Peter J. Radell

Three cases of PICU sedation with isoflurane delivered by the ‘AnaConDa®’

Prolonged sedation in the pediatric intensive care unit may be difficult because of tolerance, drug dependence and withdrawal, drug interactions and unwanted drug effects. We present three patients sedated with isoflurane via the Anesthetic Conserving Device, AnaConDa®. AnaConDa® is a modified heat and moisture exchanger that allows evaporation and delivery of inhalational anesthetics without an anesthesia machine, vaporizer or adapted ventilator. Two patients with abdominal complications and prolonged sedation for mechanical ventilation were converted to isoflurane sedation for several days. The third patient with refractory status epilepticus received isoflurane to treat epileptiform electroencephalogram activity. Patients weighing 40 and 30 kg were treated with AnaConDa® placed at the Y‐piece, while the patient weighing 20 kg was treated with AnaConDa® in the inspiratory limb of the respiratory circuit. Adequate sedation was achieved with endtidal isoflurane concentration of 0.3–0.4%, while antiepileptic effect was achieved at a higher dose, 0.9%. Intravenous sedatives could be reduced or discontinued during isoflurane sedation. Inhaled sedation of isoflurane with AnaConDa® was effective in these patients. It may provide an alternative in difficult cases needing prolonged sedation and should be evaluated further.

Short- and long-term follow-up of intensive care unit patients after sedation with isoflurane and midazolam--a pilot study.

Objective:To compare memories from the intensive care unit (ICU) and short- and long-term psychological morbidity in patients after sedation with intravenous midazolam or inhaled isoflurane. Design:Prospective long-term follow-up after randomized controlled trial. Setting:General ICU at Karolinska University Hospital, Solna, Stockholm. Patients:Forty patients in need of sedation during ventilator treatment. Interventions:Patients were randomized to receive isoflurane or midazolam for goal-directed sedation until extubation or for a maximum of 96 hrs. Measurements and Main Results:For short-term follow-up, doctors’, nurses’, and physiotherapists’ notes from the 4 days following exposure to the study drugs were reviewed for words indicating adequate or pathologic cognitive and psychological recovery. For long-term follow-up, all 6-month survivors received questionnaires including the ICU Memory Tool (ICU-MT), Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), and Well-Being Index. Additionally, several screening questions for previous posttraumatic stress symptoms were included. In the short term follow-up, no significant differences were found between groups. In the long-term follow-up, a trend toward fewer hallucinations/delusions after isoflurane sedation than after midazolam (two of ten isoflurane patients vs. five of seven midazolam patients) was found (p = .06). None of the five solely isoflurane-sedated patients reported hallucinations/delusions from the ICU. There was no difference in groups in long-term psychological morbidity as measured with HADS and IES. Memories of negative feelings in the ICU (ICU-MT) were associated with high HADS and IES scores (Fisher’s exact test, p = .02 and p = .01, respectively). Conclusions:Sedation of ICU patients with isoflurane may result in fewer delusional memories or hallucinations from the ICU compared with more commonly used intravenous sedation. Memories of negative feelings from the ICU were associated with symptoms of depression or anxiety or symptoms indicating posttraumatic stress disorder. Further study of memory and cognitive/psychological recovery after prolonged isoflurane sedation beyond 96 hrs is warranted.

Diaphragm muscle weakness in an experimental porcine intensive care unit model.

In critically ill patients, mechanisms underlying diaphragm muscle remodeling and resultant dysfunction contributing to weaning failure remain unclear. Ventilator-induced modifications as well as sepsis and administration of pharmacological agents such as corticosteroids and neuromuscular blocking agents may be involved. Thus, the objective of the present study was to examine how sepsis, systemic corticosteroid treatment (CS) and neuromuscular blocking agent administration (NMBA) aggravate ventilator-related diaphragm cell and molecular dysfunction in the intensive care unit. Piglets were exposed to different combinations of mechanical ventilation and sedation, endotoxin-induced sepsis, CS and NMBA for five days and compared with sham-operated control animals. On day 5, diaphragm muscle fibre structure (myosin heavy chain isoform proportion, cross-sectional area and contractile protein content) did not differ from controls in any of the mechanically ventilated animals. However, a decrease in single fibre maximal force normalized to cross-sectional area (specific force) was observed in all experimental piglets. Therefore, exposure to mechanical ventilation and sedation for five days has a key negative impact on diaphragm contractile function despite a preservation of muscle structure. Post-translational modifications of contractile proteins are forwarded as one probable underlying mechanism. Unexpectedly, sepsis, CS or NMBA have no significant additive effects, suggesting that mechanical ventilation and sedation are the triggering factors leading to diaphragm weakness in the intensive care unit.

Gene expression and muscle fiber function in a porcine ICU model

Skeletal muscle wasting and impaired muscle function in response to mechanical ventilation and immobilization in intensive care unit (ICU) patients are clinically challenging partly due to 1) the poorly understood intricate cellular and molecular networks and 2) the unavailability of an animal model mimicking this condition. By employing a unique porcine model mimicking the conditions in the ICU with long-term mechanical ventilation and immobilization, we have analyzed the expression profile of skeletal muscle biopsies taken at three time points during a 5-day period. Among the differentially regulated transcripts, extracellular matrix, energy metabolism, sarcomeric and LIM protein mRNA levels were downregulated, while ubiquitin proteasome system, cathepsins, oxidative stress responsive genes and heat shock proteins (HSP) mRNAs were upregulated. Despite 5 days of immobilization and mechanical ventilation single muscle fiber cross-sectional areas as well as the maximum force generating capacity at the single muscle fiber level were preserved. It is proposed that HSP induction in skeletal muscle is an inherent, primary, but temporary protective mechanism against protein degradation. To our knowledge, this is the first study that isolates the effect of immobilization and mechanical ventilation in an ICU condition from various other cofactors.

Lung Ventilation and Perfusion in Prone and Supine Postures with Reference to Anesthetized and Mechanically Ventilated Healthy Volunteers

Background:The literature on ventilation (V) and lung perfusion (Q) distributions during general anesthesia and controlled mechanical ventilation in supine and prone position is contradictory. The authors aimed to investigate whether V, Q, and ventilation to perfusion ratio (V/Q ratio) matching in anesthetized and mechanically ventilated volunteers are gravity dependent irrespective of posture. Methods:Seven healthy volunteers were studied at two different occasions during general anesthesia and controlled mechanical ventilation. One occasion studied ventral to dorsal V and Q distributions in the supine posture and the other in the prone posture. Imaging was performed in supine posture at both occasions. A dual radiotracer technique and single photon emission computed tomography were used. V and Q were simultaneously tagged with 99mTc-Technegas (Tetley Manufacturing Ltd., Sydney, Australia) and 113mIn-labeled macroaggregates of human albumin (TechneScan LyoMAA, Mallinckrodt Medica, Petten, The Netherlands), respectively. Results:No differences in V between postures were observed. Q differed between postures, being more uniform over different lung regions in prone posture and dependent in supine posture. The contribution of the vertical direction to the total V/Q ratio heterogeneity was larger in supine (31.4%) than in prone (16.4%) (P = 0.0639, two-tailed, paired t test) posture. Conclusions:During mechanical ventilation, prone posture favors a more evenly distributed Q between lung regions. V distribution is independent of posture. This results in a tendency toward lower V/Q gradients in the ventral to dorsal direction in prone compared with supine posture.

Factors Underlying the Early Limb Muscle Weakness in Acute Quadriplegic Myopathy Using an Experimental ICU Porcine Model

The basic mechanisms underlying acquired generalized muscle weakness and paralysis in critically ill patients remain poorly understood and may be related to prolonged mechanical ventilation/immobilization (MV) or to other triggering factors such as sepsis, systemic corticosteroid (CS) treatment and administration of neuromuscular blocking agents (NMBA). The present study aims at exploring the relative importance of these factors by using a unique porcine model. Piglets were all exposed to MV together with different combinations of endotoxin-induced sepsis, CS and NMBA for five days. Peroneal motor nerve conduction velocity and amplitude of the compound muscle action potential (CMAP) as well as biceps femoris muscle biopsy specimens were obtained immediately after anesthesia on the first day and at the end of the 5-day experimental period. Results showed that peroneal nerve motor conduction velocity is unaffected whereas the size of the CMAP decreases independently of the type of intervention, in all groups after 5 days. Otherwise, despite a preserved size, muscle fibre specific force (maximum force normalized to cross-sectional area) decreased dramatically for animals exposed to MV in combination with CS or/and sepsis. These results suggest that the rapid declines in CMAP amplitude and in force generation capacity are triggered by independent mechanisms with significant clinical and therapeutic implications.

Platelet-derived growth factor inhibition—a new treatment of pulmonary hypertension in congenital diaphragmatic hernia?

Increased pulmonary vascular resistance causing pulmonary artery hypertension is a major problem in the treatment of congenital diaphragmatic hernia with a strong association to mortality. We here report a patient with intractable pulmonary hypertension at 4 weeks of age unresponsive to conventional treatment. After administration of the platelet-derived growth factor (PDGF) receptor antagonist imatinib, pulmonary artery pressure gradually decreased to acceptable levels and the patients clinical condition gradually improved.

Impaired autophagy, chaperone expression, and protein synthesis in response to critical illness interventions in porcine skeletal muscle

Critical illness myopathy (CIM) is characterized by a preferential loss of the motor protein myosin, muscle wasting, and impaired muscle function in critically ill intensive care unit (ICU) patients. CIM is associated with severe morbidity and mortality and has a significant negative socioeconomic effect. Neuromuscular blocking agents, corticosteroids, sepsis, mechanical ventilation, and immobilization have been implicated as important risk factors, but the causal relationship between CIM and the risk factors has not been established. A porcine ICU model has been used to determine the immediate molecular and cellular cascades that may contribute to the pathogenesis prior to myosin loss and extensive muscle wasting. Expression profiles have been compared between pigs exposed to the ICU interventions, i.e., mechanically ventilated, sedated, and immobilized for 5 days, with pigs exposed to critical illness interventions, i.e., neuromuscular blocking agents, corticosteroids, and induced sepsis in addition to the ICU interventions for 5 days. Impaired autophagy as well as impaired chaperone expression and protein synthesis were observed in the skeletal muscle in response to critical illness interventions. A novel finding in this study is impaired core autophagy machinery in response to critical illness interventions, which when in concert with downregulated chaperone expression and protein synthesis may collectively affect the proteostasis in skeletal muscle and may exacerbate the disease progression in CIM.

Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model

Severe muscle wasting is a debilitating condition in critically ill intensive care unit (ICU) patients, characterized by general muscle weakness and dysfunction, resulting in a prolonged mobilization, delayed weaning from the ventilator, and a decreased quality of life post-ICU. The mechanisms underlying limb muscle weakness in ICU patients are complex and involve the impact of primary disease, but also factors common to critically ill ICU patients such as sepsis, mechanical ventilation (MV), immobilization, and systemic administration of corticosteroids (CS). These factors may have additive negative effects on skeletal muscle structure and function, but their respective role alone remain unknown. The primary aim of this study was to examine how CS administration potentiates ventilator and immobilization-related limb muscle dysfunction at the gene level. Comparing biceps femoris gene expression in pigs exposed to MV and CS for 5 days with only MV pigs for the same duration of time showed a distinct deregulation of 186 genes according to microarray. Surprisingly, the decreased force-generation capacity at the single muscle fiber reported in response to the addition of CS administration in mechanically ventilated and immobilized pigs was not associated with an additional upregulation of proteolytic pathways. On the other hand, an altered expression of genes regulating kinase activity, cell cycle, transcription, channel regulation, oxidative stress response, cytoskeletal, sarcomeric, and heat shock protein, as well as protein synthesis at the translational level, appears to play an additive deleterious role for the limb muscle weakness in immobilized ICU patients.

Postoperative regional distribution of pulmonary ventilation and perfusion in infants with congenital diaphragmatic hernia

BACKGROUND/PURPOSE Advances in management of patients with congenital diaphragmatic hernia (CDH) have improved mortality rates but with a risk of increased pulmonary morbidity. The prognosis for CDH survivors remains difficult to predict owing to the lack of adequate methods. We used single photon emission computed tomography (SPECT) to measure the regional distribution of ventilation and perfusion in CDH infants to quantify the degree of lung function impairment and relate it to neonatal clinical disease severity. METHODS Single photon emission computed tomography was performed in 12 CDH infants at the mean age of six months. Ventilation and perfusion were traced with 5 MBq Technegas and technetium-labelled albumin macro-aggregates, respectively. Neonatal clinical data collected during the patients stay in the pediatric intensive care unit was correlated with the SPECT data. RESULTS Single photon emission computed tomography revealed varying degrees of ventilation-perfusion abnormalities which correlated with the presence of pulmonary artery hypertension, days on ventilator and days on extracorporeal membrane oxygenation. CONCLUSIONS The grade of clinical disease severity in infants following CDH repair is closely related to the ventilation-perfusion abnormality as seen using SPECT. The persistence of pulmonary artery hypertension into the postoperative neonatal period appears to be an important pathophysiological factor related to ventilation-perfusion abnormalities. Single photon emission computed tomography provides valuable clinical information for patient follow-up.