Inpatient – Page 4

Week 36 – Rivers Trial

“Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock”

N Engl J Med. 2001 Nov 8;345(19):1368-77. [free full text]
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Sepsis is common, and severe sepsis and septic shock confer high mortality risks. Fundamentally, sepsis is a global mismatch between oxygen demand and delivery. Around the time of this seminal study by Rivers et al., there was increasing recognition of the concept of the “golden hour” in sepsis management – “where definitive recognition and treatment provide maximal benefit in terms of outcome” (1368). Rivers and his team created a “bundle” of early sepsis interventions that targeted preload, afterload, and contractility, dubbed early goal-directed therapy (EGDT), and evaluated this bundle’s effect on mortality and end-organ dysfunction.

Population: adults presenting to a single US academic center ED with ≥ 2 SIRS criteria and SBP ≤ 90 after a crystalloid challenge of 20-30ml/kg over 30min or lactate > 4mmol/L.

Notable exclusion criteria: acute CVA, MI, ACS, pulmonary edema, cardiac dysrhythmias, contraindication to central line, active GIB, trauma, “uncured cancer,” immunosuppression, or DNR status

Intervention: early goal-directed therapy

received a central venous catheter with continuous central venous O2 saturation (ScvO2) measurement
treated according to EGDT protocol (see Figure 2, or below) in ED for at least six hours
- 500ml bolus of crystalloid q30min to achieve CVP 8-12mm
- vasopressors to achieve MAP ≥ 65
- vasodilators to achieve MAP ≤ 90
- if ScvO2 < 70%, transfuse RBCs to achieve Hct ≥ 30
- if, after CVP, MAP, and Hct were thusly optimized and ScvO2 remained < 70%, dobutamine was added and uptitrated to achieve ScvO2 ≥ 70 or until max dose 20 μg/kg/min
  - dobutamine was de-escalated if MAP < 65 or HR > 120
- patients in whom hemodynamics could not be optimized were intubated and sedated, in order to decrease oxygen consumption
then transferred to inpatient ICU bed as soon as able, at which time ScvO2 measurement was discontinued
inpatient team was blinded to treatment group assignment

Comparison: standard of care

Outcome:
Primary – in-hospital mortality

Secondary

resuscitation end points
organ-dysfunction scores
coagulation-related variables
administered treatments
consumption of healthcare resources

Results:
130 patients were randomized to EGDT, and 133 to standard therapy. There were no differences in baseline characteristics (see Table 1). There was no group difference in the prevalence of antibiotics given within the first 6 hours. Standard-therapy patients spent 6.3 ± 3.2 hours in the ED, whereas EGDT patients spent 8.0 ± 2.1 (p < 0.001).

In-hospital mortality was 46.5% in the standard-therapy group, and 30.5% in the EGDT group (p = 0.009, NNT 6.25); 28-day and 60-day mortalities were also improved in the EGDT group. See Table 3.

During the initial six hours of resuscitation, there was no significant group difference in mean heart rate or CVP. MAP was higher in the EGDT group (p < 0.001), but all patients in both groups reached a MAP ≥ 65. ScvO2 ≥ 70% was met by 60.2% of standard-therapy patients and 94.9% of EGDT patients (p < 0.001). A combination endpoint of achievement of CVP, MAP, and UOP (≥ 0.5cc/kg/hr) goals was met by 86.1% of standard-therapy patients and 99.2% of EGDT patients (p < 0.001). Standard-therapy patients had lower ScvO2 and greater base deficit, while lactate and pH values were similar in both groups.

During the period of 7 to 72 hours, the organ-dysfunction scores of APACHE II, SAPS II, and MODS were higher in the standard-therapy group (see Table 2). The prothrombin time, fibrin-split products concentration, and d-dimer concentrations were higher in the standard-therapy group, while PTT, fibrinogen concentration, and platelet counts were similar.

During the initial six hours, EGDT patients received significantly more fluids, pRBCs, and inotropic support than standard-therapy patients. Rates of vasopressor use and mechanical ventilation were similar.

During the period of 7 to 72 hours, standard-therapy patients received more fluids, pRBCs, and vasopressors than the EGDT group, and were more likely to be intubated and to have pulmonary-artery catheterization. Rates of inotrope use were similar.

Overall, during the first 72 hrs, standard-therapy patients were more likely to receive vasopressors, be intubated, and undergo pulmonary-artery catheterization. EGDT patients were more likely to receive pRBC transfusion. There was no group difference in total volume of fluid administration or inotrope use.

Regarding utilization, there were no group differences in mean duration of vasopressor therapy, mechanical ventilation, or length of stay. Among patients who survived to discharge, standard-therapy patients spent longer in the hospital than EGDT patients (18.4 ± 15.0 vs. 14.6 ± 14.5 days, respectively, p = 0.04).

Implication/Discussion:
Early goal-directed therapy reduced in-hospital mortality in patients presenting to the ED with severe sepsis or septic shock, when compared with usual care.

In their discussion, the authors note that “when early therapy is not comprehensive, the progression to severe disease may be well under way at the time of admission to the intensive care unit” (1376).

The Rivers trial has been cited over 10,100 times. It has been widely discussed and dissected for decades. Most importantly, it helped catalyze a then-ongoing paradigm shift of what “usual care” in sepsis is.

Corresponding practice point from Dr. Sonti and Dr. Vinayak and their Georgetown Critical Care Top 40: “Though we do not use the ‘Rivers protocol’ as written, concepts (timely resuscitation) have certainly infiltrated our ‘standard of care’ approach.”

The Rivers trial evaluated the effect of a bundle (multiple interventions). It was a relatively complex protocol, and the transfusion of blood to Hgb > 10 may have caused significant harm.

In aggregate, the most critical elements of the modern initial resuscitation in sepsis are early administration of antibiotics (notably not protocolized by Rivers) within the first hour and the aggressive administration of IV fluids (now usually 30cc/kg of crystalloid within the first 3 hours of presentation).

More recently, there have been three large RCTs of EGDT versus usual care and/or protocols that used some of the EGDT targets: ProCESS (2014, USA), ARISE (2014, Australia), and ProMISe (2015, UK). In general terms, EGDT provided no mortality benefit compared to usual care. Prospectively, the authors of these three trials planned a meta-analysis – the 2017 PRISM study – which concluded that “EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics.” Despite patients in the Rivers trial being sicker than those of ProCESS/ARISE/ProMISe, it was not found in the subgroup analysis of PRISM that EGDT was more beneficial in sicker patients. Overall, the PRISM authors noted that “it remains possible that general advances in the provision of care for sepsis and septic shock, to the benefit of all patients, explain part or all of the difference in findings between the trial by Rivers et al. and the more recent trials.”

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. Life in The Fast Lane
4. “A randomized trial of protocol-based care for early septic shock” (ProCESS). NEJM 2014.
5. “Goal-directed resuscitation for patients with early septic shock” (ARISE). NEJM 2014.
6. “Trial of early, goal-directed resuscitation for septic shock” (ProMISe). NEJM 2015.
7. “Early, Goal-Directed Therapy for Septic Shock – A Patient-level Meta-Analysis” PRISM. NEJM 2017.
8. Surviving Sepsis Campaign
9. UpToDate, “Evaluation and management of suspected sepsis and septic shock in adults”

Summary by Duncan F. Moore, MD

Week 31 – Symptom-Triggered Benzodiazepines in Alcohol Withdrawal

“Symptom-Triggered vs Fixed-Schedule Doses of Benzodiazepine for Alcohol Withdrawal”

Arch Intern Med. 2002 May 27;162(10):1117-21. [free full text]
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Treatment of alcohol withdrawal with benzodiazepines has been the standard of care for decades. However, in the 1990s, benzodiazepine therapy for alcohol withdrawal was generally given via fixed doses. In 1994, a double-blind RCT by Saitz et al. demonstrated that symptom-triggered therapy based on responses to the CIWA-Ar scale reduced treatment duration and the amount of benzodiazepine used relative to a fixed-schedule regimen. This trial had little immediate impact in the treatment of alcohol withdrawal. The authors of this 2002 double-blind RCT sought to confirm the findings from 1994 in a larger population that did not exclude patients with a history of seizures or severe alcohol withdrawal.

Population: consecutive patients admitted to the inpatient alcohol treatment units at two European universities

Notable exclusion criteria: “major cognitive, psychiatric, or medical comorbidity”

Intervention: placebo (30mg q6hrs x4, followed by 15mg q6hrs x8), with additional oxazepam 15mg for CIWA score 8-15 and 30mg for CIWA score > 15

Comparison: scheduled oxazepam (30mg q6hrs x4, followed by 15mg q6hrs x8), with additional oxazepam 15mg for CIWA score 8-15 and 30mg for CIWA score > 15

Outcomes:

Primary

cumulative oxazepam dose at 72hrs
oxazepam treatment duration

Secondary

incidence of seizures, hallucinations, and delirium tremens at 72hrs
subjective scales of “health concerns,” anxiety, depression, energy level, physical functioning, and vitality over the preceding 3 days, assessed at 72hrs

Subgroup analysis: exclusion of symptomatic patients who did not require any oxazepam

Results:
117 patients completed the trial. 56 had been randomized to the symptom-triggered group, and 61 had been randomized to the fixed-schedule group. The groups were similar in all baseline characteristics except that the fixed-schedule group had on average a 5-hour longer interval since last drink prior to admission. Only 39% of the symptom-triggered group actually received oxazepam, while 100% of the fixed-schedule group did (p < 0.001).

Patients in the symptom-triggered group received a mean cumulative dose of 37.5mg versus 231.4mg in the fixed-schedule group (p < 0.001). The mean duration of oxazepam treatment was 20.0 hours in the symptom-triggered group versus 62.7 hours in the fixed-schedule group.

The group difference in total oxazepam dose persisted even when patients who did not receive any oxazepam were excluded. Among patients who did receive oxazepam, patients in the symptom-triggered group received 95.4 ± 107.7mg versus 231.4 ± 29.4mg in the fixed-dose group (p < 0.001).

Only one patient in the symptom-triggered group sustained a seizure. There were no seizures, hallucinations, or episodes of delirium tremens in any of the other 116 patients. The two treatment groups had similar quality-of-life and symptom scores aside from slightly higher physical functioning in the symptom-triggered group (p < 0.01). See Table 2.

Implication/Discussion:
Symptom-triggered administration of benzodiazepines in alcohol withdrawal led to a six-fold reduction in cumulative benzodiazepine use and a much shorter duration of pharmacotherapy than fixed-schedule administration. This more restrictive and responsive strategy did not increase the risk of major adverse outcomes such as seizure or DTs, and also did not result in increased patient discomfort.

Overall, this study confirmed the findings of the landmark study by Saitz et al. from eight years prior. Additionally, this trial was larger and did not exclude patients with a prior history of withdrawal seizures or severe withdrawal. The fact that both studies took place in inpatient specialty psychiatry units limits their generalizability to our inpatient general medicine populations.

Why the initial 1994 study did not gain clinical traction remains unclear. Both studies have been well-cited over the ensuing decades, and the paradigm has shifted firmly toward symptom-triggered benzodiazepine regimens using the CIWA scale. A 2010 Cochrane review cites the 1994 study only, while Wiki Journal Club and 2 Minute Medicine have entries on this 2002 study but not on the equally impressive 1994 study.

Further Reading/References:
1. “Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial.” JAMA. 1994.
2. Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar)
3. Wiki Journal Club
4. 2 Minute Medicine
5. “Benzodiazepines for alcohol withdrawal.” Cochrane Database Syst Rev. 2010.

Summary by Duncan F. Moore, MD

Week 30 – Omeprazole for Bleeding Peptic Ulcers

“Effect of Intravenous Omeprazole on Recurrent Bleeding After Endoscopic Treatment of Bleeding Peptic Ulcers”

N Engl J Med. 2000 Aug 3;343(5):310-6. [free full text]
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Intravenous proton-pump inhibitor (PPI) therapy is a cornerstone of modern therapy for bleeding peptic ulcers. However, prior to this 2000 study by Lau et al., the role of PPIs in the prevention of recurrent bleeding after endoscopic treatment was unclear. At the time, re-bleeding rates after endoscopic treatment were noted to be approximately 15-20%. Although other studies had approached this question, no high-quality, large, blinded RCT had examined adjuvant PPI use immediately following endoscopic treatment.

Population: patients with bleeding gastroduodenal ulcer visualized on endoscopy in whom hemostasis was achieved following epinephrine injection and thermocoagulation (consecutive patients, single center in Hong Kong)

Intervention: omeprazole 80mg IV bolus followed by 8mg/hr infusion x72 hrs, followed by omeprazole 20mg PO x8 wks

Comparison: placebo bolus + drip x72 hrs, followed by omeprazole 20mg PO x8 wks

Outcome:
Primary – Recurrent bleeding within 30 days

Secondary

Recurrent bleeding within 72 hrs
Mean number of units of blood transfused within 30 days
Duration of hospitalization
All-cause mortality at 30 days

Results:
120 patients were randomized to each arm. The two groups had similar baseline characteristics, including ulcer-specific characteristics. The trial was terminated early due to the finding on interim analysis of a significantly lower recurrent bleeding rate in the omeprazole arm.

Bleeding re-occurred within 30 days in 8 (6.7%) omeprazole patients versus 27 (22.5%) placebo patients (HR 3.9, 95% CI 1.7-9.0; NNT 6.3). A Cox proportional-hazards model, when adjusted for size and location of ulcers, presence/absence of coexisting illness, and history of ulcer disease, revealed a similar hazard ratio (HR 3.9, 95% CI 1.7-9.1).

Recurrent bleeding was most common during the first 72 hrs (4.2% of the omeprazole group versus 20% of the placebo group, RR 4.80, 95% CI 1.89-12.2, p<0.001). For a nice visualization of the early separation of re-bleeding rates, see the Kaplan-Meier curve in Figure 1.

The mean number of units of blood transfused within 30 days was 2.7 ± 2.5 in the omeprazole group versus 3.5 ± 3.8 in the placebo group (p = 0.04). The number of units transfused after the initial endoscopic treatment was 1.7 ± 1.9 in the omeprazole group versus 2.4 ± 3.2 in the placebo group (p = 0.03).

Regarding duration of hospitalization, 46.7% of omeprazole patients were admitted for < 5 days versus 31.7% of placebo patients (p = 0.02). Median stay was 4 days in the omeprazole group versus 5 days in the placebo group (p = 0.006).

4.2% of the omeprazole patients died within 30 days, whereas 10% of the placebo patients died (p = 0.13).

Implication/Discussion:
Treatment with intravenous omeprazole immediately following endoscopic intervention for bleeding peptic ulcer significantly reduced the rate of recurrent bleeding. This effect was most prominent within the first 3 days of therapy. This intervention also reduced blood transfusion requirements and shortened hospital stays.

The presumed mechanism of action is increased gastric pH facilitating platelet aggregation.

In 2018, the benefit of this intervention seems so obvious based on its description alone, that one would imagine that such a trial would not be funded or published in such a high-profile journal. However, the annals of medicine are littered with now-discarded interventions that made sense from a theoretical or mechanistic perspective but were demonstrated to be ineffective or even harmful (e.g. pharmacologic suppression of ventricular arrhythmias post-MI or renal denervation for refractory HTN).

Today, bleeding peptic ulcers are treated with an IV PPI twice daily. Per UpToDate, meta-analyses have not shown a benefit of continuous PPI infusion over this IV BID dosing. However, per 2012 guidelines in the American Journal of Gastroenterology, patients with active bleeding or non-bleeding visible vessels should receive both endoscopic intervention and IV PPI bolus followed by infusion.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Overview of the Treatment of Bleeding Peptic Ulcers”
4. Laine L, Jensen DM. “Management of patients with ulcer bleeding.” Am J Gastroenterol. 2012.

Summary by Duncan F. Moore, MD

Week 21 – HACA

“Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest”

by the Hypothermia After Cardiac Arrest Study Group

N Engl J Med. 2002 Feb 21;346(8):549-56. [free full text]
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Neurologic injury after cardiac arrest is a significant source of morbidity and mortality. It is hypothesized that brain reperfusion injury (via the generation of free radicals and other inflammatory mediators) following ischemic time is the primary pathophysiologic basis. Animal models and limited human studies have demonstrated that patients treated with mild hypothermia following cardiac arrest have improved neurologic outcome. The 2002 HACA study sought to prospectively evaluate the utility of therapeutic hypothermia in reducing neurologic sequelae and mortality post-arrest.

Population: European patients who achieve return of spontaneous circulation after presenting to the ED in cardiac arrest

inclusion criteria: witnessed arrest, ventricular fibrillation or non-perfusing ventricular tachycardia as initial rhythm, estimated interval 5 to 15 min from collapse to first resuscitation attempt, no more than 60 min from collapse to ROSC, age 18-75

pertinent exclusion: pt already < 30ºC on admission, comatose state prior to arrest d/t CNS drugs, response to commands following ROSC

Intervention: Cooling to target temperature 32-34ºC with maintenance for 24 hrs followed by passive rewarming. Pts received pancuronium for neuromuscular blockade to prevent shivering.

Comparison: Standard intensive care

Outcomes:

Primary: a “favorable neurologic outcome” at 6 months defined as Pittsburgh cerebral-performance scale category 1 (good recovery) or 2 (moderate disability). (Of note, the examiner was blinded to treatment group allocation.)

Secondary:
– all-cause mortality at 6 months
– specific complications within the first 7 days: bleeding “of any severity,” pneumonia, sepsis, pancreatitis, renal failure, pulmonary edema, seizures, arrhythmias, and pressure sores

Results:
3551 consecutive patients were assessed for enrollment and ultimately 275 met inclusion criteria and were randomized. The normothermia group had more baseline DM and CAD and were more likely to have received BLS from a bystander prior to the ED.

Regarding neurologic outcome at 6 months, 75 of 136 (55%) of the hypothermia group had a favorable neurologic outcome, versus 54/137 (39%) in the normothermia group (RR 1.40, 95% CI 1.08-1.81, p = 0.009; NNT = 6). After adjusting for all baseline characteristics, the RR increased slightly to 1.47 (95% CI 1.09-1.82).

Regarding death at 6 months, 41% of the hypothermia group had died, versus 55% of the normothermia group (RR 0.74, 95% CI 0.58-0.95, p = 0.02; NNT = 7). After adjusting for all baseline characteristics, RR = 0.62 (95% CI 0.36-0.95). There was no difference among the two groups in the rate of any complication or in the total number of complications during the first 7 days.

Implication/Discussion:
In ED patients with Vfib or pulseless VT arrest who did not have meaningful response to commands after ROSC, immediate therapeutic hypothermia reduced the rate of neurologic sequelae and mortality at 6 months.

Corresponding practice point from Dr. Sonti and Dr. Vinayak and their Georgetown Critical Care Top 40: “If after ROSC your patient remains unresponsive and does not have refractory hypoxemia/hypotension/coagulopathy, you should initiate therapeutic hypothermia even if the arrest was PEA. The benefit seen was substantial and any proposed biologic mechanism would seemingly apply to all causes of cardiac arrest. The investigators used pancuronium to prevent shivering; [at MGUH] there is a ‘shivering’ protocol in place and if refractory, paralytics can be used.”

This trial, as well as a concurrent publication by Benard et al., ushered in a new paradigm of therapeutic hypothermia or “targeted temperature management” (TTM) following cardiac arrest. Numerous trials in related populations and with modified interventions (e.g. target temperature 36º C) were performed over the following decade, and ultimately led to the current standard of practice.

Per UpToDate, the collective trial data suggest that “active control of the post-cardiac arrest patient’s core temperature, with a target between 32 and 36ºC, followed by active avoidance of fever, is the optimal strategy to promote patient survival.” TTM should be undertaken in all patients who do not follow commands or have purposeful movements following ROSC. Expert opinion at UpToDate recommends maintaining temperature control for at least 48 hours. There is no strict contraindication to TTM.

Further Reading/References:
1. 2 Minute Medicine
2. Wiki Journal Club
3. Georgetown Critical Care Top 40, page 23 (Jan. 2016)
4. PulmCCM.org, “Hypothermia did not help after out-of-hospital cardiac arrest, in largest study yet”
5. Cochrane Review, “Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation”
6. The NNT, “Mild Therapeutic Hypothermia for Neuroprotection Following CPR”
7. UpToDate, “Post-cardiac arrest management in adults”

Summary by Duncan F. Moore, MD

Week 17 – PROSEVA

“Prone Positioning in Severe Acute Respiratory Distress Syndrome”

by the PROSEVA Study Group

N Engl J Med. 2013 June 6; 368(23):2159-2168 [free full text]
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Prone positioning had been used for many years in ICU patients with ARDS in order to improve oxygenation. Per Dr. Sonti’s Georgetown Critical Care Top 40, the physiologic basis for benefit with proning lies in the idea that atelectatic regions of lung typically occur in the most dependent portion of an ARDS patient, with hyperinflation affecting the remaining lung. Periodic reversal of these regions via moving the patient from supine to prone and vice versa ensures no one region of the lung will have extended exposure to either atelectasis or overdistention. Although the oxygenation benefits have been long noted, the PROSEVA trial established mortality benefit.

Population: Patients were selected from 26 ICUs in France and 1 in Spain which had daily practice with prone positioning for at least 5 years.

Inclusion: ARDS patients intubated and ventilated <36hr with severe ARDS (defined as PaO2:FiO2 ratio <150, PEEP>5, and TV of about 6ml/kg of predicted body weight)

(NB: by the Berlin definition for ARDS, severe ARDS is defined as PaO2:FiO2 ratio <100)

Intervention: Proning patients within 36 hours of mechanical ventilation for at least 16 consecutive hours (N=237)

Control: Leaving patients in a semirecumbent (supine) position (N=229)

Outcome:

Primary: mortality at day 28

Secondary: mortality at day 90, rate of successful (no reintubation or use of noninvasive ventilation x48hr) extubation, time to successful extubation, length of stay in the ICU, complications, use of noninvasive ventilation, tracheotomy rate, number of days free from organ dysfunction, ventilator settings, measurements of ABG, and respiratory system mechanics during the first week after randomization

Results:
At the time of randomization in the study, the majority of characteristics were similar between the two groups, although the authors noted differences in the SOFA score and the use of neuromuscular blockers and vasopressors. The supine group at baseline had a higher SOFA score indicating more severe organ failure, and also had higher rate of vasopressor usage. The prone group had a higher rate of usage of neuromuscular blockade.

The primary outcome of 28 day mortality was significantly lower in the prone group than in the supine group, at 16.0% vs 32.8% (P<0.001, NNT = 6.0). This mortality decrease was still statistically significant when adjusted for the SOFA score.

Secondary outcomes were notable for a significantly higher rate of successful extubation in the prone group (hazard ratio 0.45; 95% CI 0.29-0.7, P<0.001). Additionally, the PaO2:FiO2 ratio was significantly higher in the supine group, whereas the PEEP and FiO2 were significantly lower. The remainder of secondary outcomes were statistically similar.

Discussion:
PROSEVA showed a significant mortality benefit with early use of prone positioning in severe ARDS. This mortality benefit was considerably larger than seen in past meta-analyses, which was likely due to this study selecting specifically for patients with severe disease as well as specifying longer prone-positioning sessions than employed in prior studies. Critics have noted the unexpected difference in baseline characteristics between the two arms of the study. While these critiques are reasonable, the authors mitigate at least some of these complaints by adjusting the mortality for the statistically significant differences. With such a radical mortality benefit it might be surprising that more patients are not proned at our institution. One reason is that relatively few of our patients have severe ARDS. Additionally, proning places a high demand on resources and requires a coordinated effort of multiple staff. All treatment centers in this study had specially-trained staff that had been performing proning on a daily basis for at least 5 years, and thus were very familiar with the process. With this in mind, we consider the use of proning in patients meeting criteria for severe ARDS.

References and further reading:
1. 2 Minute Medicine
2. Wiki Journal Club
3. Georgetown Critical Care Top 40, pages 8-9
4. Life in the Fastlane, Critical Care Compendium, “Prone Position and Mechanical Ventilation”
5. PulmCCM.org, “ICU Physiology in 1000 Words: The Hemodynamics of Prone”

Summary by Gordon Pelegrin, MD

Week 15 – TRICC

“A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care”

N Engl J Med. 1999 Feb 11; 340(6): 409-417. [free full text]
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Although intuitively a hemoglobin closer to normal physiologic concentration seems like it would be beneficial, the vast majority of the time in inpatient settings we use a hemoglobin concentration of >7g/dL as our threshold for transfusion in anemia. Historically, higher hemoglobin cutoffs were used, often aiming to keep Hgb >10g/dL. In 1999, the landmark TRICC trial was published showing no mortality benefit in the liberal transfusion strategy and even harm in certain subgroup analysis.

Population:

Inclusion: critically ill patients expected to be in ICU > 24h, Hgb ≤ 9g/dL within 72hr of ICU admission, and clinically euvolemic after fluid resuscitation

Exclusion criteria: age < 16, inability to receive blood products, active bleed, chronic anemia, pregnancy, brain death, consideration of withdrawal of care, and admission after routine cardiac procedure.

Intervention: liberal strategy (transfuse to Hgb goal 10-12g/dL, N=420)

Comparison: restrictive strategy (transfuse to Hgb goal 7-9g/dL, N=418)

Primary outcome: 30-day all-cause mortality

Secondary outcomes: 60-day all-cause mortality, mortality during hospital stay (ICU plus step-down), multiple-organ dysfunction score, change in organ dysfunction from baseline

Subgroup analyses: patients with APACHE II score ≤ 20 (i.e. less-ill patients), patients younger than 55, cardiac disease, severe infection/septic shock, and trauma

Results:
The primary outcome of 30-day mortality was similar between the two groups (18.7% vs. 23.3%, p = 0.11). Secondary outcomes of mortality rates during hospitalization were lower in the restrictive strategy (22.2% vs. 28.1%, p = 0.05). 60-day all-cause mortality trended towards lower in the restrictive strategy although did not reach statistical significance (22.7% vs. 26.5 %, p = 0.23). Between the two groups there was no significant difference in multiple-organ dysfunction score or change in organ dysfunction from baseline.

Subgroup analysis was most notable for finding statistically significant benefits for the restrictive strategy in the patients with APACHE II score ≤ 20 and patients younger than 55. In these patients, a restrictive strategy showed decrease in 30-day mortality and a lower multiple-organ dysfunction score. In the subgroups of primary disease process (i.e. cardiac disease, severe infection/septic shock, and trauma) there was no significant difference.

Complications in the ICU were monitored, and there was a significant increase in cardiac events (primarily pulmonary edema) in the liberal strategy compared to the restrictive strategy.

Discussion/Implication:
TRICC showed no difference in 30-day mortality between a restrictive and liberal transfusion strategy. Secondary outcomes were notable for a decrease in inpatient mortality with the restrictive strategy. Furthermore, subgroup analysis showed benefit in various metrics for a restrictive transfusion strategy when adjusting for younger and less-ill patients. This evidence laid the groundwork for our current standard of transfusing to hemoglobin >7g/dL. A restrictive strategy has also been supported by more recent studies. In 2014 the Transfusion Thresholds in Septic Shock (TRISS) study showed no change in 90-day mortality with a restrictive strategy. Additionally, in 2013 the Transfusion Strategy for Acute Upper Gastrointestinal Bleeding study showed reduced 40-day mortality in the restrictive strategy. However, it excluded patients who had massive exsanguination or low rebleeding risk, thus making it difficult to generalize to our patient population. Currently, the Surviving Sepsis Campaign endorses only transfusing RBCs when Hgb <7g/dL unless there are extenuating circumstances such as MI, severe hypoxemia, or active hemorrhage.

References and Further reading:
1. TRISS @ Wiki Journal Club, full text, Georgetown Critical Care Top 40 pages 14-15
2. Transfusion strategy for acute upper gastrointestinal bleeding @ Wiki Journal Club, full text
3. “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2016”
4. Wiki Journal Club

Summary by Gordon Pelegrin, MD

Week 14 – ARDSNet aka ARMA

“Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome”

by the Acute Respiratory Distress Syndrome Network (ARDSNet)

N Engl J Med. 2000 May 4;342(18):1301-8. [free full text]
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Acute respiratory distress syndrome (ARDS) is an inflammatory and highly morbid lung injury found in many critically ill patients. In the 1990s, it was hypothesized that overdistention of aerated lung volumes and elevated airway pressures might contribute to the severity of ARDS, and indeed some work in animal models supported this theory. Prior to the ARDSNet study, four randomized trials had been conducted investigating the possible protective effect of ventilation with lower tidal volumes, but their results were conflicting.

Population: patients with ARDS diagnosed within < 36 hrs
Intervention: initial tidal volume 6 ml/kg predicted body weight, downtitrated as necessary to maintain plateau pressure ≤ 30 cm of water
Comparison: initial tidal volume 12 ml/kg predicted body weight, downtitrated as necessary to maintain plateau pressure ≤ 50 cm of water

Outcomes:

primary
1) in-hospital mortality
2) ventilator-free days within the first 28 days

secondary
1) number of days without organ failure
2) occurrence of barotrauma
3) reduction in IL-6 concentration from day 0 to day 3

Results:
861 patients were randomized before the trial was stopped early due to the increased mortality in the control arm noted during interim analysis. In-hospital mortality was 31.0% in the lower tidal volume group and 39.8% in the traditional tidal volume group (p = 0.007, NNT = 11.4). Ventilator free days were 12±11 in the lower tidal volume group vs. 10±11 in the traditional group (n = 0.007). The lower tidal volume group had more days without organ failure (15±11 vs. 12±11, p = 0.006). There was no difference in rates of barotrauma among the two groups. IL-6 concentration decrease between days 0 and 3 was greater in the low tidal volume group (p < 0.001), and IL-6 concentration at day 3 was lower in the low tidal volume group (p = 0.002).

Implication/Discussion:
Low tidal volume ventilation decreases mortality in ARDS relative to “traditional” tidal volumes.

The authors felt that this study confirmed the results of prior animal models and conclusively answered the question of whether or not low tidal volume ventilation provided a mortality benefit. In fact, in the years following, low tidal volume ventilation became the standard of care, and a robust body of literature followed this study to further delineate a “lung protective strategy.”

Critics of the study noted that at the time of the study the standard of care/“traditional” tidal volume in ARDS was less than the 12 ml/kg used in the comparison arm. (Non-enrolled patients at the participating centers were receiving a mean tidal volume of 10.3 ml/kg.) Thus not only was the trial making a comparison to a faulty control, but it was also potentially harming patients in the control arm. Here is an excellent summary of the ethical issues and debate regarding this specific issue and regarding control arms of RCTs in general.

Corresponding practice point from Dr. Sonti and Dr. Vinayak and their Georgetown Critical Care Top 40: “Low tidal volume ventilation is the standard of care in patients with ARDS (P/F < 300). Use ≤ 6 ml/kg predicted body weight, follow plateau pressures, and be cautious of mixed modes in which you set a tidal volume but the ventilator can adjust and choose a larger one.”

PulmCCM is an excellent blog, and they have a nice page reviewing this topic and summarizing some of the research and guidelines that have followed.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. PulmCCM “Mechanical Ventilation in ARDS: Research Update”
4. Georgetown Critical Care Top 40, page 6

Summary by Duncan F. Moore, MD

Week 8 – CORTICUS

“Hydrocortisone Therapy for Patients with Septic Shock”

N Engl J Med. 2008 Jan 10;358(2):111-24. [free full text]
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Steroid therapy in septic shock has been a hotly debated topic since the 1980s. The Annane trial in 2002 suggested that there was a mortality benefit to early steroid therapy and so for almost a decade this became standard of care. In 2008 the CORTICUS trial was performed suggesting otherwise.

Population:
– inclusion criteria: ICU patients with septic shock onset with past 72 hrs (defined as SBP < 90 despite fluids or need for vasopressors, and hypoperfusion or organ dysfunction from sepsis)
– exclusion criteria: “underlying disease with a poor prognosis,” life expectancy < 24hrs, immunosuppression, recent corticosteroid use

Intervention: hydrocortisone 50mg IV q6h x5 days with taper

Comparison: placebo injections q6h x5 days plus taper

Outcome:

Primary: 28 day mortality among patients who did not have a response to ACTH stim test (cortisol rise < 9mcg/dL)

Secondary:
– 28 day mortality in patients who had a positive response to ACTH stim test
– 28 day mortality in all patients
– reversal of shock (defined as SBP ≥ 90 for at least 24hrs without vasopressors) in all patients
– time to reversal of shock in all patients

Results:
In ACTH non-responders (N=233): intervention vs. control 28 day mortality was 39.2% vs. 36.1% (p=0.69)

In ACTH responders (N=254): intervention vs. control 28 day mortality was 28.8% vs. 28.7% (p=1.00); reversal of shock 84.7%% vs. 76.5% (p=0.13)

Among all patients:
– intervention vs. control 28 day mortality was 34.3% vs. 31.5% (p=0.51)
– reversal of shock 79.7% vs. 74.2% (p=0.18)
– duration of time to reversal of shock was significantly shorter among patients receiving hydrocortisone (per Kaplan-Meier analysis, p<0.001; see Figure 2), median time to reversal 3.3 days vs. 5.8 days (95% CI 5.2 – 6.9)

Discussion:
The CORTICUS trial demonstrated no mortality benefit of steroid therapy in septic shock, regardless of a patient’s response to ACTH. Despite the lack of mortality benefit, it demonstrated an earlier resolution of shock with steroids. This lack of mortality benefit sharply contrasted with the previous Annane study. Several reasons have been posited for this including poor powering of the CORTICUS study (it did not reach the desired N=800), CORTICUS inclusion starting within 72 hrs of septic shock vs. Annane starting within 8 hrs, and Annane patients generally being sicker (including their inclusion criterion of mechanical ventilation). Subsequent meta-analyses disagree about the mortality benefit of steroids, but meta-regression analyses suggest benefit among the sickest patients. All studies agree about the improvement in shock reversal. The 2016 Surviving Sepsis Campaign guidelines recommend IV hydrocortisone in septic shock in patients who continue to be hemodynamically unstable despite adequate fluid resuscitation and vasopressor therapy.

Per Drs. Sonti and Vinayak of the GUH MICU (excerpted from their excellent Georgetown Critical Care Top 40): “Practically, we use steroids when reaching for a second pressor or if there is multiorgan system dysfunction. Our liver patients may have deficient cortisol production due to inadequate precursor lipid production; use of corticosteroids in these patients represents physiologic replacement rather than adjunct supplement.”

References / Further Reading:
1. Wiki Journal Club
2. 2 Minute Medicine
3. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock (2016), section “Corticosteroids”
4. Annane trial (2002) [free full text]
5. Georgetown Critical Care Top 40 [iTunes / iBooks link]
6. UpToDate,“Glucocorticoid therapy in septic shock”

Summary by Gordon Pelegrin, MD

Week 5 – Albumin in SBP

“Effect of Intravenous Albumin on Renal Impairment and Mortality in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis”

N Engl J Med. 1999 Aug 5;341(6):403-9. [free full text]

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Renal failure commonly develops in the setting of SBP, and its development is a sensitive predictor of in-hospital mortality. The renal impairment is thought to stem from decreased effective arterial blood volume secondary to the systemic inflammatory response to the infection. In our current practice, there are certain circumstances in which we administer albumin early in the SBP disease course in order to reduce the risk of renal failure and mortality. Ultimately, our current protocol originated from the 1999 study of albumin in SBP by Sort et al.

Population: adults with SBP (see paper for extensive list of exclusion criteria)
Intervention: cefotaxime and albumin infusion 1.5gm/kg within 6hrs of enrollment, followed by 1gm/kg on day 3
Comparison: cefotaxime alone
Outcome:
1º: development of “renal impairment” (a “nonreversible” increase in BUN or Cr by more than 50% to a value greater than 30 mg/dL or 1.5 mg/dL, respectively) during hospitalization
2º: mortality during hospitalization

Results:
126 patients were randomized. Both groups had similar baseline characteristics, and both had similar rates of resolution of infection. Renal impairment occurred in 10% of the albumin group and 33% of the cefotaxime-alone group (p=0.02). In-hospital mortality was 10% in the albumin group and 29% in the cefotaxime-alone group (p=0.01). 78% of patients that developed renal impairment died in-hospital, while only 3% of patients who did not develop renal impairment died. Plasma renin activity was significantly higher on days 3, 6, and 9 in the cefotaxime-alone group than in the albumin group, while there were no significant differences in MAP among the two groups at those time intervals. Multivariate analysis of all trial participants revealed that baseline serum bilirubin and creatinine were independent predictors of the development of renal impairment.

Implication/Discussion:
Albumin administration reduces renal impairment and improves mortality in patients with SBP.

The findings of this landmark trial were refined by a brief 2007 report by Sigal et al. “Restricted use of albumin for spontaneous bacterial peritonitis.” “High-risk” patients, identified by baseline serum bilirubin of ≥ 4.0 mg/dL or Cr ≥ 1.0 mg/dL were given the intervention of albumin 1.5gm/kg on day 1 and 1gm/kg on day 3, and low-risk patients were not given albumin. None of the 15 low-risk patients developed renal impairment or died, whereas 12 of 21 (57%) of the high-risk group developed renal impairment, and 5 of the 21 (24%) died. The authors concluded that patients with bilirubin < 4.0 and Cr < 1.0 do not need scheduled albumin in the treatment of SBP.

The current (2012) American Association for the Study of Liver Diseases guidelines for the management of adult patients with ascites due to cirrhosis do not definitively recommend criteria for albumin administration in SBP – they instead summarize the above two studies.

A 2013 meta-analysis of four reports/trials (including the two above) concluded that albumin infusion reduced renal impairment and improved mortality with pooled odds ratios approximately commensurate with those of the 1999 study by Sort et al.

Ultimately, the current recommended practice per expert opinion is to perform albumin administration per the protocol outlined by Sigal et al. (2007).

Further Reading:
1. AASLD Guidelines for Management of Adult Patients with Ascites Due to Cirrhosis (skip to page 77)
2. Sigal et al. “Restricted use of albumin for spontaneous bacterial peritonitis”
3. Meta-analysis: “Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials”
4. Wiki Journal Club
5. 2 Minute Medicine

Summary by Duncan F. Moore, MD

Week 3 – Dexamethasone in Bacterial Meningitis

“Dexamethasone in Adults With Bacterial Meningitis”

N Engl J Med 2002; 347:1549-1556 [NEJM free full text]

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The current standard of care in the treatment of suspected bacterial meningitis in the developed world includes the administration of dexamethasone prior to or at the time of antibiotic initiation. The initial evaluation of this practice in part stemmed from animal studies which demonstrated that dexamethasone reduces CSF concentrations of inflammatory markers as well as neurologic sequelae after meningitis. RCTs in the pediatric literature also demonstrated clinical benefit. The best prospective trial in adults was this 2002 study by de Gans et al.

Population: adults with suspected meningitis

Intervention: dexamethasone 10mg IV q6hrs x4 days started 15-20 minutes before first IV abx

Comparison: placebo IV with same administration as above

Outcome:
primary = Glasgow Outcome Scale at 8 weeks (1 = death, 2 = vegetative state, 3 = unable to live independently, 4 = unable to return to school/work, 5 = able to return to school/work)
secondary = death, focal neurologic abnormalities, and others
subgroup analyses performed by organism

Results/Conclusion:
301 patients were randomized. At 8 weeks, 15% of dexamethasone patients had an unfavorable outcome (Glasgow Outcome Scale score of 1-4), vs. 25% of placebo patients (RR 0.59, 95% CI 0.37 – 0.94, p= 0.03). Among patients with pneumococcal meningitis, 26% of dexamethasone patients had an unfavorable outcome, vs. 52% of placebo patients. There was no significant difference among treatment arms within the subgroup of patients infected with meningococcal meningitis. Overall, death occurred in 7% of dexamethasone patients and 15% of placebo patients (RR 0.48, 95% CI 0.24 – 0.96, p = 0.04). In pneumococcal meningitis, 14% of dexamethasone patients died, vs. 34% of placebo patients. There was no difference in rates of focal neurologic abnormalities or hearing loss in either treatment arm (including within any subgroup).

Implication/Discussion:
Early adjunctive dexamethasone improves mortality in bacterial meningitis.

As noted in the above subgroup analysis, this benefit appears to be driven by the efficacy within the pneumococcal meningitis subgroup. Of note, the standard initial treatment regimen in this study was amoxicillin 2gm q4hrs for 7-10 days, not our standard ceftriaxone + vancomycin +/- ampicillin. Largely on the basis of this study alone, the IDSA guidelines for the treatment of bacterial meningitis (2004) recommend dexamethasone 0.15 mg/kg q6hrs for 2-4 days with first dose administered 10-20 min before or concomitant with initiation of antibiotics. Dexamethasone should be continued only if CSF Gram stain, CSF culture, or blood cultures are consistent with pneumococcus.

Further Reading:
1. IDSA guidelines for management of bacterial meningitis (2004)
2. Wiki Journal Club
3. 2 Minute Medicine

Summary by Duncan F. Moore, MD