Fluid Resuscitation for Septic Shock – A 50-Year Perspective: From Dogma to Skepticism

Robert A. Raschke, MD

Arooj Kayani, MD 

Samir Sultan, DO

Stephanie Fountain, MD

Moustafa Abidali, DO

Kyle Henry, MD

Banner University Medical Center Phoenix

Phoenix, AZ USA 

Few clinicians would challenge the contention that fluid resuscitation of sepsis improves tissue perfusion thereby protecting end-organs from injury. This is an underlying tenet of current Surviving Sepsis Campaign (SSC) recommendations (1) and Center for Medicare and Medicaid Services (CMS) mandate that hospitals report sepsis bundle compliance as a measure of healthcare quality.  It has persisted for decades despite the lack of convincing empirical evidence that fluid resuscitation improves clinical outcomes. To the contrary, large randomized controlled trials have shown that aggressive intravenous fluid resuscitation prolongs the need for mechanical ventilation (2) and increases mortality in some patients (3) – more on these studies later.  Furthermore, the pathophysiological rationale commonly used to explain why fluid resuscitation ought to be beneficial has been challenged by a growing body of evidence.  This article started as a journal club held by our Pulmonary Critical Care fellows, but we expanded the scope to review other related studies over the past 50 years that challenge the current accepted paradigm of aggressive fluid resuscitation of sepsis and septic shock.

The positive results of River’s early goal-directed therapy (EGDT) trial in the early 2000s (4) were inexplicable to many that followed previous literature. EGDT required aggressive fluid resuscitation to achieve a central venous pressure (CVP) >8-12 cmH₂O, culminating in a mean positive fluid balance >13 L at 72 hours. But it had been recognized for decades that CVP could not reasonably be used in this manner. In 1965, Dr. Max Weil (considered by some the founder of critical care medicine) made the observation that the CVP is primarily an index of right ventricular function rather than an index of volume status (5). The widely-held concept (which has persisted since 1965) that low venous pressure indicates low blood volume was developed using data from normal subjects and was not valid in critical illness. Elevated CVP reflects incompetence of the heart to accept the blood returned to it. As such, CVP ought to be used primarily to limit over-resuscitation rather than to indicate when more fluids are needed (5).

These early observations and decades of corroborating evidence were set-aside for yet another decade as EGDT was systematically endorsed. Near the peak of enthusiasm for EGDT, a meta-analysis of 24 studies demonstrated no significant relationship between CVP and blood volume (r²=0.02) or fluid responsiveness (r²=0.03) (6). A graph from that article based on 1500 simultaneous measurements of CVP and blood volume graphically illustrates the apparent lack of any association, supporting Dr Weil’s clinical observations from over 40 years earlier (Figure 1). 

Figure 1. Graph of simultaneous measurements of blood volume and central venous pressure (CVP) in a heterogenous cohort of 188 ICU patients demonstrating no association between these two variables (r=0.27) (6).

Nevertheless, EGDT was avidly endorsed by authoritarian professional organizations and immense time and effort expended on national and international efforts to promote it’s systematic implementation. Several observational studies showed that systematic implementation of EGDT in healthcare institutions decreased sepsis mortality (7,8). However,  the use of historical controls in these studies allowed other simultaneous changes in ICU practice and the Hawthorne effect to potentially confound their results.

In 2006, the ARDS clinical trials network published a multi-center controlled trial that randomized 1000 patients with acute lung injury to liberal or conservative fluid management (2). Approximately 70% of the patients in the study satisfied current criteria for sepsis (were classified as having sepsis or pneumonia with acute organ system dysfunction). Critical appraisal of the study revealed that >90% of screened patients were excluded, complicated fluid management protocols were unlikely to be practical for routine use and the study was not blinded. But the study methodology was otherwise essentially sound. Liberal fluid management achieved a more positive fluid balance over the first 7 days (+6992 +/-502 mL vs. -136 +/- 491 mL p<0.001), but failed to reduce the incidence of shock or acute renal failure requiring dialysis. It was instead associated with significantly prolonged ventilator dependence (12.1 vs. 14.6 ventilator-free days, p<0.001) and prolonged ICU length-of-stay (11.2 vs. 13.4 ICU-free days, p<0.001).  These results seemed contrary to those of Rivers and we struggled at the time to reconcile the two. Our shared impression at journal club is that aggressive fluid resuscitation followed by permissive hypervolemia, such as seen in the liberal fluid management arm of this study, is still common in current practice. This study suggests that this approach significantly prolongs recovery from acute lung injury. 

Maitland’s study of fluid boluses in African children in 2011 is remarkable as the only large prospective randomized controlled trial (RCT) to study the clinical effect of early fluid resuscitation in patients with severe infections (3). The study randomized children with high fever and clinical evidence of impaired perfusion to three groups: 5% albumin bolus, normal saline bolus or no bolus. The safety monitoring committee ended the study after 3141 of 3600 projected patients had been enrolled, based on evidence that administration of either type of fluid bolus significantly increased mortality (RR 1.45 95%CI: 1.13-1.86 p=0.003). Methodology was limited by available healthcare infrastructure. Although the proportion of patients with sepsis cannot be calculated, 39% had a lactate >5 mmol/L. The study had reasonable internal validity, but significant challenges to external validity – the mean patient age was 23 months, and 57% had malaria.  However, the authors noted: “The excess mortality with fluid resuscitation was consistent across all subgroups, irrespective of physiological derangement (whether or not the patient was in shock) or underlying microbial pathogen, raising fundamental questions about our understanding of the pathophysiology of critical illness.” The authors speculated that the neuro-hormonal vasoconstrictor response to shock might confer protection by reducing perfusion to non-vital tissues and that rapid reversal with fluid resuscitation could therefore be harmful. This specific hypothesis was supported by a post-hoc analysis that showed that the increased mortality associated with fluid boluses could not be explained by an increase in pulmonary or cerebral edema.  Although the generalizability of this study is limited, there is no comparable RCT of fluid boluses in any other group of patients to refute it’s findings.

The review of resuscitation fluids by Myberg and Mythen in 2013 (9) emphasized ongoing uncertainty and reasoned against a protocolized approach driving aggressive fluid resuscitation stating “the requirements for and response to fluid resuscitation vary greatly during the course of any critical illness. No single physiological or biochemical measurement adequately reflects the complexity of fluid depletion or the response to fluid resuscitation.”  They reviewed observational evidence that the development of positive fluid balance and elevated CVP were associated with increased mortality in patients with sepsis. They pointed out that intravenous fluids should be considered as a drug with potentially serious side effects: interstitial edema - and in the case of normal saline, hyperchloremic acidosis and acute kidney injury. They recommended modest amounts of balanced isotonic salt solutions guided by clinical consideration of multiple individual patient factors, cautioned against continuing fluid resuscitation after the first 24 hours of illness and encouraged early initiation of norepinephrine.

Myberg’s review was published about the time that the results of three randomized controlled trials, which cumulatively enrolled 4201 patients at 138 emergency departments and ICUs internationally conclusively refuted any clinical benefit of EGDT (10-12). Shortly thereafter, CMS paradoxically mandated monthly sepsis bundle compliance reporting as a measure of healthcare quality, strongly incentivizing hospitals to systematically institute sepsis bundles, even though they had just been proven to be ineffective.

We greatly enjoyed the review of fluid therapy in sepsis by Marik and Bellomo (13). They argue that the standard pathophysiological explanation for the theoretical benefit of fluid resuscitation in sepsis is contradicted by a growing body of evidence. Septic shock is not characterized by hypovolemia but rather by vasoplegia and injury to the endothelial glycocalyx. Resultant microvascular permeability and propensity to interstitial edema impairs organ function. As such, restoration of vascular tone (including that of capacitance veins) is the preferred initial intervention to restore perfusion. Elevating the CVP > 8 cm H₂O with fluid boluses does not reliably improve preload and cardiac output as commonly supposed. Instead, it most often overfills the heart, inducing acute diastolic dysfunction in a majority of patients. This paradoxically reduces stroke volume and moves the patient onto the flat portion of the Frank Starling curve mitigating any potential augmentation of cardiac fluid by further fluid administration. Elevated CVPs in this setting are not an indication of successful fluid resuscitation but rather a sign of cardiac incompetence to accommodate iatrogenic hypervolemia. Cardiac natriuretic peptides released in response to cardiac overfilling cleave glycoproteins that make up the endothelial glycocalyx further injuring it. Venous back-pressure worsens organ perfusion and increases interstitial edema, particularly affecting the kidneys. However, cellular hypoxia and bioenergetics failure does not occur and is not the cause of lactic acidosis in septic shock as is often supposed. Elevated lactate levels are instead caused by bioenergetic-coupling of epinephrine-induced stimulation of Na/K ATPase activity to aerobic glycolysis. The critical level of oxygen delivery below which oxygen consumption falls is almost never associated with septic shock, and increasing oxygen delivery has been not been shown to improve oxygen consumption or lower lactate levels. Attempts to specifically increase oxygen delivery in sepsis have in fact worsened survival. 

Furthermore, only a minority of patients with sepsis respond with increased stroke volume after a fluid bolus. Hemodynamic improvements seen in “fluid responders” return to baseline within an hour. 95% of administered fluid is rapidly sequestered in tissues where it contributes to organ dysfunction. Goal-directed fluid administration achieves only a transient hemodynamic improvement in a minority of patients at the cost of accumulating injurious tissue edema in all. Analysis of five serial randomized controlled trials that ultimately disproved the efficacy of EGDT shows that sepsis mortality has been fallen significantly over the past 15 years in association with a tendency towards significantly more conservative fluid management (approx. 13L/72hrs vs. 6L/72 hours) suggesting that a more conservative approach to fluid resuscitation may explain improved survival (Figure 2).

Figure 2. Fluid administerered between enrollment and 72 h and 90-day mortality in the control arm of the early goal directed therapy (EGDT) studies performed between 2001 and 2015. APACHE II=APACHE II severity of illness scoring system.

Marik and Bellomo (13) recommend early administration of norepinephrine, which can be safely administered via a well-functioning peripheral intravenous catheter and cautious administration of small volume fluid boluses (200-500 mL) only in patients in whom passive leg raise (a reversible fluid bolus) can be demonstrated to augment stroke volume. They argue that CVP, central venous oxygen saturation and lactate should not be used to guide fluid management, and should in fact not even be measured.

Taken individually, each of these studies seems anomalous in the context of our preconceived notion that aggressive fluid resuscitation must be beneficial. Taken together, they comprise a cohesive argument that ought to change our bedside care.  There certainly isn’t any convincing or enduring empirical evidence that aggressive fluid resuscitation of sepsis is clinically beneficial. There is only flawed pathophysiologic rationale and dogma. The common practice of aggressive fluid resuscitation followed by prolonged permissive hypervolemia should be actively avoided. As we struggle to comply with a CMS mandate regarding sepsis bundle compliance in the face of overwhelming evidence that it doesn’t work, we recommend a focus on early administration of appropriate antibiotics and maintenance of adequate perfusion pressure with vasopressors – the only bundle components likely to be associated with improved patient outcomes.

References

1. Dellinger RP, Levy MM, Rhodes A, et al. ; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. [CrossRef] [PubMed]
2. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564-75. [CrossRef] [PubMed]
3. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011 Jun 30;364(26):2483-95. [CrossRef] [PubMed]
4. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. [CrossRef] [PubMed]
5. Weil MH, Shubin H, Rosoff L. Fluid repletion in circulatory shock. JAMA. 1965;192:84–90. [CrossRef] [PubMed]
6. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest. 2008 Jul;134(1):172-8. [CrossRef] [PubMed]
7. Ferrer R, Artigas A, Levy MM, et al. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008 May 21;299(19):2294-303. [CrossRef] [PubMed]
8. Rhodes A, Phillips G, Beale R, et al. The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study). Intensive Care Med. 2015 Sep;41(9):1620-8. [CrossRef] [PubMed]
9. Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013 Sep 26;369(13):1243-51. [CrossRef] [PubMed]
10. ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. [CrossRef] [PubMed]
11. ARISE Investigators; ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496-506. [CrossRef] [PubMed]
12. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015 Apr 2;372(14):1301-11. [CrossRef] [PubMed]
13. Marik P, Bellomo R. A rational approach to fluid therapy in sepsis. Br J Anaesth. 2016 Mar;116(3):339-49. [CrossRef] [PubMed] 

Cite as: Raschke RA, Kayani A, Sultan S, Fountain S, Abidali M, Henry K.  Fluid resuscitation for septic shock – a 50-year perspective: from dogma to skepticism. Southwest J Pulm Crit Care. 2016;13(2):65-70. doi: http://dx.doi.org/10.13175/swjpcc073-16 PDF 

Clinical Performance Of An Automated Systemic Inflammatory Response Syndrome (SIRS) / Organ Dysfunction Alert: A System-Based Patient Safety Project

Robert A Raschke, MD, MS

Huw Owen-Reece, MBBS

Hargobind Khurana, MD 

Robert H Groves Jr, MD

Steven C Curry, MD

Mary Martin, PharmD

Brenda Stoffer

Suresh Uppalapu, MD 

Heemesh Seth, DO

Nithya Menon, MD 

Banner Good Samaritan Medical Center, Phoenix Arizona

Abstract

Objective: We have employed our electronic medical record (EMR) in an effort to identify patients at the onset of severe sepsis through an automated analysis that identifies simultaneous occurrence of systemic inflammatory response syndrome (SIRS) and organ dysfunction. The purpose of this study was to determine the positive predictive value of this alert for severe sepsis and other important outcomes in hospitalized adults.

Design: Prospective cohort.

Setting: Banner Good Samaritan Medical Center, Phoenix AZ

Patients: Forty adult inpatients who triggered alert logic within our EMR indicating simultaneous occurrence of SIRS and organ dysfunction.

Interventions: Interview of bedside nurse and chart review within six hours of alert firing to determine the clinical event that triggered each alert.

Results: Eleven of 40 patients (28%) had a major clinical event (immediately life-threatening illness) associated with the alert firing. Severe sepsis or septic shock accounted for four of these – yielding a positive predictive value of 0.10 (95%CI: 0.04-0.23) of the alert for detection of severe sepsis. The positive predictive value of the alert for detection of major clinical events was 0.28 (95%CI: 0.16-0.43), and for detecting either a major or minor clinical event was 0.45 (95%CI: 0.31-0.60). Twenty-two of 40 patients (55%) experienced a false alert.

Conclusions: Our first-generation SIRS/organ dysfunction alert has a low positive predictive value for severe sepsis, and generates many false alerts, but shows promise for the detection of acute clinical events that require immediate attention. We are currently investigating refinements of our automated alert system which we believe have potential to enhance patient safety.

Introduction

Severe sepsis is defined as systemic inflammatory response syndrome (SIRS) of infectious etiology with secondary organ dysfunction. It is estimated that 750,000 patients suffer severe sepsis annually in the United States - 3 cases per 1000 population (1). Mortality has fallen over the past several decades, but ranges from 20-30% in recent studies (1,3). Results of recent treatment trials for severe sepsis are consistent with the hypothesis that early diagnosis and treatment are important (2,3), but reliable systems for early recognition of severe sepsis in hospitalized patients are not widely available.  

We have sought to improve patient safety at our institution by using our integrated electronic medical record (EMR) to identify patients at the onset of severe sepsis through a logic algorithm that analyzes vital signs and laboratory data. This logic function identifies patients with simultaneous systemic inflammatory response syndrome (SIRS) and organ dysfunction, but cannot distinguish whether an acute infection is the cause of these findings. The purpose of this study was to determine what clinical events – infectious or non-infectious - actually cause the vital sign and laboratory changes that trigger this alert, and what the positive predictive valve of the alert is for detecting the onset of severe sepsis in hospitalized adult patients.

Methods

This was a prospective cohort study carried out at Banner Good Samaritan Medical Center – a 700-bed University-affiliated teaching hospital in Phoenix AZ. It was part of an ongoing quality improvement project and was thereby exempted from IRB approval. The SIRS / organ dysfunction alert logic was developed at Banner Health using Cerner Discern Expert^®, Cerner Corporation, North Kansas City MO, USA. The logic function monitored the EMR for standard SIRS criteria and laboratory evidence of organ dysfunction with thresholds consistent with standard definition of severe sepsis (Table 1) (4,5).

Table 1. Specific criteria for the logic function of our SIRS/organ failure alert. 

When any single criterion for SIRS was met, the program searched the prior 6 hours for the most recent vital signs, and the prior 30 hours for the most recent white blood cell count. If a second SIRS criterion was met, the program identified the patient as exhibiting SIRS, but did not trigger an alert. When any single laboratory criterion for organ dysfunction was met (table 1), the program identified the patient as suffering organ dysfunction. If criteria for SIRS and organ dysfunction overlap in any 8 hour window, the alert fired, triggering a real-time notification in the Cerner Millenium^® EMR alerting clinicians to the possibility of severe sepsis or septic shock. The alert has been in clinical application since 2010. 

We sampled 40 non-consecutive inpatients in the first three months of 2014 by a nonrandom method blinded to the patient’s clinical condition. On days of data collection, all alerts that had fired within the prior 6 hours were reviewed, regardless of patient location or diagnosis. The patient bedside was visited by a physician researcher during the six-hour window after alert firing and the nurse interviewed in order to determine the circumstances that caused the alert to fire. The patient might be briefly examined if necessary to confirm the nursing impression. Chart review was also performed to assist in this determination. Demographics, admission diagnosis, vital signs and laboratory data that triggered the alert logic, and any treatment the associated clinical event required were also recorded. Chart review was repeated 48 hours later to review microbiological test results and physician progress notes that might shed further light on the clinical event that triggered the alert.

The “clinical event” associated with each alert was defined as the most likely acute explanation for the vital sign and laboratory abnormalities that triggered the alert. A clinical event might be an acute illness, such as pneumonia with septic shock, or a non-illness event, such as initiation of dialysis. Clinical events could include the illness that necessitated admission if the alert fired within 24 hours of admission, or secondary illnesses - for instance, a catheter-associated blood stream infection.

The severity of clinical events related to alert firings were classified into three tiers. 

1. Major clinical events were acute life-threatening illnesses that required emergent resuscitation with any one or more of the following: >1 L intravenous fluid resuscitation, vasopressor infusion, >2 units of packed red blood cell transfusion, endotracheal intubation, advanced cardiac life support, or emergent surgical intervention.
2. Minor clinical events were acute non-life-threatening illnesses that required urgent treatments not included in the definition of major clinical events above.
3. False alerts were said to have occurred when no acute illness was recognized in temporal relationship to the alert firing. 

The positive predictive value of the alert for detecting severe sepsis, major clinical events, and major or minor clinical events were calculated, with 95% confidence intervals.

Results

Nineteen women and 21 men, with ages ranging from 22 to 103 years were included. Twenty-two of forty (55%) were in the ICU at the time the alert fired, and 18 on the floors. Vital signs and laboratory values that triggered the alert logic are listed in Table 2. 

Table 2. SIRS / organ dysfunction alert trigger criteria in forty patients. 

Eleven of 40 patients (28%) had a major clinical event associated with the alert firing – two of these occurred outside the ICU. Severe sepsis or septic shock accounted for four of these major clinical events – yielding a positive predictive value of 0.10 (95%CI: 0.04-0.23) of the alert for detection of severe sepsis or septic shock. The seven remaining patients with major events suffered acute pulmonary edema, pulmonary embolism, ischemic bowel, pancreatitis, acute cardiogenic shock, acute right heart failure secondary to pulmonary hypertension, and an incarcerated enteric hernia. The positive predictive value of the alert for detection of major clinical events was 0.28 (95%CI: 0.16-0.43).

Major clinical events were clearly recognized before the alert fired in nine of 11 cases, as evidenced by the patient having been admitted or transferred to the intensive care unit specifically for the event of interest, and/or having received treatment such as intubation or initiation of intravenous vasopressors before the alert fired. In two cases, the alert fired at about the same time that treatment of the acute clinical event commenced, and it was unclear what role it played in clinical recognition of the event.

Seven of 40 patients (17%) had a minor clinical event associated with the alert firing. These included two patients with anemia, and one each with hypotension from an antihypertensive medication, dialysis disequilibrium, post-operative pain, dehydration, and paroxysmal atrial fibrillation. The positive predictive value of the alert for detecting either a major or minor clinical event was 0.45 (95%CI: 0.31-0.60).

Twenty-two of 40 patients (55%) were not experiencing any identifiable acute illness that could explain the alert firing - these were considered false alerts. Aberrant vital signs triggered false alerts during dialysis (2), turning or sitting-up post-operative patients (2), an endoscopy procedure, and a family argument. Other false alerts were attributable to the pharmacological effect of calcium channel blocker, oximeter malfunction, error in vital sign entry, and widely discrepant blood pressures between right and left arms. The remaining false alerts were triggered by slightly abnormal vital signs with no identifiable cause.

Four patients (10%) did not survive to discharge – two had major clinical events, one a minor clinical event and one a false alert – in the later two cases, the cause of death was unrelated to the clinical event that triggered the alert.  

We examined alert triggering criteria to better understand how the discriminant ability of the alert might be improved. We noted that 15 of 40 (37%) alerts triggered with respiratory rates of 21 or 22 bpm, however these included six alerts associated with major clinical events. Twelve of 40 (30%) alerts triggered with heart rates in 91-95 bpm range, including two alerts associated with major clinical events. Laboratory results contributed to 31 of 40 alert firings – but in 12 cases they were stable or improving at the time they triggered the alert. In no case was a stable or improving laboratory value associated with a major clinical event.

Discussion

It’s important to study the effects of any quality improvement project in order to determine whether it is having the desired results. Our small pilot study suggests that our first-generation SIRS/organ dysfunction alert has a low positive predictive value for severe sepsis, and generates many false alerts. This is partially a reflection of the low specificity of SIRS criteria for sepsis (6). The high number of false positive alerts has led to alert-fatigue among physicians and nurses providing bedside patient care – a phenomenon which is not unique to our institution (7).  

Our alert demonstrated greater potential utility to detect acute clinical deterioration than to detect sepsis. Buck and colleagues (7) used an EMR-based logic system to activate a sepsis alert similar to ours, and observed similar results in that only 17% of alert patients had a sepsis-related discharge diagnosis, but 40% had a major illness which required urgent intervention. We have used the results of our study to re-task future iterations of our alert to detect acute clinical deterioration rather than sepsis.

Other researchers provide guidance in this regard. Vital sign and laboratory result criteria similar to the ones used in our study have been previously shown to predict in-hospital cardiac arrest (8), predict 30-day mortality (9), generate early warning scores to detect acute clinical deterioration (9), and activate medical emergency teams (8,10). A recent large study by Churpek and colleagues (11) validated a risk stratification tool that utilized vital signs, laboratory findings and demographics to predict the combined outcome of cardiac arrest, ICU transfer or death on the wards. The model yielded notable discriminant accuracy with an area under the receiver operating curve (AUROC) of 0.77.

We are currently investigating revisions in our alert logic to improve detection of acute clinical deterioration. The alert logic now trends laboratory values associated with organ dysfunction. We are studying whether adding a reflex serum lactate to the automatic alert response might help identify patients who are acutely deteriorating (12).   

Our study has many apparent weaknesses, but it should be noted that it was carried out originally only to provide data to help guide local efforts to improve patient safety. In this regard, it succeeded in guiding our (and perhaps other’s) future efforts in what will more likely be a useful direction.

We failed to clearly determine what role our automated alert played in bedside decision-making. In most cases, clinicians were already evaluating or treating the clinical event that triggered the alert before the alert fired. However, we feel that a safety net is a wise precaution even in a high-reliability system. It should also be noted that our institution has medicine and surgery residency teaching programs, a critical care fellowship, 24/7 in-house intensivist coverage, and remote video ICU coverage. The benefit of EMR-based automated alerts is likely to be amplified in less well-staffed institutions. Refined versions of EMR-based automated alerts, such as the ones we are currently investigating, have potential to enhance patient safety. 

References

1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303-10. [CrossRef] [PubMed]
2. Rivers E, Nguyen B, Havstad S, Ressler J, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-77. [CrossRef] [PubMed]
3. The ProCESS investigators. A randomized controlled trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-93. [CrossRef] [PubMed]
4. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G. International Sepsis Definitions Conference. Crit Care Med. 2003;31(4):1250-6. [CrossRef] [PubMed]
5. Dellinger RP, Levy MM, Rhodes A, et al, Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580. [CrossRef] [PubMed]
6. Pittet D, Range-Frausto S, Tarara LN, et al. Systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock: incidence, morbidities and outcomes in surgical ICU patients. Intensive Care Med. 1995;21:302-9. [CrossRef] [PubMed]
7. Buck KM. Developing an early sepsis alert program. J Nurs Care Qual. 2014;29(2):124-32. [CrossRef] [PubMed]
8. Hodgetts TJ, Kenward G, Ioannis G, et al. The identification of risk factors for cardiac arrest and formulation of activation criteria to alert a medical emergency team. Resuscitation. 2002;54:125-31. [CrossRef] [PubMed]
9. Goldhill DR, McNarry AF. Physiological abnormalities in early warning scores are related to mortality in adult inpatients. Br J Anaesth. 2004;92:882-4. [CrossRef] [PubMed]
10. Kenward G, Castle N, Hodgetts T, Shaikh L. Evaluation of a medical emergency team one year after implementation. Resuscitation. 2004;61:257-63. [CrossRef] [PubMed]
11. Churpek MM, Yuen TC, Winslow C, et al. Multicenter development of validation of a risk stratification tool for ward patients. Am J Respir Crit Care Med. 2014;190:649-55. [CrossRef] [PubMed]
12. Bakker J, Nijsten MWN, Jansen TC. Clinical use of the lactate monitoring in critically-ill patients. Ann Intensive Care. 2013;3:12-20. [CrossRef] [PubMed] 

Reference as: Raschke RA, Owen-Reece H, Khurana H, Groves RH Jr, Curry SC, Martin M, Stoffer B, Uppalapu S, Seth H, Menon N. Clinical performance of an automated systemic inflammatory response syndrome (sirs) / organ dysfunction alert: a system-based patient safety project. Southwest J Pulm Crit Care. 2014;9(4):223-9. doi: http://dx.doi.org/10.13175/swjpcc121-14 PDF

Critical Care Review: the High Price of Sugar

Reference as: Robbins RA, Singarajah CU. Critical care review: the high price of sugar. Southwest J Pulm Crit Care 2011;3: 78-86. (Click here for PDF version)

Richard A. Robbins, MD

Clement U. Singarajah, MD

The Phoenix Pulmonary and Critical Care Research and Education Foundation, Phoenix, AZ

Abstract

The intensive control of blood glucose had been proposed to be important in increasing survival in the intensive care unit (ICU) despite only one positive randomized trial. The concept was supported by guidelines released by several regulatory organizations including the Joint Commission of Healthcare Organizations and the Institute of Healthcare Improvement. However, the large, randomized, multi-center NICE-SUGAR trial published in 2009 showed tight control of glucose in the ICU is actually hazardous with a 14% increase in mortality. The historical basis and data used to support intense control of glucose in the ICU are reviewed and illustrate the harm that can result when guidelines are based on weak evidence.

Intensive Control of Glucose in Diabetes

Diabetes has long been associated with vascular complications. These are divided into microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular complications (coronary artery disease, stroke, and peripheral vascular disease). The concept that intense control of glucose results in improved vascular outcomes in diabetes dates back decades but has been plagued with controversy. The University Group Diabetes Program Study (UGDPS), which began in 1959, was designed to evaluate the relationship between blood sugar control and vascular complications in patients with newly diagnosed type II diabetes. The investigators found that control of blood sugar levels was ineffective in preventing the micro- and macrovascular complications associated with diabetes, regardless of the type of therapy (1). This prompted the American Diabetes Association (ADA) and the American Medical Association to withdrawn their support of UDGPS (2). In 1978, at a meeting of diabetes researchers, clinicians, and epidemiologists from the ADA, the National Institutes of Health (NIH), the Centers for Disease Control, and various university centers, it was concluded that there was “no definite evidence that treatment to regulate blood sugar levels is effective beyond relieving symptoms and controlling acute metabolic disturbances” (2).

This controversy prompted the NIH to organize the Diabetes Control and Complications Trial. This was a large, multi-center, randomized study which compared intensive to conventional treatment in preventing vascular complications in insulin-dependent, type I diabetics. Published in 1993, the results of this trial demonstrated that intensive therapy effectively delayed the onset and slowed the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with insulin-dependent diabetes (3). However, the mortality rate, incidence of macrovascular complications, and incidence of diabetic ketoacidosis were not significantly reduced. Weight gain and episodes of hypoglycemia were significantly more common in the intensive therapy group.

Published in 1998 but started in 1977, the UK Prospective Diabetes Study (UKPDS) was designed to determine if intensive blood glucose control reduced the risk of micro- or macrovascular complications in type II diabetes (4). This study is important since over 90% of adult diabetics, including the majority of diabetics in an adult ICU, have type II diabetes. This large, multi-center, randomized study compared conventional therapy with diet alone to an intense glucose control with diet and either a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or insulin. The goals of the study were to maintain fasting blood glucose of less than 270 mg/dL (15 mmol/L) in the conventional group and less than 108 mg/dL (6 mmol/L) in the intensive control group. Consistent with the blood sugar goals of the study, the hemoglobin A1C was reduced in the intensive therapy group compared to the conventional group (7.0% vs. 7.9%, p<0.05). The results in this study of type II diabetics were similar to the Diabetes Control and Complications Trial in type I diabetics. Microvascular complications, particularly retinal complications, were significantly reduced in the intensive therapy group but macrovascular complications were not. Mortality was not reduced and hypoglycemia and weight gain were more common in the intensive therapy group.

Intensive Control of Blood Glucose in the ICU

Hyperglycemia associated with insulin resistance is common in critically ill patients, even those who have not previously had diabetes (5-7). It had been reported that pronounced hyperglycemia might lead to complications. For example, studies reported that in acute myocardial infarction therapy to maintain blood glucose below 215 mg /dL (11.9 mmol/L) improved long-term outcomes (8-10). Furthermore, high serum levels of insulin-like growth factor-binding protein 1, which reflect insulin resistance, increase the risk of death (11, 12).

Spurred by the above data and the overwhelming opinion of diabetes experts that intensive control of glucose improves outcomes in diabetes and should in the ICU, van den Berge et al. (13) compared intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg/dL) to conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg/dL and maintenance of glucose at a level between 180 and 200 mg/dL) in ICU patients. The study was large with 1548 subjects but was a single center study from a surgical intensive care unit with 63% of the patients post-cardiac surgery. Reported in 2001, the results showed that intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (p<0.04). The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than five days (20.2 percent with conventional treatment, as compared with 10.6 percent with intensive insulin therapy; p=0.005).

The results of van den Berge’s original study were supported by a nonrandomized, single center study reported by Krinsley (14) in 2004. This study from a combined 14 bed medical/surgical ICU consisted of 800 consecutive patients after initiation of a intensive control protocol compared to 800 patients admitted immediately preceding initiation, i.e., a before and after design. The protocol involved intensive monitoring and treatment to maintain plasma glucose values lower than 140 mg/dL. Hospital mortality decreased 29.3% (p=0.002), and length of stay in the ICU decreased 10.8% (p=0.01) with intensive control of glucose. Despite the before and after comparison, some considered this single center study as confirmatory evidence for the mortality benefit of intensive glucose control.

It has been pointed out that van den Berge’s study had multiple limitations (15). Van den Berge’s 2001 study was a non-blinded, single center and including predominately patients after cardiac surgery, Other limitations included the unusual practices of most patients receiving intravenous glucose on arrival at the intensive care unit (ICU) at 200 to 300 g/d (the equivalent of 2-3 L of 10% glucose per day) and initiation of total parenteral nutrition, or enteral feeding, or combined feeding for all patients within 24 hours. Also, the mortality of cardiac surgery patients in the control group was 5.1% which is unacceptably high in most centers.

Kringsley’s study also had limitations (15). This was a single-center, retrospective, unblinded study and likely reflect a powerful Hawthorne effect (intense glucose control = investigator commitment and bedside presence, more tests, more attention, more patient visits, more interventions, and overall better care). Intensive insulin therapy comes at a substantial price: a greater than 6-fold increase in the risk of hypoglycemia and a marked increase in bedside nurse workload.

When many regulatory guidelines were initiated in the mid 2000’s,  not all data about glucose control and insulin in acute illness pointed to a benefit. The Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 study with more than 1000 randomized patients with myocardial infarction to intense compared to conventional glucose control failed to show a mortality benefit (16). Similarly, the Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation (CREATE)-Estudios Cardiologicas Latin America Study Group (ECLA) study with over 20,000 randomized patients with myocardial infarction failed to show a benefit of a glucose, insulin and potassium infusion regimen compared to usual care (17).

Regulatory Guidelines

By 2005 the Joint Commission on Accreditation of Healthcare Organization (Joint Commission) and the Institute for Healthcare Improvement (IHI) recommended tight glucose control for the critically ill as a core quality of care measure for all U.S. hospitals (18). Furthermore, an international initiative by several professional societies, including the American Thoracic Society, promoted a care “bundle” for severe sepsis that also includes intensive glycemic control.

Concerns about Intensive Glucose Control in the ICU

The medical literature is rife with initially positive trials followed by studies with equivocal or negative trials and occasionally followed by studies with actual harm to patients (19). Intensive control of glucose is a good example of this progression in medical research.

In late 2005, editorials urged waiting on further studies before widespread implement of tight control of glucose as usual care in the ICU. Bellomo and Egi (17) recommended awaiting the results of two large multi-center, randomized trials of tight control of glucose in the ICU, the GluControl study and the NICE SUGAR study. Angus and Abraham (18) echoed the limitations of van den Berge’s study and also advocated caution in the widespread initiation of intensive glucose control in the ICU.

Van den Berge’s group that initially reported the positive results in surgical ICU patients followed their 2001 publication with a report of medical ICU patients in 2006 (20).  In this prospective, randomized study of adult patients admitted to the medical ICU, the authors were unable to reproduce the reduction of in-hospital mortality with intensive glucose control seen in their surgical ICU patients (40.0 vs. 37.3% mortality, p= 0.33). However, the authors reported a significant improvement in morbidity with a reduction in newly acquired kidney injury, accelerated weaning from mechanical ventilation, and accelerated discharge from the ICU and the hospital. However, among the 433 patients who stayed in the medical ICU for less than three days, mortality was greater among those receiving intensive insulin therapy.  Since the mean length of stay in our medical intensive care at the Phoenix VA was a little less than 3 days, many of our group became concerned that intensive control of glucose would not improve mortality and might actually prove harmful.

The GluControl study was undertaken in 2004 to test the hypothesis that intensive control of glucose (80-110 mg/dL) improves survival of patients treated in  medical/surgical intensive care units (ICU) compared to a control target of 140-180 mg/dL. Planned enrollment was 3500 subjects but the trial was stopped in 2006 after a little over 1000 subjects because interim analysis revealed numerous protocol violations resulting in hypoglycemia. The results were initially reported as an abstract at the 20th Congress of the European Society of Intensive Care in 2008 and a full length manuscript was published in 2009 (21,22). ICU, 28-day and hospital mortality were similar in both groups. ICU and hospital length of stay were identical. Hypoglycemia defined as a blood glucose below 40 mg/dL was seen in 8.7% of the intensive therapy group vs. 2.7% in the conventional group.

Further concern about the concept of intensive glucose control was raised by Weiner et al. (23) in 2008. They searched the medical literature (MEDLINE, the Cochrane Library, clinical trial registries, reference lists, and abstracts from conferences from both the American Thoracic Society and the Society of Critical Care Medicine) and identified 29 randomized controlled trials totaling 8432 patients.  A meta-analysis did not reveal a significant difference between intensive glucose control and usual care overall (21.6% vs. 23.3%) but did reveal an increased risk of hypoglycemia (glucose ≤40 mg/dL, 13.7% vs. 2.5%). In fact, the only study that showed a mortality advantage was van den Berge’s original study in 2001.

The NICE SUGAR Study

The landmark NICE SUGAR study (24) was published in the spring of 2009. This large study randomized 6104 patients to either intensive glucose control, with a target blood glucose range of 81 to 108 mg/dL, or conventional glucose control, with a target of <180 mg/dL. The main finding of the study was that intensive glucose control resulted in a 14% increase in morality. Furthermore, the adverse treatment effect on mortality did not differ significantly between surgical patients and medical patients. As in previous trials, severe hypoglycemia (blood glucose level ≤40 mg /dL) was significantly more common in the intensive-control group (6.8%) compared to the conventional-control group (0.5%, p<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU or hospital, the median number of days of mechanical ventilation or days of  renal-replacement therapy (p>0.05, all comparisons).

Follow up data was presented by Egi et al. (25) in patients admitted to 2 ICUs. The authors analyzed all those who had a blood glucose of <81 mg/dL to determine if there was an independent association between hypoglycemia and outcome. Of the 4946 patients admitted to the ICUs, 1109 had at least 1 episode of hypoglycemia. Mortality was higher in these patients (36.6%) compared with 19.7% in the nonhypoglycemic control patients (p<0.001). Mortality increased significantly with increasing severity of hypoglycemia (p<0.001). In fact, a minimum glucose of <36 mg/dL was associated with over a four-fold increase in ICU mortality compared to a minimum blood sugar of 72-81 mg/dL. After adjustment for insulin therapy, hypoglycemia was independently associated with increased risk of death, cardiovascular death, and death due to infectious disease.

Regulatory Agency Guidelines Following the NICE SUGAR Study

Following publication of the NICE SUGAR study most regulatory agencies dropped their recommendations for intensive glucose control in the ICU. However, remnants of the concept persist. IHI continues to promote “…effective glucose control in the intensive care unit (ICU) [which] has been shown to decrease morbidity across a large range of conditions and also to decrease mortality” (26). In another posting entitled “Establish a Glycemic Control Policy in Your ICU” (27) IHI states, “Typically, clinicians’ fear of inducing hypoglycemia is the first obstacle to overcome in launching an improvement effort. Doctors remain wary of inducing hypoglycemia and may not have confidence in selecting appropriate doses. Nurses fear hypoglycemia and remain concerned about protocolized adjustments to intravenous insulin rates of administration. The balance of evidence suggests, however, that once these barriers are addressed, ICU patients receive better care with appropriate glycemic control.”  Since hypoglycemia is associated with increased mortality in the ICU (22), this doctor and nurse fear of hypoglycemia seems well founded.

Hyperglycemia

Even though hypoglycemia is associated with excess mortality, hyperglycemia is also undesirable. As Falciglia et al. (28) point out, mortality increases with increasing admission glucose in the ICU. Although this is not the same as saying correcting the hyperglycemia improves mortality, it does suggest that hyperglycemia is undesirable. Furthermore, it has long been known that mortality is increased in patients with myocardial infarction and hyperglycemia (29). However, this increase in mortality with hyperglycemia does not apply to all disease states. For example, hyperglycemia in COPD or liver failure is not associated with increased mortality (28). This may have implications if the patients in a particular ICU population have predominately cardiac, respiratory or liver disease. However, even in this study an increase in mortality was noted with an admission blood sugar of <70 mg/dL to the ICU compared to a blood sugar of 70-100 mg/dL and approximates the mortality seen with an admission glucose of >300 mg/dL.

Conclusions and Recommendations

Based on the available evidence, we would suggest maintaining blood glucose levels of less than 180-200 mg/dL while avoiding blood sugars less than 80 mg/dL in the ICU. Intensive control of glucose is not evidence based, harmful, and should be discouraged. One might be somewhat more aggressive to maintain the blood sugar below 150 mg/dL in patients who are post-operative cardiac patients or receiving large infusions of glucose such as in van den Berge’s original study (13). However, avoidance of hypoglycemia is probably more important than maintaining a blood sugar below a certain level.

The rush to publish guidelines creating a standard of care of intensive regulatory control of glucose in the ICU seems irrational in retrospect and demonstrates a potentially continued threat to patient safety. In addition, these guidelines increased the workload of both nurses and clinicians. Although often thought to be revenue neutral, these mandates come at the price of increasing personnel costs both in implementation and monitoring of a guideline. Since personnel costs account for about 60-70% of the total costs in most health care systems, such mandates may be quite costly, or as the mandate for intensive glucose regulation illustrate, may actually be harmful. If the increase in mortality of 14% with intense glucose control is true as in the NICE SUGAR trial, this would calculate to one excess death for every 84 patients treated with this protocol (24,30). It seems unlikely that any ICU guidelines mandated in the future could compensate for the excess deaths caused by the mandated implementation of intense control of glucose. Fortunately, it is doubtful that implementation was 100%.

In an editorial entitled “Intensive insulin therapy in critical illness: when is the evidence enough?” Angus and Abraham (18) addressed the issue of when there is sufficient evidence for a concept to be widely applied as a guideline. Comparing the evaluation of intensive control of glucose in the ICU to evaluation of novel pharmacologic therapies, they point out that promising phase II studies are insufficient for regulatory approval. Instead, one, and usually two, large multicenter phase III trials are necessary to confirm reliability. The same principle is echoed in evidence-based medicine, where grade A recommendations are based on two or more large, positive, randomized, and multicenter trials. This seems a reasonable suggestion. Strong recommendations of this clinical importance should only be made when two or more large randomized controlled trials concur. However, it also seems unlikely that a mere review article such as this or the multiple recommendations from clinicians such as occurred with intensive control of glucose in the ICU will attenuate the exuberance of regulatory agents to mandate physicians and nurses to conform to their guidelines. Perhaps what is needed is an independent Federal or private agency to review and approve guidelines, and as Angus and Abraham suggest require at least two randomized, multicenter trials before implementation. As long as regulatory agencies accept no responsibility for harmful recommendations, it seems likely that in the absence of regulation, mistakes similar to the mandate to intensively regulate glucose in the ICU are likely to reoccur.

References

1. University Group Diabetes Program: A study of the effects of 9. hypoglycemic agents on vascular complications in patients with adult-onset diabetes (parts I and II). Diabetes 1970;19:747-830.
2. Kilo C. Value of glucose control in preventing complications of diabetes. Am J Med 1985;79:33-7.
3. The diabetes control and complications trial research group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86.
4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. 
5. Wolfe RR, Allsop JR, Burke JF. Glucose metabolism in man: responses to intravenous glucose infusion. Metabolism 1979;28:210-20.
6. Wolfe RR, Herndon DN, Jahoor F, Miyoshi H, Wolfe M. Effect of severe burn injury on substrate cycling by glucose and fatty acids. N Engl J Med 1987;317:403-8.
7. Shangraw RE, Jahoor F, Miyoshi H, et al. Differentiation between septic and postburn insulin resistance. Metabolism 1989;38:983-9.
8. Malmberg K, Norhammar A, 8. Wedel H, Ryden L. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 1999;99:2626-32.
9. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997;314:1512-5.
10. Malmberg K, Ryden L, Efendic S, et al. A randomized trial of insulin glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects of mortality at 1 year. J Am Coll Cardiol 1995;26:57-65.
11. Van den Berghe G, Wouters P, Weekers F, et al. Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness. J Clin Endocrinol Metab 1999;84:1311-23.
12. Van den Berghe G, Baxter RC, Weekers F, Wouters P, Bowers CY, Veldhuis JD. A paradoxical gender dissociation within the growth hormone/ insulin-like growth factor I axis during protracted critical illness. J Clin Endocrinol Metab 2000;85:183-92.
13. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359-67.
14. Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc 2004;79:992-1000.
15. Bellomo R, Egi M. Glycemic Control in the Intensive Care Unit: Why We Should Wait for NICE-SUGAR. Mayo Clin Proc 2005;80:1546-8.
16. Malmberg K, Ryden L, Wedel H, et al., DIGAMI 2 Investigators. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005;26:650-661. 
17. Mehta SR, Yusuf S, Diaz R, et al. CREATE-ELCA Trial Group Investigators. ST-segment elevation myocardial infarction: the REATE-ECLA randomized controlled trial. JAMA 2005;293:437-446.
18. Angus DC, Abraham E. Intensive insulin therapy in critical illness: when is the evidence enough? Am J Resp Crit Care 2005;172:1358-9.
19. McGauran N, Wieseler B, Kreis J, Schüler YB, Kölsch H, Kaiser T. Reporting bias in medical research - a narrative review. Trials 2010;11:37.
20. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical ICU. New Engl J Med 2006;354:449-61.
21. Devos P, Preiser JC, Melot C. Impact of tight glucose control by intensive insulin therapy on ICU mortality and the rate of hypoglycaemia: final results of the Glucontrol study. Intensive Care Med 2007;33:S189 [abstract].
22. Preiser JC, Devos P, Ruiz-Santana S, Mélot C, Annane D, Groeneveld J, Iapichino G, Leverve X, Nitenberg G, Singer P, Wernerman J, Joannidis M, Stecher A, Chioléro R. A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med 2009;35:1738-48.
23. Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA 2008;300:933-44.
24. NICE-SUGAR Study Investigators. Intensive versus conventional insulin therapy in critically ill patients. N Engl J Med 2009;360:1283-97.
25. Egi M, Bellomo R, Stachowski E, et al. Hypoglycemia and outcome in critically ill patients. Mayo Clin Proc 2010;85:217-224.
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28. Falciglia M,Freyberg RW, Almenoff PL, D'Alessio DA, Render ML. Hyperglycemia-related mortality in critically ill patients varies with admission diagnosis. Crit Care Med 2009;37:3001-9.
29. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic review. Lancet 2000:355:773-8.
30. Robbins RA. Changes in medicine: the decline of physician autonomy. Southwest J Pulm Crit Care 2011;3:49-51.

Analysis of Overall Level of Evidence Behind The Institute of Healthcare Improvement Ventilator-Associated Pneumonia Guidelines

Reference as: Padrnos L, Bui T, Pattee JJ, Whitmore EJ, Iqbal M, Lee S, Singarajah CU, Robbins RA. Analysis of overall level of evidence behind the Institute of Healthcare Improvement ventilator-associated pneumonia guidelines. Southwest J Pulm Crit Care 2011;3:40-8. (Click here for PDF version of manuscript)

Leslie Padrnos^1,4(lpadrnos@email.arizona.edu)

Tony Bui^1,4 (tony.bui@cox.net)

Justin J. Pattee^2,4 (backageyard@gmail.com)

Elsa J. Whitmore^2,4 (elsa_whitmore@hotmail.com)

 Maaz Iqbal^1,4 (maaziqbal@gmail.com)

Steven Lee^3,4 (timmah2k@gmail.com)

Clement U. Singarajah^2,4 (clement.singarajah@va.gov)

 Richard A. Robbins^1,4,5 (rickrobbins@cox.net)

¹University of Arizona College of Medicine

²Midwestern University-Arizona College of Osteopathic Medicine

³Kirksville College of Osteopathic Medicine

⁴Phoenix VA Medical Center

⁵Phoenix Pulmonary and Critical Care Research and Education Foundation

None of the authors report any significant conflicts of interest.

Abstract

Background 

Clinical practice guidelines are developed to assist in patient care but the evidence basis for many guidelines has recently been called into question.

Methods 

We conducted a literature review using PubMed and analyzed the overall quality of evidence and made strength of recommendation behind 6 Institute of Health Care (IHI) guidelines for prevention of ventilator associated pneumonia (VAP). Quality of evidence was assessed by the American Thoracic Society levels of evidence (levels I through III) with addition of level IV when evidence existed that the guideline increased VAP. We also examined our own intensive care units (ICUs) for evidence of a correlation between guideline compliance and the development of VAP.

Results 

None of the guidelines could be given more than a moderate recommendation. Only one of the guidelines (head of bed elevation) was graded at level II and could be given a moderate recommendation. One was graded at level IV (stress ulcer disease prophylaxis). The remainder were graded level III and given weak recommendations. In our ICUs compliance with the guidelines did not correlate with a reduction in VAP (p<0.05).

Conclusions 

Most of the IHI guidelines are based on level III evidence. Data from our ICUs did not support guideline compliance as a method of reducing VAP. Until more data from well-designed controlled clinical trials become available, physicians should remain cautious when using current IHI VAP guidelines to direct patient care decisions or as an assessment of the quality of care.

Introduction

The growth of guideline publications addressing nearly every aspect of patient care has been remarkable. Over the past 30 years numerous medical regulatory organizations have been founded to improve the quality of care. Many of these organizations have developed medical regulatory guidelines with 6870 listed in the National Guideline Clearinghouse (1). Many of these guidelines were rapidly adopted by healthcare organizations as a method to improve care.

Interest has grown in critically appraising not only individual clinical practice guidelines but also entire guideline sets of different medical (sub)specialties based on their rapid proliferation and in many instances an overall lack of efficacy in improving care (2,3). We assessed the quality of evidence underlying recommendations from one medical regulatory organization, the Institute for Healthcare Improvement (IHI), regarding one set of guidelines, the ventilator associated pneumonia (VAP) guidelines or VAP bundles (4). This was done by senior medical students during a month long rotation in the Phoenix Veterans Administration ICU. 

Methods

The study was approved by the Western Institutional Review Board.

Literature Search

In each instance PubMed was searched using VAP which was cross referenced with each component of the VAP bundle (as modified by the Veterans Administration) using the following MESH terms: 1. Elevation of the head of the bed; 2. Daily sedation vacation; 3. Daily readiness to wean or extubate; 4. Daily spontaneous breathing trial; 5. Peptic ulcer disease prophylaxis; and 6. Deep venous thrombosis prophylaxis. In addition, each individual component of the term was cross referenced with VAP. We also reviewed “Related citations” as listed on PubMed. Additional studies were identified using the “Related citations” in Pubmed from studies listed as supporting evidence on the IHI website and from the references of these studies.

Each study was assessed for appropriateness to the guideline. Studies were required to be prospective and controlled in design. Only studies demonstrating a reduction in VAP were considered, i.e., surrogate outcomes such as reduction in duration of mechanical ventilation were not considered. 

The American Thoracic Society grading system was used to assess the underlying quality of evidence for the IHI VAP guidelines (5) (Table 1). Only evidence supporting a reduction in VAP was considered. We added category IV when there was literature evidence of potentially increasing VAP with the use of the recommendation. A consensus was reached in each case. 

Table I. Levels of Evidence

Level of Evidence	Definition
Level I (high)	Evidence from well-conducted, randomized controlled trials.
Level II (moderate)	Evidence from well-designed, controlled trials without randomization (including cohort, patient series, and case-control Studies). Level II studies also include any large case series in which systematic analysis of disease patterns was conducted, as well as reports of data on new therapies that were not collected in a randomized fashion.
Level III (low)	Evidence from case studies and expert opinion. In some instances, therapy recommendations come from antibiotic susceptibility data without clinical observations.
Level IV	No evidence of improvement with some evidence of an increase in a negative outcome.

Guideline Compliance and VAP Incidence

We also assessed our ICUs for additional evidence of the effectiveness of the VAP bundle. Data was collected for a period of 50 months from January, 2007 through February, 2011. This was after the Veterans Administration requirements for VAP reporting and IHI compliance was instituted. Diagnosis and compliance were assessed by a single quality assurance nurse using a standardized protocol (6). Statistical analysis was done using a Pearson correlation coefficient with a two-tailed test. Significance was defined as p<0.05.

Results

Literature Review

Numbers of articles identified by PubMed search and used for grading the level of evidence and strength of recommendation are given in Table 2. Also included are the level of evidence and the strength of the recommendation.

Table 2.

Guideline

Total Articles

No. of Articles Used (references)

Level of Evidence

Strength of Recommendation

Elevation of the head of the bed	31	8 (7-14)	II	Moderate
Daily sedation vacation	66	4 (15-18)	III	Weak
Daily readiness to wean or extubate	47	3 (19-21)	III	Weak
Daily spontaneous breathing trial	29	1 (22)	III	Weak
Peptic ulcer disease prophylaxis	52	9 (23-29)	IV	Weak
Deep venous thrombosis prophylaxis.	14	2 (30-31)	III	Weak

Head of Bed Elevation

A literature search identified 31 articles of which 8 were used in evaluating this guideline (7-14). However, only 2 specifically studied head of bed elevation with one supporting and another not supporting the intervention (7,8). Consequently it was graded as level II and the strength of recommendation was graded as moderate.

Daily Spontaneous Breathing Trial, Daily Readiness to Wean, and Daily Sedation Vacation

From 1-4 studies were identified for each of these interventions, however, none demonstrated a reduction in VAP. Consequently, it was judged that the evidence basis was level III and the strength of recommendation was graded as weak.

Stress Ulcer Disease Prophylaxis

We found no evidence that stress ulcer disease prophylaxis decreased VAP (23-29). There was some evidence that acid suppressive therapy increased pneumonia and VAP. Consequently, it was judged to be a level IV (possibly increasing VAP). 

Deep Venous Thrombosis Prophylaxis

We could find no evidence that deep venous thrombosis prophylaxis decreased VAP (30,31).

Guideline Compliance and VAP Incidence

Beginning in the first quarter of fiscal year 2007 there was a significant decrease in the incidence of VAP in our hospital (33). This coincided with the requirement for the monitoring of VAP, compliance with the VAP bundles and our adoption of endotracheal aspiration with nonquantitative culture of the aspirate as opposed to bronchoalveolar lavage which had been out standard practice. We changed practices because bronchoalveolar lavage with quantitative cultures appeared to offer no improvement in clinical outcomes to endotracheal aspiration (34). In our medical and surgical ICUs, 5097 audits representing 5800 ventilator-days were assessed. Nineteen cases of VAP were identified with an average of 2.1 VAP infections/1000 ventilator-days.  We assessed our surgical and medical ICUs, combined and separately, for a correlation between total bundle compliance and each component of the VAP bundle with VAP incidence (Appendices 1-3). There was no significant correlation between compliance with the bundles and VAP (p<0.05).

Discussion

This manuscript questions the validity of the VAP bundles as proposed by the IHI. We found that a systematic review of the literature revealed predominately weak evidence to support these guidelines. Only one guideline (head of bed elevation) was supported by a randomized trial (7), but an additional, larger trial showed no decrease in VAP (8). Furthermore, data from our own ICUs showed no evidence of IHI VAP guideline compliance with a reduction in VAP.

Head of bed elevation is a relatively simple and easy to perform intervention which may reduce VAP. Studies examining aspiration have shown a reduction in critical care patients with the head of bed elevation but it is unclear whether this translates into a reduction in VAP (36,37). Drakulovic et al. (7) reported a randomized controlled trial in 86 mechanically ventilated patients assigned to semi-recumbent or supine body position.  The trial demonstrated that suspected cases of ventilator-associated pneumonia had an incidence of 34 percent while in the semi-recumbent position suspected cases had an incidence of 8 percent (p=0.003).  However, another study in 221 subjects demonstrated that the target head elevation of 45 degrees was not achieved for 85% of the study time, and these patients more frequently changed position than supine-positioned patients (8). The achieved difference in treatment position (28 degrees vs. 10 degrees) did not prevent the development of ventilator-associated pneumonia. The other 5 articles identified either did not identify head of bed elevation directly or as part of a bundle. Most were a before and after design and not randomized. Therefore, it is difficult to draw any meaningful conclusions.

The IHI groups daily "sedation vacations" and assessing the patient’s “readiness to extubate.” The logic is that more rapid extubation leads to a reduction in VAP. Kress et al. (15) conducted a randomized controlled trial in 128 adult patients on mechanical ventilation, randomized to either daily interruption of sedation irrespective of clinical state or interruption at the clinician’s discretion. Daily interruption resulted in a reduction in the duration of mechanical ventilation from 7.3 days to 4.9 days (p=0.004). However, in a retrospective review of the data, the authors were unable to show a significant reduction in VAP (16).

Stress ulcer prophylaxis and deep venous thrombosis prophylaxis are routine in most ICUs. However, stress ulcer prophylaxis with enteral feeding is probably as effective as acid suppressive therapy and acid suppressive therapy may increase the incidence of VAP (38). Deep venous thrombosis prophylaxis has been shown to decrease the incidence of pulmonary emboli but not improve mortality (32). Although we use these interventions in our ICU, we would suggest that these would be more appropriate for recommendations rather than guidelines.

The diagnosis of VAP is difficult, requiring clinical judgment even in the presence of objective clinical criteria (6). The difficulty in diagnosis, along with the negative consequences for failure to follow the IHI guidelines, makes before and after comparisons of the incidence of VAP unreliable. Therefore, we sought evidence for the effectiveness of VAP prevention guidelines reasoning that the better the compliance with the guidelines, the lower the incidence of VAP. We were unable to show that improved VAP guideline compliance correlated with a reduced incidence of VAP.

The IHI guidelines would not meet the criteria outlined earlier in an editorial in the Southwest Journal of Pulmonary and Critical Care for a good guideline:

Our study has several limitations. No literature review is totally comprehensive. It is possible that studies relevant to the IHI VAP guidelines, especially those written in a foreign language, were not identified. Second, the Phoenix VA data may be underpowered to show a small beneficial effect despite having over 5000 patient audits. Third, as with other healthcare facilities, the VAP guidelines at our institution were mandated and monitored. The threat of negative consequences may have compromised the objective assessment of the data, likely invalidating a before and after comparison. Fourth, correlation between guideline compliance and VAP incidence is not a substitute for a randomized trial. Unfortunately, the later is not possible given that guideline compliance is mandated.

It is unclear why the IHI guidelines have received such wide acceptance given their weak evidence basis. Agencies involved in guideline writing should show restraint in guideline formulation based on opinion or weak or conflicting evidence. Only those interventions based on strong evidence which can make a real difference to patients should be designated as guidelines.

Acknowledgements

The authors acknowledge Janice Allen, MSN, RN who collected the VAP data reported from the Phoenix VA.

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Appendices

Click here for Appendix 1. VAP rate in all ICUs

Click here for Appendix 2. VAP in medical ICU

Click here for Appendix 3. VAP in surgical ICU