Temporal physiologic patterns of shock and circulatory dysfunction based on early descriptions by invasive and noninvasive monitoring

In the past, most investigators failed to consider time relationships in their studies of circulatory problems. Because of this, data obtained in middle- or late-stage shock during organ failure are often presented as being characteristic of specific shock syndromes. Even "early" studies are not physiologically early, but instead have often come to mean early after ICU admission or early after life-threatening hypotensive events. The hypotensive episode represents decompensation of protective circulatory mechanisms, not the beginning of circulatory dysfunction. Early monitoring demonstrates that circulatory changes do not start with hypotension, but with the precipitating event, i.e., hemorrhage, trauma, surgery, or sepsis. When monitoring is started after hypotension, the first half of the problem is missed. It is, therefore, appropriate to focus on the earliest period of circulatory dysfunction with noninvasive methods to evaluate pathophysiology, to predict outcome, and to propose therapeutic protocols to improve outcome. Invasive monitoring is generally accepted as the "gold standard" for critically ill patients. The pulmonary artery flotation catheter has translated information to the bedside previously only available in cardiac catheterization laboratories, forever changing the way we treat ICU patients. Newer high-tech hardware and software innovations in the impedance method give more accurate and reliable cardiac index (CI) measurements that now satisfactorily agree with thermodilution in most clinical conditions. Minor disparities are more than made up for by the continuous online display of data. This impedance device, combined with pulse oximetry and transcutaneous oximetry, provides a feasible, noninvasive hemodynamic monitoring system that can be applied in a manner similar to electrocardiogram electrodes in the emergency department, operating room, ICU, hospital floors, and doctor's offices. More importantly, noninvasive monitoring provides a continuous, online, real-time display of hemodynamic data needed to titrate therapy rapidly and expeditiously. This is a major advantage, since therapy is more effective if given prophylactically or early and then titrated to optimal goals. Noninvasive monitoring provides a powerful method for objective evaluation of early, rapidly changing circulatory dynamics beginning with the precipitating event. This gives a new and different view of circulatory failure, exceeding the boundaries of our old concepts of shock based on blood pressure, subjective symptoms, and imprecise signs. Data of survivors revealed increased cardiac function (CI and oxygen delivery) shortly after surgery, trauma, and sepsis; this response is needed to meet the increased metabolic demands defined by the increased oxygen consumption. Nonsurvivors have limited responses to the added metabolic demands of external stressors. Therapy should augment naturally occurring compensations, but it must be given promptly within appropriate time limits.     

Oxygen delivery in critical illness

Oxygen consumption is physiologically dependent on DO2 below the critical DO2. Thus, patients in overt shock have physiologic dependence of VO2 on DO2. The first priority of prevention and reversal of tissue hypoxia is to balance oxygen demand and oxygen supply. Pathologic dependence of VO2 on DO2 has not yet been demonstrated convincingly in critically ill patients. Furthermore, in our opinion, contradicting results of RCTs of supernormal DO2 versus normal DO2 do not support routine maintenance of supernormal levels of DO2. Finally, we suggest that intensivists continue to assess DO2 and VO2 carefully. Global assessment of VO2 and DO2 appears inadequate to detect occult tissue hypoxia in most critically ill patients. However, research focused on regional assessment such as gastric tonometer measurement of gastric mucosal PCO2 and pH provides opportunity for safe, convenient detection of occult tissue hypoxia in critically ill patients.     

Protein metabolism in critical illness

In summary, protein metabolism of critically ill patients is a field open to new investigations that will help us to understand better the mechanism behind 'autocannibalism', which is still today associated with mortality. Although the underlying disease is the major determinant of mortality, nutritional depletion will add morbidity, an addition that grows over time in the ICU. With conventional treatment the velocity of the catabolic process can at best be slowed down and the patient be bought time for other types of treatment to work. New forms of specific nutrition and adjuvant therapies may give us tools to prevent muscle depletion, without endangering the supply of essential substrates to the tissues in the splanchnic area. Muscle is at present a limiting organ for the ICU patient in two respects. A depleted muscle can no longer provide enough substrates for the splanchnic organs to maintain intestinal integrity and to maintain a high immunocompetence. In addition, a depleted muscle will be restored back to normal only very slowly; in elderly patients restoration may not even occur at all. The effects of an attenuation of muscle depletion on rehabilitation time have yet to be evaluated. An understanding of protein metabolism may be the key to better patient care in the ICU in the future.     

Noninvasive, infrared monitoring of cerebral and myocardial oxygen sufficiency and circulatory parameters

The relatively good transparency of biological materials in the near infrared region of the spectrum permits sufficient photon transmission through organs in situ for the monitoring of cellular events. Observations by infrared transillumination in the exposed heart and in the brain in cephalo without surgical intervention show that oxygen sufficiency for cytochrome a,a3, function, changes in tissue blood volume, and the average hemoglobin-oxyhemoglobin equilibrium can be recorded effectively and in continuous fashion for research and clinical purposes. The copper atom associated with heme a3 did not respond to anoxia and may be reduced under normoxic conditions, whereas the heme-a copper was at least partially reducible.     

Factors influencing outcome of prolonged norepinephrine therapy for shock in critical surgical illness

Immunocytochemistry for manganese-superoxide dismutase (Mn-SOD) was studied in 12 normal adenohypophyses and 38 various pituitary lesions. The proportions of cells with granular immunoreactivity for Mn-SOD in normal adenohypophysis ranged from 9.8% to 29.6% (mean +/- SD; 18.4+/-6.2%). Some positive cells tended to accumulate in clusters, distribution of which corresponded well with those immunopositive for mitochondrial protein and cytochrome oxidase. The number of Mn-SOD-positive cells increased in adjacent residual adenohypophysis in eight of nine recent infarcts, in two of five old infarcts, in all four cases of lymphocytic hypophysitis, in two of four abscess cases and in one of three metastatic tumour cases, whereas the immunoreactivities of mitochondrial protein- and cytochrome oxidase-positive cells either did not vary or decreased. The intensity of the histological inflammatory reactions showed a positive correlation with reactivity for Mn-SOD in these lesions. Of eight adenomas, the surrounding area of compressed adenohypophysis showed increased numbers of Mn-SOD- and mitochondrial protein-/cytochrome oxidase-positive cells in four and six cases respectively. It is suggested that positivity for Mn-SOD may be related to some functional activity of mitochondria. It is further suggested that adenohypophysial cells have a high potential to induce Mn-SOD by inflammatory and ischaemic stress and, in addition, by enhanced mitochondrial activity.     

Predictors of outcome from critical illness. Shock and cardiopulmonary resuscitation

Many of our patients in ICUs suffer from shock, be it due to sepsis, trauma, arrest, or other causes. These patients continue to have a very high mortality rate in spite of very labor intensive and expensive treatment. The ability to identify patients who are likely to succumb to their illness is of utmost importance. Of the multitude of scoring systems published, the APACHE seems to accurately stratify shock patients according to severity of illness. However, these systems tend to be more useful for stratifying risk groups of patients than assessing the risk of death. Hemodynamic data can specifically assess the severity of the shock state in an individual patient. Those who maintain a relatively low cardiac index (< 4.5 L/m/M2) and oxygen delivery (< 15 mL/m/kg or 600 mL/m/M2) have persistent tissue hypoperfusion. Arterial lactate concentrations reflect the severity of this perfusion defect and correlate with outcome. Therefore, by restoring tissue perfusion, we can clearly improve mortality. CPP, although not generally obtainable during cardiac arrest, is the major physiologic determinant of outcome from CPR. ETCO2 monitoring during cardiac arrest in humans correlates with resuscitability, however, provides a rapid noninvasive monitor of cardiac output, and therefore has secured its role as an invaluable tool for assessing the effectiveness of CPR. An ETCO2 over 10 mm Hg is associated with effective CPR. A rapid rise in ETCO2 during CPR heralds recovery of spontaneous circulation. In conclusion, the use of prognostic indicators as predictors of outcome is supported as an important adjunct to the management of critically ill patients. These indicators serve as useful monitors to evaluate treatment and guide clinical management. Understanding the underlying pathophysiologic mechanisms responsible for the wide variety of illnesses associated with circulatory failure is crucial in our concerted effort to reduce mortality in these patients. As knowledge is gained, we hopefully will be able to develop more accurate and specific predictors of outcome to prudently select patients most likely to benefit.     

Harmful dysfunction, disorder, disease, illness, and evolution.

Can psychiatric disorders be conceptualized as harmful dysfunctions (J. C. Wakefield, 1992a. 1992b, 1999; S. O. Lilienfeld & L. Marino, 1995)? Wakefield's (1992a) central concept of disorder as harmful dysfunction is discussed by placing it in the context of a complementary discussion of disease, illness, the sick role, and evolution (D. F. Klein, 1978). S. O. Lilienfeld and L. Marino (1995) contended that proper biological function cannot be determined. This argument obscures the key significance of involuntary impairment of evolved functions. The claim that the Roschian concept has no counterpart in reality is incorrect and does not support the conclusion that dysfunctions are irreducibly evaluative and therefore arbitrary. J. C. Wakefield's (1999) views in this area are supplemented. The role of monothetic and polythetic categorization, extremal terms, and the concept of normality in nosology is considered. This analysis refutes the implication that deviance and illness are equivalent. The resolution of this debate is practically relevant to emphasizing areas of research investment, such as therapeutics. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A critical analysis of the minimal brain dysfunction syndrome.

Overactive and distractible youngsters who underachieve in school often represent a large proportion of child clinical populations. The hypothesis that these children suffer from minor neurological impairments not demonstrable through conventional neurodiagnostic methods enjoys widespread influence. Proponents of this minimal brain dysfunction viewpoint typically admit that there is little direct evidence to support their position, yet they tend to minimize its weaknesses and dangers. Attention to the literature in this field reveals numerous pitfalls that can be avoided by alternative cognitive–developmental hypotheses. These alternative interpretations do not ignore relevant brain–behavior relationships, but their tenets are more consistent with the available evidence and may ultimately lead to improved strategies of intervention. (72 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of endotoxins and bile acids in the pathogenesis of septic circulatory shock

It has long been known that the toxic effects of endotoxins under experimental conditions can be induced only when they are administered parenterally. However, in naturally occurring enteroendotoxemic diseases (e. g. septic and intestinal ischemic shocks) the endotoxins--which are produced by gram negative members of intestinal flora-, absorb from the intestinal tract to the blood circulation and can elicit pathological processes. It is an important distinction between natural and experimental endotoxin shock. If the common bile duct of rats were chronically cannulated a significant amount of perorally administered endotoxin was absorbed into the blood. This endotoxin shock can be prevented by bile acids. The physiological surfactants, the bile acids, are important facts in the defense of macroorganisms against endotoxins (physico-chemical defense). The production and passage of bile acids depend from the function of liver and the cholecystokinine (CCK) synthesis of small intestine wall. If the bile (bile acid) content of the intestinal canal decreases the endotoxin can translocate to the body and elicits toxic symptoms. So most important parts of defense against endotoxins in natural conditions are the CCK and bile acids. The consequence of damage of liver (place of bile acid synthesis) or small intestine (place of CCK synthesis) is the absorption of endotoxins.     

Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis

BACKGROUND & AIMS: Therapeutic paracentesis may be associated with a circulatory dysfunction, manifested by a marked increase of the plasma renin activity and plasma norepinephrine. The aim of the study was to characterize the systemic and hepatic hemodynamic changes associated with paracentesis-induced circulatory dysfunction. METHODS: Changes in plasma renin, aldosterone, and norepinephrine, and in systemic and hepatic hemodynamics were assessed 1 hour and 6 days after complete mobilization of ascites in 37 patients treated by total paracentesis plus intravenous dextran-70 infusion. RESULTS: Paracentesis-induced circulatory dysfunction occurred in 10 patients (renin and norepinephrine increased from 9.0 +/- 10.5 to 28.8 +/- 19.0 ng.mL-1.h-1 and from 752.0 +/- 364.0 to 1223.0 +/- 294.0 pg/mL, respectively) and was associated with significant reduction in systemic vascular resistance (-13.0% +/- 2.6%; P < 0.05) and increase in hepatic venous pressure gradient (from 19.5 +/- 1.5 to 22.5 +/- 2.4 mm Hg; P < 0.01). In the remaining 27 patients, mobilization of ascites also induced a significant but smaller reduction in systemic vascular resistance (-5.0% +/- 1.6%; P < 0.05) without significant changes in renin, norepinephrine, and hepatic venous pressure gradient. CONCLUSIONS: Paracentesis-induced circulatory dysfunction is predominantly caused by an accentuation of the arteriolar vasodilation already present in untreated cirrhotic patients with ascites. The homeostatic activation of endogenous vasoactive systems may account for the increased intrahepatic vascular resistance associated with this condition.     

Gender differences in psychiatric illness and treatments: a critical review

Controversy exists about the causation of gender differences long observed in the prevalence of mental disorders. Recent epidemiological, biochemical, and genetic research has shed further light upon both their etiologies and treatments. Both controversies and research are reviewed and critically examined.     

HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects

Mutations in HERG are associated with human chromosome 7-linked congenital long QT (LQT-2) syndrome. We used electrophysiological, biochemical, and immunohistochemical methods to study the molecular mechanisms of HERG channel dysfunction caused by LQT-2 mutations. Wild type HERG and LQT-2 mutations were studied by stable and transient expression in HEK 293 cells. We found that some mutations (Y611H and V822M) caused defects in biosynthetic processing of HERG channels with the protein retained in the endoplasmic reticulum. Other mutations (I593R and G628S) were processed similarly to wild type HERG protein, but these mutations did not produce functional channels. In contrast, the T474I mutation expressed HERG current but with altered gating properties. These findings suggest that the loss of HERG channel function in LQT-2 mutations is caused by multiple mechanisms including abnormal channel processing, the generation of nonfunctional channels, and altered channel gating.     

Predominant involvement of motor fibres in patients with critical illness polyneuropathy

Critical illness polyneuropathy (CIP) is a recognized cause of muscle weakness and failure of weaning from a ventilator. In order to characterize the features of CIP, we have examined 28 consecutive surgical patients with severe sepsis using bedside electrophysiology. Of the 28 patients (median APACHE II score 31), 20 developed moderate to severe CIP, as shown by the presence of moderate to severe denervation activity on resting EMG. The median nerve compound muscle action potential (CMAP) amplitudes were reduced to 3.24 (SEM 0.48) mV, while sensory nerve action potential (SNAP) amplitudes obtained from the same nerve were normal (13.1 (1.9) microV). In approximately 50% of these patients, the reduction in CMAP exceeded 50% of the lower limit of normal. Similar results were obtained from stimulation of the ulnar nerve. We conclude that CIP is a major complication in patients with severe sepsis and prolonged artificial ventilation. It predominantly involves motor fibres and thus markedly interferes with weaning from the ventilator.     

Relationship of admission thyroid function tests to outcome in critical illness

One hundred and eighty patients had serum thyrotropin, total triiodothyronine and free thyroxine concentrations measured within 3 h of admission to the Intensive Therapy Unit to assess whether thyroid function tests could predict outcome in critical illness. Overall mortality was 30.6%. Nonsurvivors were older (p = 0.001), and had higher APACHE II scores (p < 0.001) and predicted mortalities (p < 0.001). There was no difference in the median values of thyrotropin, total triiodothyronine and free thyroxine concentrations between survivors and nonsurvivors. Thyrotropin concentration was subnormal in 15 patients, normal in 152 and elevated in 13 patients. In contrast, 80 patients had subnormal triiodothyronine concentration. Free thyroxine was subnormal in five patients. Thyrotropin, total triiodothyronine and free thyroxine concentrations were not related to outcome (p = 0.360, p = 0.622, p = 0.726, respectively). No variable independently predicted death. Total triiodothyronine concentrations were lower in patients who received dopamine before admission to the intensive therapy unit than those who did not (p = 0.008); thyrotropin and free thyroxine concentrations were not influenced by dopamine administration. Serum concentrations of thyrotropin, total triiodothyronine and free thyroxine measured within 3 h of admission to the intensive therapy unit are not predictive of outcome.