly lower in critically ill patients (control patients, 5.76 ± 0.07 vs. critically ill patients, 5.70 ± 0.06, P = 0.036) (Figure 1B). Thus, fast-twitch diaphragm fibers from critically ill patients not only have reduced maximal force, but also require more calcium to generate force. We exposed diaphragm fibers of a representative subset of control patients (nos. I, IV, VI) and critically ill patients (nos. 1, 3, 4, 5) to the fast skeletal troponin activator, CK-2066260, which improves the sensitivity of the calcium sensor in the muscle sarcomere. Compared with vehicle, 5 μM of CK-2066260 significantly increased the calcium sensitivity of diaphragm fibers both in control patients (pCa50: 5.75 ± 0.04 vs. 6.18 ± 0.1, respectively; P < 0.001) and in critically ill patients (5.70 ± 0.07 vs. 6.00 ± 0.13, respectively; P < 0.01) (Figure 1C). Importantly, at physiological calcium concentrations, CK-2066260 restored the contractile force of fast-twitch diaphragm fibers of critically ill patients back to levels observed in untreated fibers from control patients (force at pCa 5.8: untreated control patients, 0.22 ± 0.05 vs. treated critically ill patients, 0.22 ± 0.07 mN; P = 0.954). See the online supplement for details. The current study is the first to show that atrophy and contractile weakness of diaphragm muscle fibers develop in a clinically relevant group of MV critically ill patients. Interestingly, the reduction in the contractile force of diaphragm fibers of these critically ill patients is comparable to the reduction in diaphragm strength estimated previously by phrenic nerve pacing (1, 2), indicating that the reduction in diaphragm strength in these patients largely results from muscle fiber weakness. To date, no drug is approved to improve respiratory muscle function in MV critically ill patients. We made a step toward such a strategy by testing the ability of the fast skeletal troponin activator, CK-2066260, to restore diaphragm fiber strength. We observed that, upon exposure to CK-2066260, fast-twitch diaphragm fibers from critically ill patients regained strength at calcium concentrations that reflect activation during daily live activities to levels found in untreated fibers from control patients (Figure 1C). Because approximately 50% of fibers and total fiber area in the human diaphragm consists of fast-twitch fibers (Figure E3), fast skeletal troponin activators might significantly improve in vivo diaphragm strength. The potential of fast troponin activators is further strengthened by the notion that these drugs do not affect cardiac function (4), which would be an undesirable side effect in critically ill patients. The analog of CK-2066260, tirasemtiv (formerly CK-2017357), is currently under study in patients with amyotrophic lateral sclerosis (clinical trial no. NCT01709149). What causes weakness of diaphragm muscle fibers in critically ill patients? It seems plausible that the observed diaphragm weakness was acquired during ICU stay, as we used strict exclusion criteria to rule out that our study patients had pre-existing diaphragm weakness. Also, during their stay in the ICU, patients received nutrition according to an optimized nutrition algorithm (7). A commonly suggested concept is that mechanical ventilation per se rapidly induces weakness and atrophy of muscle fibers due to contractile inactivity of the diaphragm (8–12). The critically ill patients we studied received MV for 28–603 hours before biopsy, a time frame that was associated with significant reductions in the CSA of diaphragm fibers in braindead organ donors (8, 13). Thus, the diaphragm muscle fiber atrophy and weakness that we observed may, at least partly, be explained by mechanical ventilation per se. Other ICU-related phenomena that could contribute to diaphragm muscle weakness include underlying disease, such as sepsis (14, 15). Clearly, to elucidate the main factors that contribute to the observed diaphragm muscle fiber weakness requires studies with larger cohorts of various patient groups.

Tumor cavitation in patients with stage III non-small-cell lung cancer undergoing concurrent chemoradiotherapy: Incidence and outcomes

Introduction: Commonly reported complications after concurrent chemoradiotherapy (CCRT) in patients with stage III non–small-cell lung cancer (NSCLC) include febrile neutropenia, radiation esophagitis, and pneumonitis. We studied the incidence of tumor cavitation and/or “tumor abscess” after CCRT in a single-institutional cohort. Methods: Between 2003 and 2010, 87 patients with stage III NSCLC underwent cisplatin-based CCRT and all subsequent follow-up at the VU University Medical Center. Diagnostic and radiotherapy planning computed tomography scans were reviewed for tumor cavitation, which was defined as a nonbronchial air-containing cavity located within the primary tumor. Pulmonary toxicities scored as Common Toxicity Criteria v3.0 of grade III or more, occurring within 90 days after end of radiotherapy, were analyzed. Results: In the entire cohort, tumor cavitation was observed on computed tomography scans of 16 patients (18%). The histology in cavitated tumors was squamous cell (n = 14), large cell (n = 1), or adenocarcinoma (n = 1). Twenty patients (23%) experienced pulmonary toxicity of grade III or more, other than radiation pneumonitis. Eight patients with a tumor cavitation (seven squamous cell carcinoma) developed severe pulmonary complications; tumor abscess (n = 5), fatal hemorrhage (n = 2), and fatal embolism (n = 1). Two patients with a tumor abscess required open-window thoracostomy post-CCRT. The median overall survival for patients with or without tumor cavitation were 9.9 and 16.3 months, respectively (p = 0.09). Conclusions: With CCRT, acute pulmonary toxicity of grade III or more developed in 50% of patients with stage III NSCLC, who also had radiological features of tumor cavitation. The optimal treatment of patients with this presentation is unclear given the high risk of a tumor abscess.

The Hemodynamics of Human Septic Shock Relate to Circulating Innate Immunity Factors

The role of innate immunity, e.g., complement activation and cytokine release in the hemodynamic alterations in the course of human septic shock is largely unknown. We prospectively studied 14 consecutive septic shock patients with a pulmonary artery catheter in place. For 3 days after admission, hemodynamic variables and plasma levels of C3a, a product of complement activation, and interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) were measured 6-hourly. Doses of vasoactive drugs were recorded. Of the 14 patients, 8 died in the ICU. Patients had a hyperdynamic circulation with tachycardia, mild hypotension, increased cardiac index, peripheral vasodilation and myocardial depression. C3a, IL-6 and TNF-α plasma levels were supranormal in 123 of 138 (89%), 132 of 138 (96%) and 83 of 111 (75%) measurements, respectively. Independently of blood culture results, treatment with vasoactive drugs and outcome, mean arterial blood pressure and systemic vascular resistance index were lower when IL-6 levels were higher and left ventricular function was less depressed when C3a levels were higher in the course of septic shock. The TNF-α levels did not invariably relate to peripheral vascular and myocardial function parameters. Our serial observations suggest that, in human septic shock, peripheral vasodilation is most strongly and independently, of all inflammatory factors, associated with IL-6 release, whereas complement activation partly offsets the myocardial depression of the syndrome. Innate immunity factors may thus differ in their contribution to the course of hemodynamic abnormalities of septic shock.

Novel applications of therapeutic hypothermia: report of three cases

Therapeutic hypothermia can provide neuroprotection in various situations where global or focal neurological injury has occurred. Hypothermia has been shown to be effective in a large number of animal experiments. In clinical trials, hypothermia has been used in patients with postanoxic injury following cardiopulmonary resuscitation, in traumatic brain injury with high intracranial pressure, in the perioperative setting during various surgical procedures and for various other indications. There is thus evidence that hypothermia can be effective in various situations of neurological injury, although a number of questions remain unanswered. We describe three patients with unusual causes of neurological injury, whose clinical situation was in fundamental aspects analogous to conditions where hypothermia has been shown to be effective.

FDG-PET/CT response evaluation during EGFR-TKI treatment in patients with NSCLC

Over recent years, [18F]-fluorodeoxyglucose positron emission tomography acquired together with low dose computed tomography (FDG-PET/CT) has proven its role as a staging modality in patients with non-small cell lung cancer (NSCLC). The purpose of this review was to present the evidence to use FDG-PET/CT for response evaluation in patients with NSCLC, treated with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI). All published articles from 1 November 2003 to 1 November 2013 reporting on 18F-FDG-PET response evaluation during EGFR-TKI treatment in patients with NSCLC were collected. In total 7 studies, including data of 210 patients were eligible for analyses. Our report shows that FDG-PET/CT response during EGFR-TKI therapy has potential in targeted treatment for NSCLC. FDG-PET/CT response is associated with clinical and radiologic response and with survival. Furthermore FDG-PET/CT response monitoring can be performed as early as 1-2 wk after initiation of EGFR-TKI treatment. Patients with substantial decrease of metabolic activity during EGFR-TKI treatment will probably benefit from continued treatment. If metabolic response does not occur within the first weeks of EGFR-TKI treatment, patients may be spared (further) unnecessary toxicity of ineffective treatment. Refining FDG-PET response criteria may help the clinician to decide on continuation or discontinuation of targeted treatment.

High circulating N-terminal pro-B-type natriuretic peptide is associated with greater systolic cardiac dysfunction and nonresponsiveness to fluids in septic vs nonseptic critically ill patients

PURPOSE It is still unclear whether circulating levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) reflect cardiac filling and function in the critically ill patient, particularly during sepsis and a proinflammatory response that may induce NT-proBNP release from the heart. MATERIALS AND METHODS We prospectively evaluated the value of NT-proBNP as a marker of cardiac loading, function, and response to fluid loading in 18 septic and 68 nonseptic, critically ill patients in the intensive care unit of a university medical center. Transpulmonary thermal dilution and pressure measurements were done, and plasma NT-proBNP was determined before and after colloid fluid loading. RESULTS Compared with nonseptic patients, NT-proBNP plasma levels were higher and systolic cardiac function indices were lower in patients with sepsis than those without sepsis. N-terminal pro-B-type natriuretic peptide best related, from all hemodynamic parameters before and after fluid loading, to systolic cardiac function (rather than diastolic filling) variables, independently of confounders such as renal dysfunction (judged from serum creatinine). In addition, a high NT-proBNP (>3467 pg/mL) predicted absence of fluid responsiveness in sepsis only. CONCLUSIONS Our data suggest that an increased circulating NT-proBNP plasma level is an independent marker of greater systolic cardiac dysfunction, irrespective of filling status, and is a better predictor of fluid nonresponsiveness in septic vs nonseptic, critically ill patients.

Trimodality therapy for superior sulcus tumours: Evolution and evaluation of a treatment protocol

AIM We studied the clinical outcomes of a trimodality protocol used for the treatment of superior sulcus tumours (SST) in a tertiary referral centre. METHODS The details of all patients who underwent treatment for a SST between January 2003 and December 2009 were retrospectively analysed. Following pre-treatment staging, all patients underwent concurrent chemoradiotherapy with cisplatin/etoposide, followed by surgery. Outcomes studied were treatment-related complications, pathological response rates, recurrence rates and survival. RESULTS Fifty-four patients were treated by chemotherapy (cisplatin/etoposide) and concurrent radiotherapy (46-66 Gy) followed by surgical resection. Minimum follow-up was 23 months. No 30-day mortality was observed. A complete (R0) resection was performed in 44 out of 54 patients. None had an R2 resection. Two-year survival was 50% (95%CI: 36.7-63.3). Patients who achieved a pathological complete response (n = 16) had a 2-year survival of 81% (95%CI: 62.1-100.0) versus a 37% 2-year survival (95%CI: 21.5-52.1) in patients with remaining vital tumour in their resection specimens (n = 38; P = 0.003). Five patients developed a local recurrence, and 23 patients a distant metastasis, mainly to the brain (n = 15). Two patients died from causes unrelated to cancer. CONCLUSIONS Trimodality treatment of SST in accordance to our protocol achieved results comparable to previous reports. Pathological response rates to induction were an important prognostic factor, and distant metastasis remains a major problem.