Acute Phase Of Critical Illness Research Articles

Optimizing Energy Supply by Parenteral Nutrition in the Critically-Ill: Muscle Weakness and its Monitoring

Critical illness is mostly defined as a life-threatening process affecting numerous systems of the body [1]. Unfortunately, despite all implemented strategies, critical illness could be associated with significant morbidity or mortality [2,3]. Although the early signs of critical illness are commonly neglected, a period of physiological weakening usually heralds the situation. Very clinical staff and even visitors play a pivotal role throughout appropriate assessment and intervention steps [4]. Muscle weakness in the critically-ill, as a major complication in ICUs, is associated with increased length of ICU stay and mortality. It has recently been suggested that substantial macronutrient deficit at early stages of the critical illness does not necessarily affect muscle wasting [5]. Numerous variables could directly contribute to the muscle weakness of the critically-ill patients following Neuromuscular Blocking Drugs (NMBDs) administration including the dosage, administration method (intermittent vs. bolus) and duration and also the approaches used for monitoring neuromuscular block depth. The latter seems to be inevitable, especially in the critically-ill patients, in order to guide the proper administration of drugs, avoid overdosing, maintain muscle activity and detect reactions among concomitant medications or pathophysiologic changes [6]. Based on the recent guidelines NMBDs are recommend to be used in critically-ill patients only when absolutely necessary, the depth of muscle paralysis be monitored to avoid overdosing and metabolite accumulation, and that drug administration be curtailed periodically to allow interruption of sustained NMBDs effect [7]. Furthermore, late parenteral regimen has also been suggested to be considered as a model of caloric restriction which would be associated with the elimination of damaged organelles [8]. However, it should be taken into consideration that insulin resistance in the criticallyill patients results in an unavoidable increase in glucose production, up to 1500 kcal/day in acute phase after injury. Therefore, the caloric debt during the acute phase of critical illness should no longer be calculated as the difference between energy expenditure and caloric intake but rather as the difference between energy expenditure and the sum of (endogenous+exogenous) calories [9]. Consequently, it seems that early parenteral nutrition without considering the mentioned pathophysiologic changes could result in overfeeding and its complications in other organs. Hence, prior to considering supplemental parenteral nutrition in patients with insufficient intake, optimization of the tolerance to ideal feeding is recommended.

Chapter 8 - Hypothalamic–pituitary hormones during critical illness: a dynamic neuroendocrine response

Independent of the underlying condition, critical illness is characterized by a uniform dysregulation of the hypothalamic-pituitary-peripheral axes. In most axes a clear biphasic pattern can be distinguished. The acute phase of critical illness is characterized by low peripheral effector hormone levels such as T3, IGF-1 and testosterone, despite an actively secreting pituitary. The adrenal axis with high cortisol levels in the presence of low ACTH levels is a noteworthy exception. In the prolonged phase of critical illness, low peripheral effector hormone levels coincide with a uniform suppression of the neuroendocrine axes, predominantly of hypothalamic origin. The severity of the alterations in the different neuroendocrine axes is associated with a high risk of morbidity and mortality, but it remains unknown whether the observed changes are cause or consequence of adverse outcome. Several studies have identified therapeutic potential of hypothalamic releasing factors, but clinical outcome remains to be investigated with sufficiently powered randomized controlled trials.

Strategies to combat chronic critical illness

The population of chronically critically ill patients is growing as advances in intensive care management improve survival from the acute phase of critical illness. These patients are characterized by complex medical needs and heavy resource utilization. This article reviews evidence supporting a comprehensive approach to the prevention and management of chronic critical illness (CCI). The most efficient approach to weaning patients with CCI at long-term acute care hospitals is daily unassisted breathing trials through a tracheostomy collar. However, a substantial number of patients transferred to long-term acute care hospitals pass their spontaneous weaning trials. Transfer to long-term acute care hospitals is associated with higher acute care costs and payments, but lower costs through the entire episode of illness. Universal decontamination is more effective than targeted decontamination or screening and isolation for preventing nosocomial bloodstream infections. Combating CCI begins with prevention in the acute phase of illness. Management strategies include a spectrum of ventilatory, nutritional, and rehabilitation support. Further patient-centered outcome-based research in this specific population is needed to continue to help guide optimal care.

Small Nerve Fiber Pathology in Critical Illness

BackgroundDegeneration of intraepidermal nerve fibers (IENF) is a hallmark of small fiber neuropathy of different etiology, whose clinical picture is dominated by neuropathic pain. It is unknown if critical illness can affect IENF.MethodsWe enrolled 14 adult neurocritical care patients with prolonged intensive care unit (ICU) stay and artificial ventilation (≥ 3 days), and no previous history or risk factors for neuromuscular disease. All patients underwent neurological examination including evaluation of consciousness, sensory functions, muscle strength, nerve conduction study and needle electromyography, autonomic dysfunction using the finger wrinkling test, and skin biopsy for quantification of IENF and sweat gland innervation density during ICU stay and at follow-up visit. Development of infection, sepsis and multiple organ failure was recorded throughout the ICU stay.ResultsOf the 14 patients recruited, 13 (93%) had infections, sepsis or multiple organ failure. All had severe and non-length dependent loss of IENF. Sweat gland innervation was reduced in all except one patient. Of the 7 patients available for follow-up visit, three complained of diffuse sensory loss and burning pain, and another three showed clinical dysautonomia.ConclusionsSmall fiber pathology can develop in the acute phase of critical illness and may explain chronic sensory impairment and pain in neurocritical care survivors. Its impact on long term disability warrants further studies involving also non-neurologic critical care patients.

Factores clínicos asociados al éxito de la ventilación asistida proporcional en la fase aguda del paciente crítico: estudio piloto

ReasonProportional assist ventilation plus (PAV+) applies pressure depending on the patient's inspiratory effort, automatically adjusting flow and volume assist to changes in respiratory mechanics. We aimed to assess the clinical factors associated with the success of PAV+ as first-line support in the acute phase of critical illness. MethodsA prospective cohort study was carried out. Mechanically ventilated patients>24h were switched from assist-control ventilation to PAV+ as soon as they regained spontaneous breathing activity. PAV+ was set to deliver the highest assistance. We compared patients in whom PAV+ succeeded versus those in whom it failed. ResultsPAV+ succeeded in 12 (63%) patients, but failed in 7 (37%) due to tachypnea (n=4), hypercapnia (n=2), and metabolic acidosis (n=1), but without statistical significance. Both groups had similar clinical parameters. On the day of inclusion, total work of breathing per breath was lower in the successful PAV+ group (WOBTOT: 0.95 [0.8-1.35] vs. 1.6 [1.4-1.8] J/L; P<.007). The area under the ROC curve was 0.89±0.08 for WOBTOT. The best cut-off for predicting PAV+ success was WOBTOT<1.4J/L (sensitivity: 1 [0.7-1], specificity: 0.6 [0.4-0.6], PPV: 0.7 [0.5-0.7], and NPV: 1 [0.6-1]). ConclusionPAV+ proved feasible as first-line ventilatory support in 63% of the patients, mostly in individuals without extreme derangements in WOBTOT. Tachypnea and hypercapnia were the clinical factors associated with failure, though statistical significance was not reached.

The evolution of nutrition in critical care: how much, how soon?

Critical care is a very recent advance in the history of human evolution. Prior to the existence of ICU care, when the saber-tooth tiger attacked you had but a few critical hours to recover or you died. Mother Nature, and her survival of the fittest mentality, would never have favored the survival of the modern ICU patient. We now support ICU patients for weeks, or even months. During this period, patients appear to undergo phases of critical illness. A simplification of this concept would include an acute phase, a chronic phase, and a recovery phase. Given this, our nutrition care should probably be different in each phase, and targeted to address the evolution of the metabolic response to injury. For example, as insulin resistance is maximal in the acute phase of critical illness, perhaps we have evolved to benefit from a more hypocaloric, high-protein intervention to minimize muscle catabolism. In the chronic phase, and especially in the recovery phase, more aggressive calorie delivery and perhaps proanabolic therapy may be needed. As the body has evolved limited stores of some key nutrients, adequate nutrition may hinge on more than just how many calories we provide. The provision of adequate protein and other key nutrients at the right time may also be vital. This review will attempt to utilize the fundamentals of our evolution as humans and the rapidly growing body of new clinical research to answer questions about how to administer the right nutrients, in the right amounts, at the right time.

Variability of insulin sensitivity during the first 4 days of critical illness: implications for tight glycemic control

BackgroundEffective tight glycemic control (TGC) can improve outcomes in critical care patients, but it is difficult to achieve consistently. Insulin sensitivity defines the metabolic balance between insulin concentration and insulin-mediated glucose disposal. Hence, variability of insulin sensitivity can cause variable glycemia. This study quantifies and compares the daily evolution of insulin sensitivity level and variability for critical care patients receiving TGC.MethodsThis is a retrospective analysis of data from the SPRINT TGC study involving patients admitted to a mixed medical-surgical ICU between August 2005 and May 2007. Only patients who commenced TGC within 12 hours of ICU admission and spent at least 24 hours on the SPRINT protocol were included (N = 164). Model-based insulin sensitivity (SI) was identified each hour. Absolute level and hour-to-hour percent changes in SI were assessed on cohort and per-patient bases. Levels and variability of SI were compared over time on 24-hour and 6-hour timescales for the first 4 days of ICU stay.ResultsCohort and per-patient median SI levels increased by 34% and 33% (p < 0.001) between days 1 and 2 of ICU stay. Concomitantly, cohort and per-patient SI variability decreased by 32% and 36% (p < 0.001). For 72% of the cohort, median SI on day 2 was higher than on day 1. The day 1–2 results are the only clear, statistically significant trends across both analyses. Analysis of the first 24 hours using 6-hour blocks of SI data showed that most of the improvement in insulin sensitivity level and variability seen between days 1 and 2 occurred during the first 12–18 hours of day 1.ConclusionsCritically ill patients have significantly lower and more variable insulin sensitivity on day 1 than later in their ICU stay and particularly during the first 12 hours. This rapid improvement is likely due to the decline of counter-regulatory hormones as the acute phase of critical illness progresses. Clinically, these results suggest that while using TGC protocols with patients during their first few days of ICU stay, extra care should be afforded. Increased measurement frequency, higher target glycemic bands, conservative insulin dosing, and modulation of carbohydrate nutrition should be considered to minimize safely the outcome glycemic variability and reduce the risk of hypoglycemia.

Critical Illness Neuromyopathy and the Role of Physical Therapy and Rehabilitation in Critically Ill Patients

Neuromuscular complications of critical illness are common, and can be severe and persistent, with substantial impairment in physical function and long-term quality of life. While the etiology of ICU-acquired weakness (ICUAW) is multifactorial, both direct (ie, critical illness neuromyopathy) and indirect (ie, immobility/disuse atrophy) complications of critical illness contribute to it. ICUAW is often difficult to diagnose clinically during the acute phase of critical illness, due to the frequent use of deep sedation, encephalopathy, and delirium, which impair physical examination for patient strength. Despite its limitations, physical examination is the starting point for identification of ICUAW in the cooperative patient. Given the relative cost, invasiveness, and need for expertise, electrophysiological testing and/or muscle biopsy may be reserved for weak patients with slower than expected improvement on serial clinical examination. Currently there are limited interventions to prevent or treat ICUAW, with tight glycemic control having the greatest supporting evidence. There is a paucity of clinical trials evaluating the specific role of early rehabilitation in the chronic critically ill. However, a number of studies support the benefit of intensive rehabilitation in patients receiving chronic mechanical ventilation. Furthermore, emerging data demonstrate the safety, feasibility, and potential benefit of early mobility in critically ill patients, with the need for multicenter randomized trials to evaluate potential short- and long-term benefits of early mobility, including the potential to prevent the need for prolonged mechanical ventilation and/or the development of chronic critical illness, and other novel treatments on patients' muscle strength, physical function, quality of life, and resource utilization. Finally, the barriers, feasibility, and efficacy of early mobility in both medical and other ICUs (eg, surgical, neurological, pediatric), as well as in the chronic critically ill, have not been formally evaluated and require exploration in future clinical trials.

Patient-Ventilator Interaction During Acute Lung Injury, and the Role of Spontaneous Breathing: Part 1: Respiratory Muscle Function During Critical Illness

Since the early 1970s there has been an ongoing debate regarding the wisdom of promoting unassisted spontaneous breathing throughout the course of critical illness in patients with severe respiratory failure. The basis of this debate has focused on the clinical relevance of opposite problems. Historically, the term "disuse atrophy" has described a situation wherein sustained inactivity of the respiratory muscles (ie, passive ventilation) results in deconditioning and weakness. More recently it has been referred to as "ventilator-induced diaphragmatic dysfunction." In contrast, "use atrophy" describes a situation where chronic high-tension inspiratory work causes structural damage to the diaphragm and weakness. Both laboratory and clinical studies demonstrated that relatively brief periods of complete respiratory muscle inactivity, as well as intense muscle loading, result in acute inflammation, loss of muscle mass, and weakness. Yet in critical illness other factors also affect respiratory muscle function, including prolonged use of neuromuscular blocking agents, administration of corticosteroids, and sepsis. This makes the attribution of acquired respiratory muscle weakness and ventilator-dependence to either ventilator-induced diaphragmatic dysfunction or loaded breathing extremely difficult. Regardless, the clinical implications of this research strongly suggest that passive mechanical ventilation should be avoided whenever possible. However, promotion of unassisted spontaneous breathing in the acute phase of critical illness also may carry a substantial risk of respiratory muscle injury and weakness. Use of mechanical ventilation modes in a manner that induces spontaneous breathing effort, while simultaneously reducing the work load on the respiratory muscles, is probably sufficient to minimize both problems.

Assessment of the hypothalamic–pituitary–adrenal axis in critical illness

Cortisol is the main corticosteroid secreted from the human adrenal cortex, and it has a crucial role for survival in stressful conditions. An adequate increase in levels of cortisol helps patients to cope with the severity of the disease in the acute phase of critical illness. Either higher or lower than expected cortisol levels were found to be related to increased mortality. Prolonged activation of the hypothalamic–pituitary–adrenal (HPA) axis can result in hypercortisolemia or hypocortisolemia; both can be detrimental to recovery from critical illness. Primary and secondary adrenal insufficiency, relative adrenal insufficiency, tissue resistance to glucocorticoids, adrenocorticotrophic hormone deficiency and immune-mediated inhibition of the HPA axis can be the cause of the impairment of the secretion or action of cortisol in critically ill patients. Recently, some authors offered the term ‘critical illness-related corticosteroid insufficiency’ to better point out the relative adrenal insufficiency that is seen during critical illness. Patients with critical illness-related corticosteroid insufficiency not only have insufficient circulating cortisol but also have impaired cellular utilization of cortisol. In this article, how adrenal dysfunction presents in critical illness and how appropriate diagnosis and management can be achieved in the critical care setting will be discussed.

Inactivation of sodium channels underlies reversible neuropathy during critical illness in rats

Neuropathy and myopathy can cause weakness during critical illness. To determine whether reduced excitability of peripheral nerves, rather than degeneration, is the mechanism underlying acute neuropathy in critically ill patients, we prospectively followed patients during the acute phase of critical illness and early recovery and assessed nerve conduction. During the period of early recovery from critical illness, patients recovered from neuropathy within days. This rapidly reversible neuropathy has not to our knowledge been previously described in critically ill patients and may be a novel type of neuropathy. In vivo intracellular recordings from dorsal root axons in septic rats revealed reduced action potential amplitude, demonstrating that reduced excitability of nerve was the mechanism underlying neuropathy. When action potentials were triggered by hyperpolarizing pulses, their amplitudes largely recovered, indicating that inactivation of sodium channels was an important contributor to reduced excitability. There was no depolarization of axon resting potential in septic rats, which ruled out a contribution of resting potential to the increased inactivation of sodium channels. Our data suggest that a hyperpolarized shift in the voltage dependence of sodium channel inactivation causes increased sodium inactivation and reduced excitability. Acquired sodium channelopathy may be the mechanism underlying acute neuropathy in critically ill patients.

Plasma arginine and citrulline concentrations in critically ill children: strong relation with inflammation

Background: The amino acid arginine plays a key role in many metabolic processes in health and disease. Low arginine concentrations are found in various illnesses in children.Objective: The objective was to investigate the relation between plasma concentrations of arginine (and precursor amino acids) and severity of inflammation in critically ill children.Design: This was an observational cohort study in children with viral respiratory disease (n = 21; control group), accidental or surgical trauma (n = 19), or sepsis (n = 19) who were admitted to a pediatric intensive care unit.Results: Plasma arginine and citrulline concentrations were lower in subjects with sepsis and trauma than in those with viral disease (arginine: 33 ± 4, 37 ± 4, and 69 ± 8 μmol/L, respectively, P < 0.01 for both; citrulline: 10 ± 1, 14 ± 1, and 23 ± 2 μmol/L, respectively, P < 0.01 for both) and correlated strongly and inversely with severity of inflammation as indicated by plasma CRP concentration (r = −0.645 and r = −0.660, respectively; P < 0.001 for both). During recovery, plasma arginine and citrulline concentrations increased and were strongly related to the reduction in inflammation as shown by the inverse correlation between arginine and citrulline concentrations and the CRP concentration on days 3 (r = −0.832 and r = −0.756, P < 0.001 for both) and 7 (r = −0.784 and r = −0.694, P < 0.001 for both).Conclusions: Plasma concentrations of arginine and citrulline are low during the acute phase of critical illness in children and normalize again during recovery. Plasma arginine and citrulline are strongly related to the severity of inflammation indicated by plasma CRP concentrations.

The Spectrum of Encephalopathy in Critical Illness

Beyond the cerebral impact of cardiac arrest, recent research indicates a high prevalence of neurological disturbances such as delirium and coma among patients admitted to the intensive care unit (ICU). These disturbances, grouped here under the term "encephalopathy," may be overlooked while attention is devoted to reversing life-threatening imbalances in cardiac and pulmonary function. Nevertheless, there is ample evidence that encephalopathy is an independent predictor of mortality. Factors associated with encephalopathy include primary cerebral disorders such as stroke, trauma, and meningitis, or systemic derangements including sepsis, organ failure, and exposure to pharmacological agents and toxins. Although encephalopathy may resolve with treatment of the underlying disorder, there is mounting evidence that cerebral dysfunction persists beyond the acute phase of critical illness. ICU survivors often suffer chronic impairments in cognitive ability, suggesting occult brain injury. The pathogenesis and natural history of encephalopathy, still poorly understood, need further clarification to spur the development of effective preventive and therapeutic interventions.

ESPEN Guidelines on Enteral Nutrition: Intensive care

Enteral nutrition (EN) via tube feeding is, today, the preferred way of feeding the critically ill patient and an important means of counteracting for the catabolic state induced by severe diseases. These guidelines are intended to give evidence-based recommendations for the use of EN in patients who have a complicated course during their ICU stay, focusing particularly on those who develop a severe inflammatory response, i.e. patients who have failure of at least one organ during their ICU stay. These guidelines were developed by an interdisciplinary expert group in accordance with officially accepted standards and are based on all relevant publications since 1985. They were discussed and accepted in a consensus conference. EN should be given to all ICU patients who are not expected to be taking a full oral diet within three days. It should have begun during the first 24h using a standard high-protein formula. During the acute and initial phases of critical illness an exogenous energy supply in excess of 20-25 kcal/kg BW/day should be avoided, whereas, during recovery, the aim should be to provide values of 25-30 total kcal/kg BW/day. Supplementary parenteral nutrition remains a reserve tool and should be given only to those patients who do not reach their target nutrient intake on EN alone. There is no general indication for immune-modulating formulae in patients with severe illness or sepsis and an APACHE II Score >15. Glutamine should be supplemented in patients suffering from burns or trauma.

The immunoneuroendocrine axis in critical illness: beneficial adaptation or neuroendocrine exhaustion?

Over the last years, endocrinology has been incorporated in critical care medicine, and acknowledgment of the complex neuro-endocrine adaption of critical illness has led to new insights and major breakthroughs in clarifying pathophysiological mechanisms and the targeting of therapeutic strategies. This review focuses on the important role of the hypothalamic-pituitary-adrenal (HPA) axis during critical illness and the occurrence of neuroendocrine failure. The distinction between acute (activated anterior pituitary function and inactivated peripheral anabolic pathways) and prolonged (reduced neuroendocrine stimulation) critical illness as different neuroendocrine paradigms has brought a new approach to the critically ill patient. The HPA adaptation in the prolonged phase is characterized by hypercortisolism induced by non-ACTH driven pathways as ACTH levels are low. In spite of the high-normal (total) cortisol levels, HPA insufficiency appears to be quite common. On the other hand, there is a marked depletion of corticosteroid-binding globulin (CBG) in the acute phase of critical illness, resulting in increased free and biologically active cortisol. There is a persistent marked depletion of dehydroeplandrosterone sulfate, possibly indicating adrenal exhaustion, while macrophage inhibitory factor is upregulated in sepsis, affecting and contraregulating the biological effects of glucocorticoids. The endocrine system is highly interrelated with the immune and neural systems, the neuroimmunoendocrine axis is subject to clear biphasic changes in the acute and chronic phases of critical illness, most likely reflecting a beneficial adaptation. These neuroendocrine dynamics should be considered when assessing the neuroendocrine system, in particular the HPA axis.

Does ICU-acquired paresis lengthen weaning from mechanical ventilation?

To determine whether ICU-acquired paresis (ICUAP) is an independent risk factor of prolonged weaning. Second study of a prospective cohort of 95 patients who were enrolled in an incidence and risk factor study of ICUAP. Three medical and two surgical ICUs in four hospitals. Ninety-five patients without pre-existing neuromuscular disease recovering from the acute phase of critical illness after > or =7 days of mechanical ventilation. None. Duration of weaning from mechanical ventilation was defined as the duration of mechanical ventilation between awakening (day 1) and successful weaning. Muscle strength was evaluated at day 7 after awakening using the Medical Research Council (MRC) score. Patients with an MRC <48 were considered to have ICUAP. Among the 95 patients (mean age 62.0+/-15.3 years, SAPS 2 on admission 48.7+/-17.4) who regained satisfactory awakening after 7 or more days of mechanical ventilation, 67 (70.5%) were hospitalized in a medical ICU and 28 (29.5%) in a surgical ICU. Median duration (25th-75th percentiles) of weaning was longer in patients with ICUAP than in those without ICUAP: 6 days (1-22 days) vs 3 days (1-7 days); p=0.01; log-rank analysis. In multivariate analysis, the two independent predictors of prolonged weaning were ICUAP [hazard ratio (HR): 2.4; 95% confidence interval (CI): 1.4-4.2] and chronic obstructive pulmonary disease (HR: 2.7; 95% CI: 1.6-4.5) ICU-acquired paresis is an independent predictor of prolonged weaning. Prevention of ICU-acquired neuromuscular abnormalities in patients recovering from severe acute illness should result in shorter weaning duration.

Debate: Albumin administration should not be avoided

The recent Cochrane report on albumin administration is analysed and criticised on the grounds of clinical methodology, content and interpretation. Although it is naïve and illogical to treat hypoalbuminaemia with albumin infusions, a more balanced view on the use of albumin for resuscitation in acute hypovolaemia is necessary. Once the acute phase of critical illness is past, interstitial volume is often expanded causing oedema, with a low plasma volume. We argue for the use of salt-poor albumin solutions in this situation and conclude that, on current evidence, the assertion that albumin should be avoided in all situations is irrational and untenable.

Mitochondrial protein content and in vivo synthesis rates in skeletal muscle from critically ill rats.

1. Recently we reported decreased activities of two mitochondrial marker enzymes (citrate synthase and cytochrome c oxidase) in skeletal muscle from a rat model of critical illness (zymosan injection). In the present study we investigated (i) whether these decreases in enzyme activity reflect a reduction in mitochondrial content and (ii) whether this potential reduction in mitochondrial content was the result of decreased mitochondrial protein synthesis rates. 2. Mitochondrial protein content was calculated from the activities of cytochrome c oxidase in whole-muscle homogenates and purified mitochondria. Synthesis rates of mitochondrial protein in vivo were studied by measuring the incorporation of [3H]phenylalanine into mitochondrial protein using the flooding dose technique. 3. Mitochondrial protein content was reduced to 54% of that measured in the pair-fed rats and to 71% of that measured in control rats fed ad libitum 2 days after the zymosan treatment. The decreased mitochondrial protein content observed 2 days after zymosan challenge was preceded by a reduced rate of synthesis of mitochondrial protein 16h after treatment. Both changes were of greater magnitude than the general muscle wasting and the decreased rate of synthesis of mixed protein observed in the zymosan-treated rats. 4. We conclude that the acute phase of critical illness in zymosan-treated rats is characterized by a substantial reduction in muscle mitochondria that is at least in part caused by a decreased rate of synthesis of mitochondrial protein. This derangement in mitochondrial protein metabolism may be related to the impaired muscle function observed during and after critical illness.

Derangement in aerobic and anaerobic energy metabolism in skeletal muscle of critically ill and recovering rats

As part of our research into the mechanisms of protein wasting and muscle weakness during critical illness, we here investigate various aspects of energy metabolism. Intraperitoneal injection of zymosan in rats leads to an acute phase of critical illness followed by a prolonged recovery phase. Previously we observed low activities of mitochondrial enzymes, reduced protein synthesis rates and low concentrations of glutamine in skeletal muscle of zymosan-treated rats. In the present study we investigated (1) whether decreases in high energy phosphates are present in skeletal muscle of these rats and (2) whether an impairment in the glycolytic pathway or the tricarboxylic acid cycle leads to these decreases. Concentrations of creatine phosphate and ATP were decreased in zymosan-treated rats to approx. 85% of pair-fed control values respectively on day 2 and on days 4 and 6 after treatment. Concentrations of tricarboxylic acid (TCA) cycle intermediates were decreased to 80% on day 6 after zymosan treatment. Lactate/pyruvate ratio and concentrations of lactate and glycogen were normal at all sampling times. We conclude that no major changes in concentrations of high energy phosphates and in concentrations of intermediates of TCA cycle, glycolysis and glycogenolysis were present. This indicated that, although the maximal oxidative capacity (mitochondrial content) is decreased, no derangement in energy metabolism seems to be present in skeletal muscle of critically ill and recovering rats.

Prolonged Changes in Protein and Amino Acid Metabolism after Zymosan Treatment in Rats

1. Intraperitoneal injections of zymosan were given to rats, according to a modified procedure, in order to create a pattern of illness with an acute critical phase for 36 h followed by a prolonged recovery phase lasting for at least 10 days. Changes in amino acid and protein metabolism were studied in both phases. 2. Differences between this modified and the original zymosan model are a lower mortality (16%), which is limited to the first 36 critical hours, and the absence of signs of severe illness during the prolonged recovery phase. 3. Wasting of muscle protein and decreased protein synthesis rates in muscle were observed during the acute phase of illness. Liver size and liver protein synthesis rates were increased during the same period. The decrease in the total amount of muscle protein and the increase in liver weight were still present 12 days after zymosan treatment, despite a normalization of protein synthesis rates. Large decreases were observed in the concentrations of the conditionally essential amino acids glutamine and arginine in muscle over 6 days. Decreases in plasma glutamine and arginine on day 12 after zymosan indicated that the rats were still not fully recovered on this day. 4. We conclude that injection of a single dose of zymosan in rats leads to metabolic derangements both during the acute phase of critical illness and during the prolonged recovery phase. The model seems suited for investigating the biochemical mechanisms behind these metabolic derangements and for studying therapeutic and nutritional interventions during recovery from critical illness.