June 2015 Phoenix Critical Care Journal Club: Interventions in ARDS

Mortality has been declining in the adult respiratory distress syndrome (ARDS) (1). However, the cause of the decline in mortality is unclear. The only intervention shown to improve survival has been low tidal volume ventilation but the mortality was improving before this intervention was widely used (2). Nevertheless, it was suggested that we look at system performance regarding ARDS management from a critical appraisal standpoint. This journal club was hoped to help as a starting point in that regard. Four potential beneficial interventions were discussed: 1. Conservative fluid management; 2. Optimal PEEP as determined by esophageal pressure; 3. Prone positioning; and 4. Mechanical ventilation driving pressure.

National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564-75. [CrossRef] [PubMed]

Whether ARDS patients should be "dry" by diuresis and/or fluid restriction has been debated for at least 40 years. The ARDS network attempted to answer the question with a randomized study, comparing a conservative and a liberal strategy of fluid management. The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days and organ-failure–free days and measures of lung physiology. During the study, the cumulative seven-day fluid balance was essentially zero in the conservative treatment arm and 7L positive with liberal fluid management. The rate of death at 60 days was 25.5 percent in the conservative-strategy group and 28.4 percent in the liberal-strategy group (P = 0.30). Measures of lung physiology improved in the conservative-strategy group and the number of ventilator-free days (14.6±0.5 vs. 12.1±0.5, P<0.001) and days not spent in the intensive care unit (13.4±0.4 vs. 11.2±0.4, P<0.001) also improved. The internal validity and generalizability of this study were both high. Some felt that these results support the use of a conservative strategy of fluid management in patients with acute lung injury while others felt that the benefit was small and pointed out that mortality was unaltered. There does not appear to be any benefit of fluid-overloading patients – and if avoiding 7L overload gets patients extubated 2 days earlier, it seems worth pursuing.

Talmor D, Sarge T, Malhotra A, et al. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med. 2008;359(20):2095-104. [CrossRef] [PubMed]

Survival of patients with acute lung injury or the acute respiratory distress syndrome (ARDS) has been improved by ventilation with small tidal volumes and the use of positive end-expiratory pressure (PEEP); however, the optimal level of PEEP has been difficult to determine. In a pilot study, the authors estimated transpulmonary pressure with the use of esophageal balloon catheters. ARDS patients were randomized to undergo mechanical ventilation with PEEP adjusted according to measurements of esophageal pressure (the esophageal-pressure–guided group) or according to the ARDS Network standard-of-care recommendations (the control group). The primary end point was improvement in oxygenation. The secondary end points included respiratory-system compliance and patient outcomes. This was a small RCT that only showed improvement in surrogate (not clinical) outcomes. Oxygenation and respiratory-system compliance improved (P = 0.01), and surprisingly for this small group, the 28-day mortality approached statistical significance (P=0.055). It was pointed out that the use of esophageal balloons may be difficult to implement and maintain in the ICU. Studies are currently ongoing examining outcomes with this strategy and most felt that the results should be awaited before esophageal pressure monitoring has widespread implementation.

Guérin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159-68. [CrossRef] [PubMed]

Previous trials involving patients with the acute respiratory distress syndrome (ARDS) have failed to show a beneficial effect of prone positioning during mechanical ventilatory support on outcomes. Yet, despite this lack of evidence, some have continued to use proning with the belief that studies would eventually show a benefit. For those intensivists, this study provides welcome positive evidence for proning. In this multicenter, prospective, randomized, controlled trial, 466 patients with severe ARDS were randomly assigned to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P<0.001). The incidence of complications did not differ significantly between the groups. This RCT had strong internal validity and generalizability. The NNT to save a life is six. We noted that many previous interventions in critical care that were supported by only a single well-designed RCT were later found to be ineffective or even harmful (for instance: tight glycemic control, early goal-directed therapy of sepsis, and drotrecogin-alpha for sepsis). We therefore view implementation of proning with some skepticism, but felt it may be under-utilized. It’s best application seems to be early in the course of severe ARDS. We all worried about the practicality of proning our patients, especially those with morbid obesity, but felt that if we practiced proning more frequently, we would gain practical experience. 

Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372(8):747-55. [CrossRef] [PubMed]

The newest concept to be discussed was driving pressure during mechanical ventilation. Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (VT), and higher positive end-expiratory pressures (PEEPs) can improve survival in patients with the acute respiratory distress syndrome (ARDS), but the relative importance of each of these components is uncertain. Because respiratory-system compliance (CRS) is strongly related to the volume of aerated remaining functional lung during disease (termed functional lung size), the authors hypothesized that driving pressure (ΔP = VT/CRS), in which VT is intrinsically normalized to functional lung size (instead of predicted lung size in healthy persons), would be an index more strongly associated with survival than VT or PEEP in patients who are not actively breathing. The authors examined the records of 3562 patients with ARDS enrolled in nine previously reported randomized trials and found that a 1-SD increment in ΔP (approximately 7 cm of water) was associated with increased mortality (relative risk, 1.41; 95% confidence interval [CI], 1.31 to 1.51; P<0.001), even in patients receiving “protective” plateau pressures and VT (relative risk, 1.36; 95% CI, 1.17 to 1.58; P<0.001). This study has strong internal validity, but was only hypothesis-generating in design. The concept of using driving pressure makes physiological sense, yet it is unclear if altering ΔP improves survival or if this is merely an independent marker of survival. This study invites prospective trials.  

Richard A. Robbins, MD

Robert A. Raschke, MD

References

1. Abel SJ, Finney SJ, Brett SJ, Keogh BF, Morgan CJ, Evans TW. Reduced mortality in association with the acute respiratory distress syndrome (ARDS). Thorax. 1998;53(4):292-4. [CrossRef] [PubMed]
2. Kallet RH, Jasmer RM, Pittet JF, Tang JF, Campbell AR, Dicker R, Hemphill C, Luce JM. Clinical implementation of the ARDS network protocol is associated with reduced hospital mortality compared with historical controls. Crit Care Med. 2005;33(5):925-9. [CrossRef] [PubMed]

Reference as: Robbins RA, Raschke RA. June 2015 Phoenix critical care journal club: interventions in ARDS. Southwest J Pulm Crit Care. 2015;10(6):345-7. doi: http://dx.doi.org/10.13175/swjpcc082-15 PDF

February 2015 Phoenix Critical Care Journal Club: Intracranial Pressure Monitoring for Fulminant Liver Failure

Karvellas CJ, Fix OK, Battenhouse H, Durkalski V, Sanders C, Lee WM; U S Acute Liver Failure Study Group. Outcomes and complications of intracranial pressure monitoring in acute liver failure: a retrospective cohort study. Crit Care Med. 2014;42(5):1157-67. [CrossRef] [PubMed]

The fellows performed an excellent follow-up to our last journal club in which we reviewed the above article. This cohort consisted of 140 patients who underwent ICP monitoring for grade III/VI encephalopathy, and 489 non-monitored controls. Only 87/140 (62%) of monitored patients had sufficient available data for analysis, 51% of whom had demonstrable intracranial hypertension (ICH) that was associated with nearly a doubling of mortality (43 vs.23% p=0.05). Monitoring and control groups were dissimilar. Monitored patients were statistically more likely to require mechanical ventilation, vasopressors and dialysis, and ultimately more than twice as likely to undergo liver transplant. Reasonably, monitored patients also received more treatments aimed at reducing ICH including osmotic therapy and hypothermia, although no treatment protocol was stipulated. Fatal hemorrhagic complications of ICP monitoring occurred in 3 of 56 patients for whom this outcome could be determined. Overall, 21-day mortality was similar in monitored and control patients: 33% vs. 38% p=0.24, but a subgroup analysis of patients with acute liver failure not due to acetaminophen showed that monitoring had an adjusted odds ratio of 3.0 (p=0.014).

Karvellas’ study is non-experimental, and has significant flaws, the most important of which is the lack of any specific approach to treatment of ICH. Any hypothetical mortality benefit of ICP monitoring ought to be related to rapid and effective management once intracranial hypertension is detected. In our Critical Care service, this entails immediate bedside response by 24/7 intensivists who emergently employ a protocol that has been refined over a decade, and that takes cerebral perfusion pressure into account. We have had a long-standing belief that ICP-monitoring is beneficial in these patients and previously published our treatment protocol (1). Karvellas’ study provides little information on how ICP was managed in order to reconcile their findings with ours. However it is the largest study to date, and has compelled us and our neurosurgeon associates to reconsider our long-standing practice.

Our discussions last and this month brought several pertinent issues to light through the expert input of Jeremy Payne and Doug Franz – two of our esteemed stroke-neurologists - and by extensive outside research that the fellows had the initiative to undertake, including an several literature searches and an informal survey of transplant programs around the country. The following recounting of the resulting discussions is much abbreviated.

The central issue is whether it is clinically beneficial to take immediate action if a patient with acute liver failure suffers a sudden rise in ICP, or a sudden drop in cerebral perfusion pressure (CPP) (2-5). Experienced clinicians still debate this issue, and there is no experimental evidence to resolve the debate. Clinicians who accept the premise that emergent action should be taken to correct abnormal ICP or CPP values will not likely be satisfied managing comatose acute liver failure patients without monitoring, or by using periodic methods to detect cerebral edema, such as brain CT scanning, transcranial doppler, or optic nerve width determination, that may lack sensitivity and fail to provide real-time detection of acute deterioration.

The fellows’ survey of transplant programs around the country showed a related lack of consensus. About half of programs still used ICP monitoring in certain situations, but less so than in the past. Periodic brain CT scanning, periodic transcranial dopplers and reverse jugular bulb oxygen saturations were each used as surrogates for ICP monitoring at a minority of responding transplant centers. We determined that the current state of research and the standard of practice are such that individual programs can reasonably exercise local discretion in regards to whether and how to monitor acute liver failure patients, despite the results of Karvellas’ study. Our discussion proceeded based on our non-unanimous contention that brain injury can be mitigated by emergent interventions for sudden alterations in ICP and CPP, and that the benefit of doing so outweighs the risk.

We considered multiple studies that demonstrated that non-neurosurgeons can be trained to safely place ICP monitors, but we concluded that none of us would be able to achieve the volume of procedures required to maintain competence. We considered other methods of surrogate real-time monitoring, such as jugular bulb oxygen saturation monitoring, which may be safer than ICP monitoring. But even less is known about benefits of jugular bulb oxygenation monitoring than what we know about ICP monitoring. Therefore, jugular vein oxygen saturation monitoring seems at best a topic for further research. We concluded at this point that we will invite debate with our neurosurgeons and ask for their continued support for ICP monitor placement. We might also consider a pilot trial comparing jugular vein oxygen saturation monitoring with ICP monitoring.

Robert Raschke MD, Suresh Uppalapu MD, Nick Sparacino MD and Jennifer Hall MD

Banner Good Samaritan Medical Center

Phoenix, AZ

References

1. Raschke RA, Curry SC, Rempe S, Gerkin R, Little E, Manch R, Wong M, Ramos A, Leibowitz AI. Results of a protocol for the management of patients with fulminant liver failure. Crit Care Med. 2008;36(8):2244-8. [CrossRef] [PubMed]
2. Lee WM, Stravitz RT, Larson AM. Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011. Hepatology. 2012;55(3):965-7. [CrossRef] [PubMed]
3. Siddiqui MS, Stravitz RT. Intensive care unit management of patients with liver failure. Clin Liver Dis. 2014;18(4):957-78. [CrossRef] [PubMed]
4. Lobato RD, Alen JF, Perez-Nu-ez A, Alday R, Gómez PA, Pascual B, Lagares A, Miranda P, Arrese I, Kaen A. Value of serial CT scanning and intracranial pressure monitoring for detecting new intracranial mass effect in severe head injury patients showing lesions type I-II in the initial CT scan. Neurocirugia (Astur). 2005;16(3):217-34. [CrossRef] [PubMed]
5. Behrens A, Lenfeldt N, Ambarki K, Malm J, Eklund A, Koskinen LO. Transcranial Doppler pulsatility index: not an accurate method to assess intracranial pressure. Neurosurgery. 2010;66(6):1050-7. [CrossRef] [PubMed]

Reference as: Raschke RA, Uppalapu S, Sparacino N, Hall J. February 2015 Phoenix critical care journal club: intracranial pressure monitoring for fulminant liver failure. Southwest J Pulm Crit Care. 2015;10(3):127-9. doi: http://dx.doi.org/10.13175/swjpcc037-15 PDF

August 2014 Tucson Critical Care Journal Club: Bacteremia in Cardiac Arrest

Article: Coba V, Jaehne AK, Suarez A, Dagher GA, Brown SC, Yang JJ, et al. The incidence and significance of bacteremia in out of hospital cardiac arrest. Resuscitation. 2014;85:196-202. [CrossRef] [PubMed]

Out-of-hospital cardiac arrest (OHCA) is an uncommon, but important, condition encountered in the emergency department (ED). While cardiac arrest represents the final common pathway of multiple conditions, early evaluation often focuses on cardiac abnormalities. However, observed associations between infection, particularly pneumonia, and in-hospital cardiac arrest led Coba et al. (1) to investigate the incidence of bacteremia among OHCA patients.

The study prospectively investigated 250 adult patients who presented to an academic ED with OHCA between 2007 and 2009. Two blood culture samples were drawn during resuscitation or shortly after return of spontaneous circulation through vascular devices placed for clinical purposes. Children, pregnant women, victims of trauma were excluded. To minimize false positive results, patients were classified as bacteremic if one sample was positive for a typical pathogen or both samples were positive for the same skin colonizing organism. Patients in whom only 1 sample was positive for suspected skin contaminant or in whom no growth was observed after 5 days were classified as non-bacteremic.

Of 173 patients, 65 (38%) were considered to have bacteremia preceding the cardiac arrest.  Bacteremic and non-bacteremic patients were similar along measured demographic and clinical characteristics at presentation. No differences in CPR duration, location of arrest, or presenting rhythm were noted. Few patients survived to hospital discharge, 3% of those classified as bacteremic versus 5% of those classified as non-bacteremic (p=0.66). While no differences in survival were observed at 28 days or at hospital discharge, survival to hospital admission was lower among bacteremic patients as compared to non-bacteremic patients, 25% versus 40%, respectively (p=0.04).

Among patients who survived to hospital admission, a higher proportion of bacteremic, as opposed to non-bacteremic, patients were vasopressor dependent, 93.8% vs 74.4%, respectively (p=.06). Furthermore, bacteremic patients had higher lactate levels (p=0.01), lower arterial pH (p=0.01), and higher potassium (p<0.01), BUN (p=0.02), creatinine (p=0.02), magnesium (p=0.01), and phosphorous (p=0.01) levels. Bacteremic patients were also more likely to have antibiotics started in the ED, 69% versus 30%, respectively (p=0.01). Cultures yielded a wide range of bacterial species with streptococcal and staphylococcal species being the most frequently observed.

Up to 40% of patients presenting to the ED with OHCA appear to have clinically significant bacteremia. Given that bacteremic patients were twice as likely to receive antibiotics in the ED as compared to those without bacteremia, the treating clinicians appeared to frequently recognize this possibility. Compared to those without confirmed bacteremia, those with bacteremia had physiologic abnormalities that were consistent with severe sepsis including higher lactate levels and greater metabolic acidosis.  While long-term outcomes remain poor, clinicians should still consider and appropriately treat co-existing infection when caring for cardiac arrest patients in the ED.

Additional research is needed to determine the clinical relevance of bacteremia in this setting. An important remaining question is to what extent infection precipitates cardiac arrest versus being an incidental finding in the immediate post-arrest period due to transient bacteremia caused by resuscitation efforts and/or translation of bacterial across poorly perfused gut. Given the high proportion of bacteremic patients receiving antibiotics, examination of other data (e.g., urinalysis, chest radiography, etc.) might have helped identify a plausible foci of infection.

The low survival to discharge observed in this study, <5%, would tend to hide any treatment benefit that might have accrued to patients in whom early treatment of severe sepsis was initiated. Future study in a setting with higher survival to discharge would be needed to determine whether treatment of co-existing infection in cardiac arrest patients might lead to improved survival.

Cameron Hypes MD MPH^1,2, Joe K. Gerald, MD, PhD³

¹Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Arizona Medical Center; Tucson, AZ

²Department of Emergency Medicine, University of Arizona Medical Center; Tucson, AZ

³College of Public Health, University of Arizona Medical Center; Tucson, AZ

References

1. Coba V, Jaehne AK, Suarez A, Dagher GA, Brown SC, Yang JJ, et al. The incidence and significance of bacteremia in out of hospital cardiac arrest. Resuscitation. 2014;85:196-202. [CrossRef] [PubMed]
2. Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callaway CW, et al. Part 8: Adult advanced cardiovascular life support: 2010 american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122:S729-S767. [CrossRef] [PubMed]
3. Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA. 2008;300:1423-31. [CrossRef] [PubMed]
4. Dunne RB, Compton S, Zalenski RJ, Swor R, Welch R, Bock BF. Outcomes from out-of-hospital cardiac arrest in detroit. Resuscitation. 2007;72:59-65. [CrossRef] [PubMed] 

Reference as: Hypes C, Gerald JK. August 2014 Tucson critical care journal club: bacteremia in cardiac arrest. Southwest J Pulm Crit Care. 2014;9(4):247-8. Southwest J Pulm Crit Care. 2014;9(4):247-8. doi: http://dx.doi.org/10.13175/swjpcc143-14 PDF

July 2014 Phoenix Critical Care Journal Club: Predicting the Future

Journal club was held on July 23, 2014 and six articles were reviewed. Four of the articles were on predicting mortality or complications in the ICU. We have long known that older, sicker patients are more likely to die or have complications. However, when attempts are made to go beyond this, it supports one of our favorite Yogisms, “It's tough to make predictions, especially about the future.” The last two articles were concerning the best choice for crystalloid administration in adult patients with sepsis and a review article on palliative care in the ICU.

Harhay MO, Wagner J, Ratcliffe SJ, et al. Outcomes and statistical power in adult critical care randomized trials. Am J Respir Crit Care Med. 2014;189(12):1469-78. [CrossRef] [PubMed] 

Intensive care unit (ICU)-based randomized clinical trials (RCTs) among adult critically ill patients commonly fail to detect treatment benefits. The authors examined 146 RCTs, 54 (37%) were positive (i.e., the a priori hypothesis was found to be statistically significant). The most common primary outcomes were mortality (n = 40 trials), infection-related outcomes (n = 33), and ventilation-related outcomes (n = 30), with positive results found in 10, 58, and 43%, respectively. Statistical power was discussed in 135 RCTs (92%); 92 cited a rationale for their power parameters. Twenty trials failed to achieve at least 95% of their reported target sample size, including 11 that were stopped early due to insufficient accrual/ logistical issues. It was fascinating to see that the expected mortality benefit of various investigational treatments in critical care, used to calculate the sample size of each study, was more favorable than the observed mortality benefit in 33 of 34 studies.  This probably occurs because overly-optimistic assumptions regarding the possible benefit of the intervention results in lower (more doable) sample size.  But when the assumption is found to have been incorrect, as is almost always the case, The study turns out to have been underpowered.  The authors conclude that ICU-based RCTs are commonly negative and powered to identify what appear to be unrealistic treatment effects. Additional concerns include a lack of standardized methods for assessing common outcomes, unclear justifications for statistical power calculations, insufficient patient accrual, and incorrect predictions of baseline event rates. As we have repeatedly emphasized in these journal clubs this review supports caution in reading and interpreting clinical trials. A positive result is much easier to obtain with a surrogate outcome such as infection or ventilation parameters but raises the question of the relevance of a surrogate outcome to a patient-centered outcome such as mortality.

Schmidt M, Bailey M, Sheldrake J, et al. Predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score. Am J Respir Crit Care Med. 2014;189(11):1374-82. [CrossRef] [PubMed] 

The authors created a model for predicting hospital survival at initiation of extracorporeal membrane oxygenation (ECMO) for respiratory failure. They used bootstrapping methodology to examine pre-ECMO variables independently associated with hospital survival on logistic regression, which included age, immunocompromised status, duration of mechanical ventilation before ECMO, diagnosis, central nervous system dysfunction, acute associated nonpulmonary infection, neuromuscular blockade agents or nitric oxide use, bicarbonate infusion, cardiac arrest, PaCO2, and peak inspiratory pressure to create the Respiratory ECMO Survival Prediction (RESP) score. The receiver operating characteristics curve analysis of the RESP score was c = 0.74 (95% confidence interval, 0.72–0.76). External validation, performed on 140 patients, exhibited excellent discrimination (c = 0.92; 95% confidence interval, 0.89–0.97). The results are not surprising since these variables have been used to predict survival of ICU patients in general. However, it is reassuring to know that there is nothing unique in predicting survival in patients who receive ECMO.

Oddo M, Rossetti AO. Early multimodal outcome prediction after cardiac arrest in patients treated with hypothermia. Crit Care Med. 2014;42(6):1340-7. [CrossRef] [PubMed]

Therapeutic hypothermia and pharmacological sedation may influence outcome prediction after cardiac arrest. In this prospective cohort study, the authors used  clinical examination, electroencephalography, somatosensory-evoked potentials, and serum neuron-specific enolase, to predict survival in 134 consecutive adults treated with

therapeutic hypothermia after cardiac arrest. Multivariable ordinal logistic regression identified absence of electroencephalography reactivity (p < 0.001), incomplete recovery of brainstem reflexes in normothermia (p = 0.013), and neuron-specific enolase higher than 33 μg/L (p = 0.029), but not somatosensory-evoked potentials, as independent predictors of poor outcome. The combination of clinical examination, electroencephalography reactivity, and neuron-specific enolase yielded the best predictive performance (receiving operator characteristic areas: 0.89 for mortality and 0.88 for poor outcome), with 100% positive predictive value.

This study had a fatal methodological flaw – the relationship between survival and the predictor variables was highly biased since the predictor variables were used as criteria for the decision to withdraw care.  Most previous studies have demonstrated that neurological examination alone (the lack of withdrawal to pain, or failure to recover cranial nerve reflexes at 72 hours) yielded high positive predictive values for poor outcome.  This is the most important statistical characteristic to clinicians when a family asks “what is the chance my father will wake up after this arrest?”  Therapeutic hypothermia seems to have pushed back the time frame for prognostication, but hopefully will not create the need for more ancillary testing such as EEGs or serum neuron-specific enolase.  The later is a send-out test at our hospital with a long turn-around time.  As clinicians retreat from using 32-34º C as a goal for therapeutic hypothermia, based on RCT-evidence that 36º C. is as efficacious, we  may be able to retrieve confidence in traditional bedside prognostication that served us well for decades.

The authors caution that although prognostication of poor outcome seems excellent, future studies are needed to further improve prediction of good prognosis, which still remains inaccurate.

Cecchini J, Lionnet F, Djibré M, et al. Outcomes of adult patients with sickle cell disease admitted to the ICU: a case series. Crit Care Med. 2014;42(7):1629-39. [CrossRef] [PubMed] 

This was a retrospective observational cohort study of 138 admissions of sickle cell disease patients admitted over a 6-year period to the ICU of a French teaching hospital and sickle cell disease referral center. ICU admissions were mainly indicated for sickle cell disease–related events, especially acute chest syndrome. Those patients with a more complicated outcome group (n = 28; 20%) were characterized by a more aggressive acute disease within the 48 hours preceding ICU admission, with a higher respiratory rate, a more frequent acute kidney injury, and a more sustained drop of hemoglobin (all p < 0.01). In multivariate analysis, hemoglobin less than or equal to 7.8 g/dL (odds ratio, 3.6; 95% CI, 1.1–11.9), respiratory rate more than or equal to 32 cycles/min (odds ratio, 5.6; 95% CI, 1.8–17.2), and acute kidney injury on ICU admission (odds ratio, 11.5; 95% CI, 2.5–52.6) were independently associated with a complicated outcome.  Many patients that end up in the ICU with life-threatening complications of sickle cell disease start out as floor admissions with pain crisis.  Recognition that those with worse tachypnea, anemia and renal function are at risk to deteriorate could present an opportunity to intensify treatment before sickle chest crisis evolves.

Raghunathan K, Shaw A, Nathanson B, et al. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis. Crit Care Med. 2014;42(7):1585-91. [CrossRef] [PubMed] 

The authors examined the association between choice of crystalloids and in-hospital mortality during the resuscitation of critically ill adults with sepsis with a retrospective cohort study. They used propensity score matching to control for confounding variables.  A total of 53,448 patients at multiple centers with sepsis, treated with vasopressors and crystalloids in an ICU by hospital day 2 were included. Patients treated with balanced fluids were younger and less likely to have heart or chronic renal failure, but they were more likely to receive mechanical ventilation, invasive monitoring, colloids, steroids, and larger crystalloid volumes (median 7 vs 5 L). Among 6,730 patients in a propensity-matched cohort, receipt of balanced fluids was associated with lower inhospital mortality (19.6% vs 22.8%; relative risk, 0.86; 95% CI, 0.78, 0.94). Mortality was progressively lower among patients receiving larger proportions of balanced fluids. There were no significant differences in the prevalence of acute renal failure (with and without dialysis) or in-hospital and ICU lengths of stay. We usually avoid balanced salt solutions such as Lactated Ringer's because it is sometimes difficult to remember what is actually being administered to the patient. The finding of a lower mortality with balanced salt solutions, if confirmed by a randomized study, is interesting but given the limitations of the study (observational, based on coding, nonrandomized, not confirmed by chart review, patients receiving balanced salts were less ill, etc.) it was insufficiently persuasive to convince most of us to switch.

Cook D, Rocker G. Dying with dignity in the intensive care unit. N Engl J Med. 2014;370(26):2506-14. [CrossRef] [PubMed] 

All of us have cared for patients in the ICU with little to no hope of survival. This review supports the concept that palliative care has come of age in the ICU. At both the VA and Good Samaritan we have been fortunate to have helpful palliative care teams. All of us felt that their input significantly added to care. It was also mentioned that not all patients need to die in an ICU. Palliative care can be valuable in improving death with dignity both in and out of the ICU.

Richard A. Robbins, MD

Robert A. Raschke, MD

Reference as: Robbins RA, Raschke RA. July 2014 Phoenix critical care journal club: predicting the future. Southwest J Pulm Crit Care. 2014;9(2):68-71. doi: http://dx.doi.org/10.13175/swjpcc103-14 PDF

April 2014 Tucson Critical Care Journal Club: Early Goal-Directed Therapy

The ProCESS investigators. A randomized controlled trial of protocol-based care for early septic shock. New Engl J Med. 2014 epub ahead of print. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1401602 (accessed 4/24/14).

Editor's note: The April 2014 Phoenix Critical Care Journal Club also reviewed the same article and interpreted the data somewhat differently.

In 2001, Early Goal Directed Therapy (EGDT) was demonstrated to improve 60 day mortality as compared to usual care practices, 44.3% vs. 56.9%, respectively (p=0.03) (1). EGDT and its components have since been incorporated into the major guidelines for the treatment of sepsis (2,3). The subsequent critical care literature has focused on adherence to EGDT protocols, the value of individual protocol components, and alternative protocols that are less standardized (4-6). The ProCESS trial was conducted to assess the continued benefit of protocol-based sepsis treatment strategies in a contemporary setting.

ProCESS randomized 1351 adult patients who were suspected to have septic shock (≥2 SIRS criteria plus refractory hypotension and/or elevated lactate) to the original EGDT protocol, a newer simplified protocol, or usual care. The study took place in 31 academic centers in the United States; these centers could not have been previously using septic shock treatment protocols. The simplified protocol differed from the original EGDT protocol by not mandating central venous monitoring of oxygen saturation (ScVO2) and by allowing greater flexibility of fluid, vasopressor, and transfusion treatment to achieve blood pressure and shock index goals.

The primary outcome was the difference in 60 day mortality between the two protocol-based approaches and usual care. If this comparison was significant, then the two protocol-based approaches would be compared. The initial sample size calculation estimated that 1950 patients would be needed to achieve 80% power to detect a 6-7% absolute reduction in mortality assuming that mortality would be 30—46% in the usual care group. Because mortality in the usual care group was observed to be lower than expected (20%) a smaller sample size was deemed sufficient to detect the same absolute risk reduction without loss of power.

Of the 12,707 patients who were screened, 1,351 (10%) were ultimately enrolled. Major reasons for exclusion included lack of hypoperfusion (30%), lack of refractory hypotension (26%), study logistic issues (13%), no suspected infection (11%), <2 SIRS criteria (7%), or a Do-Not-Resuscitate order (7%).

There was no statistical difference in 60 day mortality between the two protocol-based strategies and usual care, 19.5% vs. 18.9%, respectively (p=0.83).  Among secondary endpoints, the simplified protocol was associated with a greater risk of renal replacement therapy as compared to the other two groups, but this association was marginally significant (p=0.04). Admission to the ICU was more likely in the original EGDT protocol (91.3%) versus either the simplified protocol (85.4%) or usual care (86.2%, p=0.01). Serious adverse events were rare and no different across the 3 treatment groups.

There were significant differences observed across the original EGDT protocol, simplified protocol, and usual care groups with respect to the use of CVC (93.6% vs. 56.5% vs. 57.9%,respectively; p=<0.001), fluid administration within first 6 hours (2.8L vs. 3.3L vs. 2.3L, respectively; p=<0.001), vasopressor use (54.9% vs. 52.2% vs. 44.1%, respectively; p=0.003), dobutamine use (8% vs. 1.1% vs. 0.9%, respectively; p=0.001) and PRBC use (14.4% vs. 8.3% vs. 7.5%, respectively; p=0.001).

It is important to compare the mortality observed in the current study’s usual care group with that observed in the 2001 study’s usual care group, 18.9% vs. 56.9%, respectively. This difference was observed despite similarities between the current study population and the 2001 study population: APACHE 2 score (20.8 vs. 20.4, respectively), mean serum lactate level (4.8 mmol/L vs. 6.9 mmol/L, respectively), and age (62 vs. 67 yrs, respectively).

Given the advances in sepsis care that have occurred since 2001, it is difficult to interpret the current study’s results. Taken at face value, they seem to suggest that protocol-based treatment is of no benefit. However, the importance of early sepsis recognition, aggressive fluid resuscitation, and timely antibiotic administration has become widely known and has been codified by professional societies and treatment guidelines. So much so that the treatment received in the usual care arm was difficult to distinguish from that received in the EGDT group with the exception of less central venous catheterization.

In summary, ProCESS did not demonstrate any benefit from protocolized treatment of septic shock; however, we cannot help but question the utility of this result given the apparent ubiquity of EGDT as routine practice in these academic medical centers.

Bhupinder Natt MBBS, Cristine Berry MD, Christian Bime MD and Joe Gerald PhD

University of Arizona

Tucson, AZ

References

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Reference as: Natt B, Berry C, Bime C, Gerald J. April 2014 Tucson critical care journal club: early goal-directed therapy. Southwest J Pulm Crit Care. 2014;8(4):243-5. doi: http://dx.doi.org/10.13175/swjpcc058-14 PDF