Military assistance in complex emergencies: what have we learned since the Kurdish relief effort?

After the success of relief efforts to the displaced Kurdish population in northern Iraq following the Gulf War, many in the US military and the international relief community saw military forces as critical partners in the response to future complex emergencies (CEs). However, successes in subsequent military involvement in Somalia, Rwanda, the former Yugoslavia, and other CEs proved more elusive and raised many difficult issues. A review of these operations reinforces some basic lessons that must be heeded if the use of military forces in humanitarian relief is to be successful. Each CE is unique, thus, each military mission must be clearly defined and articulated. Armed forces struggle to provide both security and humanitarian relief, particularly when aggressive peace enforcement is required. Significant political and public support is necessary for military involvement and success. Military forces cannot execute humanitarian assistance missions on an ad hoc basis, but must continue to develop doctrine, policy and procedures in this area and adequately train, supply, and equip the units that will be involved in humanitarian relief. Militaries not only must cooperate and coordinate extensively with each other, but also with the governmental and non-governmental humanitarian relief organizations that will be engaged for the long term.     

Mechanical ventilation: what have we learned?

Mechanical ventilation is the second most frequently performed therapeutic intervention after treatment for cardiac arrhythmias in intensive care units today. Countless lives have been saved with its use despite being associated with a greater than 30% in-hospital mortality rate. As life expectancies increase and people with chronic illnesses survive longer, artificial support with mechanical ventilation is also expected to rise. In one survey, over half of senior internal medicine residents reported their training on mechanical ventilation as inadequate, whereas the majority of critical care nurses reported having received no formal education on its use. Technological advances resulting in the availability of sleeker ventilators with graphic waveform displays and new modes of ventilation have challenged the bedside clinicians to incorporate this new data along with evidenced-based research into their daily practice. A review of current thoughts on mechanical ventilation and weaning is presented.     

Traditional models of care delivery: what have we learned?

Traditional models of patient care delivery include total patient care and functional, team, and primary nursing. These models differ in clinical decision making, work allocation, communication, and management, with differing social and economic forces driving the choice of model. Studies regarding quality of care, cost, and satisfaction for the models provide little evidence for determining which model of care is most effective in any given situation. Despite lack of evidence, newer models continue to be implemented. This article compares the advantages and disadvantages of models, critiques the existing studies, and offers recommendations regarding the evidence needed to make informed decisions regarding care delivery models.     

The neuroscience of recovery and rehabilitation: what have we learned from animal research?

OBJECTIVES: To encourage rehabilitation specialists to develop a critical approach to the animal research literature that is relevant to human neurorehabilitation and to encourage clinicians to lend their perspectives to basic research. ATA SOURCES: Scientific publications cited in MEDLINE, PubMed, and PsychInfo, and professional presentations of leading neuroscience researchers. The focus was on current publications to 2001, with historical works included when appropriate. STUDY SELECTION: Studies were selected based on their relevance to the objectives. DATA EXTRACTION: Reviewed study methodology and findings and extracted key principles relevant to rehabilitation. DATA SYNTHESIS: Many themes emerging from neuroscience research are relevant to human rehabilitation, including issues related to timing of intervention and recovery, and characteristics of nervous system plasticity. CONCLUSIONS: Although animal research has many limitations, it provides a unique window on nervous system recovery and has generated important directions for future human research. Clinician involvement in basic animal research will improve the extent to which results are relevant to human rehabilitation and recovery.     

First-generation blood substitutes: what have we learned? Biochemical and physiological perspectives

Chemically modified or recombinant hemoglobin (Hb)-based oxygen carriers (HBOCs) have been developed as oxygen therapeutics or 'blood substitutes' for use in a variety of clinical settings. Oxidative and nitrosative reactions of acellular Hb can limit the effectiveness and compromise the safety of HBOCs. The reactions between Hb and biologically relevant redox active molecules may also perturb redox sensitive signaling pathways. In recent years, systematic in vitro and in vivo structural and functional evaluation of several HBOCs has been carried out and, in some cases, delineated the 'structural' origin of their toxicity. This enables potential protective strategies against Hb-mediated side reactions to be rationally suggested. Here the authors provide an overview of their research experiences, novel insights into the molecular basis of toxicities of these products and some lessons learned.     

Insulin pump therapy and rapid acting insulin: what have we learned?

Approximately 80 years after the discovery and first human use of insulin, we are still striving to replace insulin in a physiological manner. The development of insulin analogues with superior pharmacokinetics has made mimicking of meal and basal insulin requirements by subcutaneous injection more feasible. Administration by continuous subcutaneous insulin infusion (CSII) has provided additional flexibility in meal timing and modifying basal insulin replacement in response to circadian rhythms. Several studies have documented improved glycaemic control with CSII using a rapid-acting analogue such as insulin lispro, compared with regular human insulin. Lower postprandial glucose peaks and improved HbA1c levels were seen with insulin lispro by CSII. In addition, the frequency of hypoglycaemia was significantly reduced and the counter-regulatory hormone responses were maintained. The use of insulin lispro in CSII, compared with regular human insulin, resulted in improved hepatic glucose output in response to glucagon. The potential for problems of hyperglycaemia and ketoacidosis with interruption of insulin delivery by CSII has been studied. One study showed accelerated development of hyperglycaemia and ketosis with insulin lispro compared with regular human insulin while another showed no difference but return to normal glycaemia was faster when insulin lispro was administered. The use of CSII in the US has grown from 6,600 in 1990 to over 100,000 patients currently. With improved insulins, better methods of delivery and advances in glucose monitoring we will continue progress towards physiological insulin replacement and reduce the long-term complications of diabetes.     

Metabolic energy expenditure of ambulation in lower extremity amputees: what have we learned and what are the next steps?

Purpose: Amputation results in reduced mobility and contributes to reduced quality of life. The increased metabolic cost of ambulation has been suggested as an important contributor to reduced mobility in this population. Current research on the metabolic energy expenditure of ambulation will be critically reviewed from the perspectives of ecological validity of the research methods and the relative contribution to functional improvement in amputees. Recommendations will be made regarding possible future directions for research and their potential clinical utility. Methods: Narrative review. Results: The methods used to quantify metabolic energy expenditure of amputee ambulation do not emulate typical mobility conditions that amputees experience. Amputee mobility is characterized by short bouts of activity with starting, stopping and changes of direction. This is opposed to the typical metabolic testing protocol that requires at least 5?min of steady state linear walking on a treadmill. These studies, therefore, have limitations in ecological validity and therefore limitations in the extent to which they accurately reflect the effect of amputation level, amputation etiology and prosthetic components on energy consumption during walking. Further, the broader perspective on outcomes after dysvascular amputation and sports participation limitations, raises questions about the relative importance of improving metabolic costs and its potential effect on improving mobility in amputees. Conclusion: The greatest potential clinical impact of future research requires methods with improved ecological validity, and the ability to translate metabolic energy expenditure outcomes into functional terms that are meaningful to both clinicians and patients.

• Implications for Rehabilitation

• The search for objective measurements to define the effects of amputation on outcome and the consequences of prosthetic components on mobility has focused in part on the use of study designs incorporating metabolic measurement.

• However, there are important limitations to the ecological validity of these measures and their relative importance as an outcome measure in dysvascular amputees as well as in sports/leisure participation.

• Novel research approaches are required to quantify the functional impact of increased metabolic energy expenditure and to better understand the psychophysical limitations that result.

     

Clinical trials of mediator-directed therapy in sepsis: what have we learned?

Almost 60 randomized controlled clinical trials have been undertaken, testing the hypothesis that modulation of the endogenous host inflammatory response can improve survival for patients with a clinical diagnosis of sepsis. The results have been tantalizing, but frustrating, and no new agent has been introduced into clinical practice. Analysis of pooled data from studies of the use of an neutralizing antibody to tumor necrosis factor, or recombinant interleukin 1 receptor antagonist, show that these two approaches yield a statistically significant, but small improvement in 28 day all-cause mortality. However variability in results from one study to the next, the small absolute mortality reduction, the emerging evidence of a substantial potential for harm, and the predicted costs of recombinant biologic agents has engendered a climate of caution and pessimism. The challenge is to find methods of refining investigative approaches to maximize benefit and minimize harm. This paper reviews the recent history of sepsis clinical trials, focussing on emerging insights into the limitations of study entry criteria and measures of biologic activity and clinical benefit that may inform and direct future investigations. The biologic complexity of systemic inflammation, and the multiple interactions between clinical biology and the process of care suggest that future success in clinical research in sepsis will occur through the conduct of highly focussed investigations in a small number of dedicated centres of excellence.     

Gene- and cell-based bio-artificial pacemaker: what basic and translational lessons have we learned?

Normal rhythms originate in the sino-atrial node, a specialized cardiac tissue consisting of only a few thousands of nodal pacemaker cells. Malfunction of pacemaker cells due to diseases or aging leads to rhythm generation disorders (for example, bradycardias and sick-sinus syndrome (SSS)), which often necessitate the implantation of electronic pacemakers. Although effective, electronic devices are associated with such shortcomings as limited battery life, permanent implantation of leads, lead dislodging, the lack of autonomic responses and so on. Here, various gene- and cell-based approaches, with a particular emphasis placed on the use of pluripotent stem cells and the hyperpolarization-activated cyclic nucleotide-gated-encoded pacemaker gene family, that have been pursued in the past decade to reconstruct bio-artificial pacemakers as alternatives will be discussed in relation to the basic biological insights and translational regenerative potential.     

Gene expression in human sepsis: what have we learned?

In the previous issue of Critical Care, Tang and colleagues offer a very novel systematic review of 12 studies of gene expression in blood of human sepsis. The review concludes that there is no discernable transition from a pro- to an anti-inflammatory expression phenotype in blood in human sepsis. The authors found that upregulation of pathogen recognition receptors and signal transduction pathways was a consistent theme in expression studies. The review by Tang and colleagues has strengths, including defined screening criteria, broad literature review, strict inclusion criteria, and transparent methods for assessing strengths and weaknesses of studies. There are other issues to consider. First, one source of variation in gene expression studies in sepsis is variability in time from onset of sepsis to time of blood draw. Another source of variation is differences between tissues in gene expression at the same time in sepsis. Whole blood is a mélange of tissues (a variety of leukocytes); therefore, one assesses a weighted sum of all leukocyte classes. About half of the studies assessed peripheral mononuclear cells. A third great source of variable gene expression in sepsis is heterogeneity of causes and microbiology of sepsis. Only one study compared Gram-positive with Gram-negative sepsis. Only three studies confirmed microarray data with an independent measurement of expression. One interpretation is that two of three studies of early sepsis found increased expression of pro-inflammatory genes. In late sepsis, three of six studies found increased expression of pro-inflammatory genes whereas three of six studies found decreased expression of pro-inflammatory genes. The balance of pro- to anti-inflammatory gene expression is difficult to quantify. Sample size is highly variable in studies (n = 12 to 176). These limitations require a leap of faith to suggest that the paradigm of sepsis as a pro-inflammatory phenotype that shifts to an anti-inflammatory phenotype is flawed: the absence of evidence in expression studies is not the same as having well-conducted studies with clear negative evidence.     

Sixty years of antibodies to MNS system hybrid glycophorins: what have we learned?

The MNS system was the second blood group system discovered and at least 16 of the 46 antigens in the MNS system result from genetic recombination, producing a hybrid glycophorin. The incidence of these hybrid glycophorins is highest in East Asian populations. MNS system antigens defined by hybrid glycophorins are immunogenic with alloimmune IgG responses developing after transfusion or pregnancy; with reports originating from Asia, Europe, the Americas, and Australia. This demonstrates the global nature of problems associated with these antibodies. Since the initial report that production of anti-Mi(a) was a cause of hemolytic disease of the fetus and newborn (HDFN), antibodies to antigens defined by hybrid glycophorins have been reported in 27 cases of HDFN (1 fatal) and 8 cases of hemolytic transfusion reaction (HTR) (1 fatal). In at least 40% of these clinical cases, the disease was reported as severe. Hyporegenerative fetal anemia is a common feature of the reported HDFN cases. In all published cases, the causative antibodies were identified by reference laboratory investigative tests following clinical presentation. The failure to detect these antibodies by routine testing highlights the need for consideration of the medical importance of these antibodies when defining antibody screening practices and reagents. The aim of this review is to raise awareness of severe disease caused by antibodies to MNS antigens defined by hybrid glycophorins and, thus, to improve diagnosis and patient management.     

Endoscopic therapy for gastroesophageal reflux disease: what have we learned and what needs to be done?

GERD is a common, morbid, and expensive-to-treat disease. Clinicians have a clearly defined "therapeutic bar" for the efficacy of GERD therapy established from extensive study of current pharmacologic and surgical therapies. Endoscopic therapies for GERD are promising technologies that probably will find clinical application in subsets of patients with GERD. Integration of these new endoscopic GERD therapies into routine clinical practice requires more information from carefully performed and analyzed trials. Issues that still need to be addressed include the efficacy of these devices compared with placebo, efficacy compared with other endoscopic techniques, and efficacy versus current therapies. Addressing these issues requires the performance of well-designed, blinded studies using sham techniques and measuring clinically relevant outcomes using validated instruments. Once efficacy has been established, durability of response needs to be clearly determined. Intensive postmarketing surveillance, device registries, and long-term clinical follow-up studies will be able to document durability. The effect of retreatment for relapses or suboptimal initial treatment response should also be determined. Safety can best be established with extensive postmarketing surveillance and device registries. The impact of formal training programs on decreasing the learning curve and improving outcomes, including safety, should also be studied. Finally, the cost-effectiveness of these devices has to be determined either by economic models or clinical trials measuring actual costs. Despite these seemingly large hurdles, one, if not more, of these technologies should meet these criteria and soon be used as an effective, durable, safe, and cost-effective treatment option for patients with GERD.     

Clinical experience with Zarzio® in Europe: what have we learned?

Biosimilars are similar, but non-identical, versions of existing biological drugs for which patents have expired. Despite the rigorous approval process for biosimilars, concerns have been expressed about the efficacy and safety of these products in clinical practice. Biosimilars of filgrastim, based on the originator product Neupogen®, have been available since 2008 and are now in widespread clinical use in Europe and elsewhere. Three biosimilar G-CSFs have been approved based on a combination of physicochemical and biological protein characterisation, pharmacokinetic and pharmacodynamic assessment in healthy volunteers and efficacy and safety data in patients with cancer. To assess whether biosimilars are effective in the real-world clinical practice setting, a pooled analysis of five post-approval studies of biosimilar G-CSF (Zarzio®) that included 1,302 adult patients who received at least one cycle of chemotherapy with G-CSF support for the prevention of neutropenia was conducted. A total of 36 % of patients had a febrile neutropenia risk of >20 %, while 39.6 % had a risk of 10–20 % based on chemotherapy regimen. The occurrence of severe or febrile neutropenia was within the range of that observed in previous studies of originator G-CSF. In addition, the safety profile of Zarzio® was consistent with that reported for originator G-CSF and the known safety profile of G-CSF. Initial concerns about the use of biosimilars, at least with regard to biosimilar G-CSFs, appear to be unfounded. Adoption of cost-effective biosimilars should help reduce healthcare costs and improve patient access to biological treatments.