Hopefully, the arrival of the May issue of Shock will coincide with the end, or at least the very last vestiges, of a bizarre and seemingly interminable winter season. At the time this issue is being prepared for publication, the Winter Olympics are struggling with summertime temperatures; at the same time, more than 70% of the United States is covered by snow. The South is seeing record cold temperatures, the Northeast and Midwest record snow, and California is experiencing the worst drought in 150 years. In the words of an old familiar song, “April showers bring the flowers that bloom in May.” So I hope that the weather and all things are looking brighter as you peruse the interesting and important articles contained in the May issue.
Thematically, there are five main subject groupings in this month’s journal. A number of articles, including this month’s review article, deal in part with the epidemiology and outcomes of critical illness. This month, there are several articles dealing with cardiac dysfunction. Several other articles address nuances of resuscitation, with a particular emphasis on microvascular circulatory mechanisms and their role in pathogenesis of intestinal and pancreatic inflammation. Two articles highlight the potential role for novel therapies to favorably impact nutrition and warm hepatic ischemia-reperfusion. Finally, experimental studies were undertaken to assess or evaluate the utility or impact of very early resuscitative adjuncts, with a special emphasis on combat casualties. The May issue contains an outstanding, varied, provocative collection of articles reflecting the breadth of shock research in 2014.
Patterns of health care delivery are changing as systems evolve in the United States and around the world. More and more care, even critical care, is being provided in nontraditional settings, in the outpatient arena, or as highlighted in this month’s review article, in the emergency department (ED). Fuller and his coworkers (1) at Washington University review the impact of these changing care patterns by focusing on adult respiratory distress syndrome (ARDS). They review the existing data for ARDS risk factors and emphasize the importance of iatrogenic injury in pathogenesis. They note that ARDS is being seen more frequently as a presenting symptom in the ED (7%–9% ED prevalence), but also that lack of immediate intensive care unit (ICU) bed availability and the importance of timely interventions to optimize care of septic patients mean that ED practitioners are taking on an even greater burden of initial critical care. Equally important is the recognition that effective preventive strategies, for example, low-stretch mechanical ventilation, must be initiated early, and injurious modes of respiratory support must be avoided. Traditionally, ED mechanical ventilation apparatus, often primarily intended for transport, does not have “advanced” capabilities such as higher levels of positive end-expiratory pressure or airway pressure release ventilation. The authors also emphasize the importance of fluid management. Resuscitation not only needs to be initiated on arrival when appropriate but also there is an important “Goldilocks principle” to minimize development of ARDS and other complications. Too little resuscitation may lead to a persistent shock state, but too much can worsen pulmonary function of other vital organs. The authors emphasize the importance of advanced monitoring and care algorithms in the ED, and these should be congruent with existing ICU guidelines to ensure seamless delivery of the highest quality care. They go on to enumerate other interventions (e.g., initiation of antibiotics, blood transfusion, problems related to prehospital care, pharmacotherapy, extracorporeal circulatory support, etc.) whose proper or improper use may significantly impact the incidence and severity of ARDS. The authors recommend more studies to examine and improve prehospital and ED care to prevent and improve therapy for ARDS.
Continuing the outcome and epidemiology theme are contributions from Darmon et al. (2) and Chao et al. (3). Many studies have attempted to identify markers and risk factors for adverse ICU outcomes. Darmon and colleagues (2) approached the question in a somewhat unusual manner. They noted that numerous published articles had noted an adverse relationship between abnormal admission sodium levels (dysnatremia, encompassing both hyponatremia and hypernatremia) at the time of ICU admission. They examined data from more than 7,000 patients admitted to 18 ICUs in France between 2005 and 2012. They found that overall dysnatremia was present in 34.9% of the ICU population. What is interesting and unconventional about their analysis is that they focused on the impact of correction of dysnatremia on outcomes. They found that patients who had dysnatremia on admission, but were corrected within 3 days, had no increased risk of mortality. Thus, their data suggest that dysnatremia, per se, may not be the most important risk factor. Rather, the inability to correct this abnormality was associated with an increased risk of 28-day mortality (odds ratio of 1.3 and 1.86 for hyponatremia and hypernatremia, respectively). They note that it’s likely that the increased mortality is not mechanistically linked to sodium metabolism but suggest that this is a robust marker of systemic dysregulation that portends a worse outcome.
The article from Chao et al. and the Taiwan University Hospital Study Group on Acute Renal Failure (3) examined the impact of body mass index (BMI) on outcomes in geriatric (aged >65 years) ICU patients with acute kidney injury. They observed that mortality in this population was increased significantly at either extreme of BMI. Mortality was lowest within a broad range of BMI from 21 and 31 kg/m2. Noteworthy in their analysis was that being mild to moderately overweight was still associated with a low risk of mortality, even in the presence of acute kidney injury. It appears from their Table 1 that there was a stepwise relationship in each BMI class with known risk factors for mortality such as hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease. Based on mean APACHE (Acute Physiology and Chronic Health Evaluation) scores, all three cohorts appeared to be moderately ill (mean APACHE score, ∼13 – 18). Even so, data were not presented about the ICU length of stay, so it’s unclear how many of these patients were only in the ICU for a day or two postoperatively and how many required prolonged ICU care. Hospital length of stay (∼33 days) was extraordinarily long in all postoperative geriatric patients and may reflect qualitative differences in the Taiwanese and US health systems. The data do appear to show surprising results that have significant potential public health implications if they can be verified prospectively.
Two articles explore mechanisms of cardiac dysfunction using experimental sepsis and endotoxin models. The first article, by Thangamalai et al. (4), examines the ability of atorvastatin (ATR) to modulate impaired β-adrenergic receptor–mediated cardiac responses. They performed ex vivo measurement of myocardial contractility 20 h after in vivo cecal ligation and puncture (CLP) in mice and also obtained cardiac tissue for Western blots and other analyses. They found that CLP depressed β-adrenergic receptor mRNA and protein expression and myocardial contractility, and that pretreatment with ATR preserved these values. Previous work by the same group had shown that ATR was ineffective if administered after CLP. Whereas pretreatment is generally clinically impractical, it’s noteworthy that a very large proportion of the general population is already taking statins. This raises the question as to whether long-term statin use would confer the same benefits seen with the acute pretreatment regimen used here? Future studies will aid in clarification of these intriguing results.
The second article looking at impaired cardiac function in sepsis is by Ma and associates (5). Previous reports had demonstrated myocardial protection from intralipid (ILP) preparations, and in the current study, the authors hypothesized that left ventricular hypertrophy (LVH) would attenuate this effect. They focused their studies mechanistically on the impact of ILP on glycogen synthase kinase 3β and reperfusion injury salvage kinase. They again demonstrate cardioprotection in normal ventricles but showed that ILP did not confer any degree of protection in the presence of LVH. Their results suggest that LVH interferes with, or alters, reperfusion injury salvage kinase signaling pathways. Future studies might examine in some more detail how IPL works or, in the case of hypertrophied myocardium, why it does not.
Our understanding of resuscitation in shock and sepsis continues to change and evolve. Contributions from Ke et al. (6) and Lehmann et al. (7) focus primarily on what is occurring in the microcirculation. Lehmann et al. (7) used a mouse endotoxin and polybacterial surgical sepsis model to examine the role of an antiapoptotic protein, cellular inhibitor of apoptosis 2 (cIAP2), on recruitment of circulating macrophages to tissues in systemic inflammation. They compared cIAP2 knockout (KO) mice with wild-type animals and demonstrated that cIAP2 is necessary for macrophage tissue recruitment. More macrophages were recruited to the intestinal microcirculation after lipopolysaccharide (LPS) or sepsis, but these changes were attenuated or absent in cIAP2 KO mice. The authors speculate that their findings may permit modulation of inflammation in the clinical environment but, clearly, many additional studies will have to be performed.
The microcirculation was also the focus of the studies performed by Ke and colleagues (6) using a porcine model of severe acute pancreatitis (SAP). Pancreatic necrosis is a hallmark of clinical SAP, and numerous studies suggest that pancreatic inflammation leads to microvascular thrombosis, which contributes to necrosis and infarction. Attempts to prevent capillary thrombosis with anticoagulants have been ineffective and frequently are associated with life-threatening hemorrhagic complications. In the current study, continuous i.v. administration of low-molecular-weight heparin (LMWH) was compared with continuous regional arterial infusion (CRAI). Continuous regional arterial infusion markedly decreased necrosis compared with systemic LMWH but had little impact on histologic edema or inflammation and only a small difference in vacuolization. They did not observe any significant histologic improvement in the lung or liver. The results also showed that CRAI decreased tumor necrosis factor and interleukin 6. In this study, LMWH was initiated “soon” after induction of pancreatitis, whereas clinical patients present after pancreatitis is established. Future studies will be needed to determine if delayed CRAI can ameliorate “established” pancreatitis.
The May issue contains three articles addressing a variety of mechanistic questions relating to acute inflammation, nutrition, and metabolic processes. Tong and associates (8) studied the role of heat shock factor 1 (HSF-1) in mediating endogenous dampening of acute inflammation. Provocatively, they hypothesized that HSF-1 exerted such actions via regulation of autophagic activity. They used transgenic mice and showed a dramatic impact of the HSF-1-/- genotype on LPS-induced inflammation in liver and lung. More severe inflammation and organ injury were observed in the absence of HSF-1. The authors used an inhibitor (3-methyl adenine) and an agonist (rapamycin) of autophagy to confirm that the mechanisms of HSF-1 involved the autophagic pathways. It’s interesting to note, however, that 3-methyl adenine had no effect in HSF-1-/- animals (i.e., it did not further augment the inflammatory response). It is also very intriguing that rapamycin, an inducer of autophagy, was able to decrease the inflammatory response in HSF-1-/- animals, suggesting that autophagic mechanisms are still intact in these KO animals.
A highly novel approach was examined by Braun et al. (9) who looked at whether helium preconditioning could attenuate liver injury arising from warm ischemia-reperfusion (I/R). Ischemic preconditioning has been shown to ameliorate I/R injury, and other “noble gases” have shown effects in other tissues (e.g., xenon on myocardium). However, such effects were also associated with anesthetic effects, which helium does not have. Hepatic I/R injury can complicate liver resections and transplantation, thus, the results of these studies may have clinical utility. The authors are to be complimented for publishing an article with “negative results” because helium did not ameliorate liver injury, although it did decrease inflammation, as assessed using myeloperoxidase staining. The liver is unique in terms of having a dual blood supply and, thus, may have qualitative differences compared with other tissues studied (myocardium). Kupffer cells, which may mediate inflammatory responses associated with ischemia, are located in the portal sinusoids and thus might be “less” impacted by arterial delivery of gases. The experimental design only monitored injury to 315 minutes, so it is conceivable that attenuation of late effects of I/R could have been missed. The effects at different time points will be the focus of proposed future studies.
Critical illness is frequently accompanied by profound metabolic changes characterized by a refractory state of catabolism and impaired protein synthesis. Reports suggest that some peptide growth factors may impact these metabolic changes, but such agents are extremely expensive and their efficacy remains unclear. Laufenberg and coworkers (10) at Penn State used a low-molecular-weight (473 D) competitive agonist of insulin growth factor 1, aurintricarboxylic acid (ATA), and examined its ability to alter endotoxin- and sepsis-induced changes in muscle protein metabolism using in vitro and in vivo model systems. They demonstrated almost complete prevention of LPS–interferon-γ–mediated impairment of protein synthesis with pretreatment and, importantly, showed that delayed treatment with ATA (up to 12 h) still augmented protein synthesis. This is a very nice mechanistically focused study, and their data strongly support a mechanism in which ATA works through mTOR (mammalian target of rapamycin), with effects similar to those of insulin growth factor 1. The authors did not see any measurable impact on CLP mortality from ATA. Administration of ATA also profoundly decreased inflammatory cytokines, so the question arises as to whether ATA acts on protein synthesis via its effect on cytokines or if the cytokine inhibition is an added salutary effect of ATA. The latter appears more likely, but future studies will be needed to clarify this.
Finally, two articles address innovative adjuncts that may have future clinical utility particularly in terms of early management of severe combat casualties. Inaba and his coworkers (11) at University of Southern California and University of Arizona studied whether lyophilized platelets decreased liver hemorrhage in hypothermic swine, and Morrison et al. (12) used the UK Joint Theatre Trauma Registry to perform a “gap analysis” of the potential utility of resuscitative endovascular balloon occlusion of the aorta (REBOA) in hemorrhage. In the latter study, records were available for 1,317 casualties. The authors found no indication in 70% of casualties, a contraindication in 11%, and possible benefit in 18.5%. Thirty-two percent of the group with theoretical benefit had no signs of life at the wound scene and, thus, would be unlikely to benefit. This leaves 12.3% of all casualties in whom there may be a benefit of REBOA. The authors also point out that a significant subgroup of those who had theoretically controllable truncal hemorrhage ultimately died of their severe acute traumatic brain injury. They correctly point out that deployment of REBOA is almost certainly not achievable before the beginning of the transport process, where specialized equipment, a more stable environment, and appropriately trained personnel could be available. However, this compresses the window for utility and it would be interesting to examine how quickly and with what success rate REBOA can be placed and how much time might be “left” to slow hemorrhage. A more detailed assessment of the likely positive impact, if any, of REBOA should be undertaken.
Data from the most recent military experience have resulted in profound changes in the approach to hemorrhagic shock (13) and especially massive transfusion (14), which may also be applicable to civilian injuries (15). These evolving recommendations emphasize earlier use of packed red blood cells (or even whole blood) and liberal use of fresh-frozen plasma and platelets. The availability of functional platelets is often a “rate-limiting factor” in such approaches. Therefore, the authors are to be commended for studying how a lyophilized platelet preparation would function in the setting of moderate liver injury. They used a very complex in vivo model in an attempt to address a variety of clinical problems. Ice packs were inserted to make animals hypothermic at the time of injury, and moderate liver injury was created. Resuscitation was exclusively performed with crystalloids, and no fresh-frozen plasma or packed red blood cells were administered, which does to conform to current surgical practice. It’s also noteworthy that the pH in all three groups was relatively alkalotic (7.43 – 7.50), which is also different from the “lethal triad” of acidosis, shock, and hypothermia. The results make the important observation and provide proof of principle that administration of species-specific lyophilized platelets positively impact hemorrhage. Equally important is the observation that species-specific platelets may be required. With more study, lyophilized platelets may someday be an integral component of resuscitation for hemorrhagic shock.
So, enjoy the May issue of Shock, reflect on how our understanding of shock and resuscitation continually evolve, and take some time to savor the change of seasons.
1. Fuller BM, Mohr NM, Hotchkiss RS, Kollef MH: Reducing the burden of acute respiratory distress syndrome: the case for early intervention and the potential role of the emergency department. Shock
41: 373–382, 2014.
2. Darmon M, Pichon M, Schwebel C, Ruckly S, Adrie C, Haouache H, Azoulay E, Bouadma L, Clec’h C, Garrouste-Orgeas M, et al.: Influence of early dysnatraemia correction on survival of critically ill patients. Shock
41: 389–394, 2014.
3. Chao C-T, Wu V-C, Tsai H-B, Wu C-H, Lin Y-F, Wu K-D, Ko W-Jand the NSARF Group: Impact of body mass on outcomes of geriatric postoperative acute kidney injury patients. Shock
41: 395–400, 2014.
4. Thangamalai R, Kandasamy K, Sukumaran SV, Reddy CEN, Singh V, Choudhury S, Parida S, Singh TU, Boobalan R, Mishra SK: Atorvastatin prevents sepsis-induced downregulation of myocardial β1
-adrenoceptors and decreased cAMP response in mice. Shock
41: 401–407, 2014.
5. Ma L-L, Ge H-W, Kong F-J, Qian L-B, Hu B-C, Li Q, Xu L, Liu J-Q, Xu Y-X, Sun R-H: Ventricular hypertrophy abrogates intralipid-induced cardioprotection by alteration of reperfusion injury salvage kinase/glycogen synthase kinase 3β signal. Shock
41: 430–437, 2014.
6. Ke L, Ni H-b, Tong Z-h, Li W-q, Li N, Li J-s: Efficacy of continuous regional arterial infusion with low- molecular weight heparin for severe acute pancreatitis in a porcine model. Shock
41: 438–443, 2014.
7. Lehmann C, Zhou J, Schuster L, Gotz F, Wegner A, Cerny V, Pavlovic D, Robertson GS: Effect of deletion of cIAP2 on intestinal microcirculation in mouse endotoxemia and poly-bacterial sepsis. Shock
41: 449–452, 2014.
8. Tong Z, Jiang B, Zhang L, Liu Y, Gao M, Jiang Y, Li Y, Lu Q, Yao Y, Xiao X: HSF-1 is involved in attenuating the release of inflammatory cytokines induced by LPS through regulating autophagy. Shock
41: 444–448, 2014.
9. Braun S., Plitzko G, Biknell L, van Caster P, Schulz J, Barthuber C, Preckel B, Pannen BH, Bauer I: Pretreatment with helium does not attenuate liver injury after warm ischemia-reperfusion. Shock
41: 408–414, 2014.
10. Laufenberg L, Kazi AA, Lang CH: Salutary effect of aurintricarboxylic acid on endotoxin- and sepsis-induced changes in muscle protein synthesis and inflammation. Shock
41: 415–423, 2014.
11. Inaba K, Barmparas G, Rhee P, Branco BC, Fitzpatrick M, Okoye Ot, Demetriades D: Dried platelets in a swine model of liver injury. Shock
41: 424–429, 2014.
12. Morrison JJ, Ross JD, Rasmussen T, Midwinter MJ, Jansen JO: Resuscitative endovascular balloon occlusion of the aorta: a gap analysis of severely injured UK combat casualties. Shock
41: 383–388, 2014.
13. Hess JR, Holcomb JB, Hoyt DB: Damage control resuscitation: the need for specific blood products to treat the coagulopathy of trauma. Transfusion
46: 685–686, 2006.
14. Cotton BA, Reddy N, Hatch QM, LeFebvre E, Wade CE, Kozar RA, Gill BS, Albarado R, McNutt MK, Holcomb JB: Damage control resuscitation is associated with a reduction in resuscitation volumes and improvement in survival in 390 damage control laparotomy patients. Ann Surg
254: 598–605, 2011.
15. Duchesne JC, Hunt JP, Wahl G, Marr AB, Wang YZ, Weintraub SE, Wright MJ, McSwain NE Jr: Review of current blood transfusions strategies in a mature level I trauma center: were we wrong for the last 60 years? J Trauma
65: 272–276, 2008.