Immunomodulation strategies in the critically ill

Immunomodulation strategies in the critically ill

  • Severe sepsis is the result of an infectious stimulus that triggers a hyper-inflammatory response and results in multiple organ failure. This hyper immune response triggers a phase of immunoparalysis that results in the patient’s inability to resist and clear infections, causing the delayed mortality observed is some septic patients.
  • The inflammatory and coagulation cascades are closely linked such that a significant aspect of the disease process is attributed to the activation of the coagulation cascade by circulating inflammatory mediators.
  • Therapeutic approaches to sepsis have targeted the hyper-inflammatory response, inhibition of the subsequent coagulation cascade, and immunostimulation during the immunoparalysis phase.
  • Proven beneficial therapies for sepsis are limited to the mechanical eradication of the source of infection, antibiotics to clear the organism, the judicious use of fluids to support organ perfusion, and oxygen supplementation. Studies evaluating immunotherapeutics for the treatment of severe sepsis have failed to show efficacy in clinical trials.
  • Further research may demonstrate effectiveness using a strategy of targeting therapies based on an improved identification of the patient’s phase of sepsis, use of combination therapies, a better understanding and strategy aimed at specific host-organism interactions, and /or better specified therapies in relation to identified biomarkers.


  • Studies evaluating the use of immunotherapeutics for severe sepsis are plagued with multiple confounding factors including the pre-dominant phase of sepsis (hyperimmune versus hypoimmune), differing offending organisms, differing host-organism interactions, heterogeneity in the patient populations, and underpowered study designs.
  • Perhaps the correct immunotherapy will need to be tailored in order to decrease the immune response in the hyperimmune phase and increase it during the hypoimmune phase. In order to do so, better markers of these phases of sepsis are needed. Further studies may also find more efficacy in using multiple therapies simultaneously to obtain best results.
  • Finally, there exists a close interaction between in the immune and coagulation system. Further study of this link and therapies to temper the coagulation cascade many prove to be a successful modality of therapy in order to halt the body’s progression to multiple organ failure.



HIV in the critically ill

HIV in the critically ill

   “Adapted from Oxford Textbook of Critical Care-Oxford University Press 2016”               

  • Human immunodeficiency virus (HIV) is increasingly a controllable disease in North America and life expectancy in patients adherent to combination antiretroviral therapy (cART) is similar to the general population.
  • The majority of a admissions of HIV positive patients to the ICU are for reasons unrelated to their HIV, although presentations due to opportunistic infections and malignancies must be considered in those with previously undiagnosed infection or in those patients non-adherent to cART.
  • The CD4 count is critical in determining the degree of immune suppression in a patient and should be checked in all critically ill HIV-infected patients to determine appropriate work-up and management of HIV- related infections/complications.
  • It is important to involve an infectious disease specialist familiar with HIV in the care of a critically ill HIV-infected patient, particularly if therapy requires alterations or cessation of cART or if the patient is found to be significantly immunocompromised.
  • Antiretroviral agents have many potential drug interactions and rare toxicities which must be evaluated throughout the ICU stay as concomitant medications are introduced.

Is Glucose Control Relevant?

Controversies in Critical Care Medicine

Is Glucose Control Relevant?

(Adapted from: Is Glucose Control Relevant , Adel Bassily/Marcus, MD and Inga Khachaturova, Md/ Critical Care 957-959, McGraw Hill Education 2017)

Virtually all adult medical ICU patients experience at least 1 blood glucose value above the normal fasting level (110 mg/dL).

The stress of critical illness promotes a state of insulin resistance which is characterized by increased hepatic gluconeogenesis and glycogenolysis, impaired peripheral glucose uptake, and higher circulating concentrations of insulin. There is upregulation of hepatic glucose production triggered by elevated levels of cytokines and counterregulatory hormones such as glucagon, cortisol, growth hormone, and catecholamines.

  •  These metabolic disturbances together with common ICU treatments such as corticosteroids, sympathomimetic agents, and glucose-containing infusions explain the frequently observed phenomenon of hyerglycemia irrespective of the disease, diabetes mellitus.
  •  Large observational studies in different types of ICU populations reveal a J-shaped relationship between blood glucose levels and mortality of critical illness, with the mortality nadir somewhere between 80 and 140 mg/dL depending on the type of illness and the presence of a history of diabetes mellitus (Cely et al., 2004).
  •  Observations such as these raised concerns that acute hyperglycemia itself was contributing to poor outcomes, potentially by leaving affected patients susceptible to some of the complications that have long been observed among chronic diabetics, including high infection rates, poor wound healing, and polyneuropathy.

Cley CM., Arora P., Quartin AA., Kett DH, Schein RM. Relationship of baseline glucose homeostasis to hyperglycemia during medical critical illness. Chest. 2004; 126(3): 879-887


The groundbreaking Leuven I study in 2001, conducted in critically ill surgical patients, found a remarkable overall 3.4% ICU mortality reduction, a 9.6% mortality benefit in patients with ICU LOS more than 5 days, and a 34% hospital mortality reduction in the strict normoglycemia group (target glucose 80-110 mg/dL) compared to standard therapy (Vanden Berghe et al., 2001). These beneficial outcomes resulting from the use of intensive insulin therapy targeting normoglycemic levels sparked a strong interest in glycemic management in the ICU. Intensive insulin therapy quickly became the standard of care in both medical and surgical ICUs.

However, a follow-up study, done by the same group in 2006,3 demonstrated that in contrast to the earlier study, intensive insulin therapy did not reduce overall morality and was associated with an even higher rate of serious hypoglycemia (18.7%). In the first study, it was speculated that the benefits seen were primarily due to a surgical patient population and the primary use of parenteral nutrition.

Vanden Berghe G., Wouters P., Weekers F et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001; 345(19): 1359-1367.


Following 4 consecutive negative trials, the most comprehensive landmark NICE-SUGAR trial results were reported. They found that the intensive insulin therapy groups achieving normoglycemia had an absolute 2.6% increase in mortality (P = 0.02) and an increased incidence of hypoglycemia (6.8% vs 0.5%) Finfer et al., 2009.

The overall consensus from the available evidence suggests that intensive insulin therapy (target glucose 80-110 mg/dL) as compared to standard insulin therapy (target glucose 140-180) does not provide an overall survival benefit, may increase mortality and is associated with a higher incidence of hypoglycemia.

Finfer S, Chittock DR, Su Sy, et al. Intensive versus conventional glucose control in critically ill patients. N Engl. J Med. 2009; 360(13): 1283-1297


  • Hypoglycemia has been shown in the critically ill Patient to be independently associated with a 3-fold increase in mortality. In a trial of intensive insulin therapy, severe hypoglycemia occurred in up to 28% of patients (Arabi et al., 2008).

Arabi YM, Dabbagh OC, Tamin HM, et al. Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients. Crt. Care med. 2008; 36(12): 3190-3197

  • It is further speculated that the incidence of hypoglycemia is likely to be higher outside of clinical trials if intensive insulin protocols are used.
  •  The main consequences of acute and persistent hypoglycemia are neurologic deficits, which at times can be quite difficult to detect but remain a true concern. Hypoglycemia has been shown to cause acute electroencephalographic alterations. In a 4-year follow-up of patients treated with intensive insulin therapy (target blood glucose 80-110 mg/ dL), this population was found to have impairments in quality of life and social functioning as compared to patients who received conventional insulin therapy.
  • The relationship between hypoglycemia and outcome may be explained by an association with severity of illness and an increased risk of death, or a true deleterious biologic effect in critically ill patients. Hypoglycemia might exert biologic toxicity by increasing the systemic inflammatory response, inducing neuroglycopenia, inhibiting the corticosteroid response to stress, impairing sympathetic nervous system responsiveness, causing cerebral vasodilatation or by unidentified mechanisms.
  • Furthermore, many experimental studies have demonstrated that both insulin and hypoglycemia can induce hypotension, vasodilatation, nitric oxide release, sympathetic system response exhaustion, and decreased ability to respond to repeated stress.


  • The repeated observation that hyperglycemia is associated with poorer outcomes among critically ill patients, together with the theoretical harm of acutely elevated blood glucose, represents the basis for focusing on glycemic control in the intensive care setting.
  •  However, the possibility remains that elevated blood glucose levels are actually beneficial to the critically ill individual, and that stress hyperglycemia is an appropriate and adaptive response to life-threatening illness, as no randomized trial investigating glycemic control has studied the effect of truly permissive hyperglycemia.
  • Potential benefits of hyperglycemia include promotion of glucose delivery in the face of ischemic insults (enhanced glucose diffusion gradient), with insulin resistance favoring redistribution of available glucose stores toward cells of the immune and nervous systems, and away from peripheral tissues.
  •  Recent observational studies have provided some support for this view, reasserting the possibility that hyperglycemia is simply a marker of illness severity when controlled for hyperlactatemia. Our ability to identify patients most likely to suffer harm from hyperglycemia remains incomplete.


  • Glucose variability (the difference between daily minimum and maximum glucose levels) may be a reflection of Dysglycemia induced by severity of illness, inadequate control of glycemia by the treating clinicians resulting in excessive fluctuations of BG levels, or both.
  • Additionally, patients with increased glucose variability are more likely to have experienced hypoglycemia, complicating the assessment of glucose variability versus hypoglycemia and mortality. Over the last several years a plethora of data, from observational studies evaluating a wide variety of acutely and critically ill populations, has confirmed the correlation between glucose variability and increased odds of death.
  • These findings raise the question that attempting to control hyperglycemia may be a major contributing actor in glucose variability and subsequent detrimental outcomes.


Antidepressants in Critical Illness

Key points in Critical Care Medicine:

Antidepressants in critical illness

“Adapted from Oxford Textbook of Critical Care-Oxford University Press 2016”

  • Selective serotonin reuptake inhibitors (SSRIs), Serotonin Norepinephrine reuptake inhibitors (SNRIs), Bupropion and Mirtazapine are typically the first-line agents for the treatment of depression in the intensive care unit (ICU) setting given their safety and tolerability.
  • Serotonin syndrome is a significant risk in overdose of most antidepressants and can also be seen in the setting of combining more than one antidepressant.
  • Stimulants can be used safely and effectively to treat apathy, loss of appetite, and low energy in ICU patients.
  • Antidepressants should typically be continued during ICU stays (except in the presence of delirium), as abrupt cessation may produce withdrawal phenomenon.
  • Current evidence does not recommend prophylactic initiation of antidepressants following trauma.



Managing ICU Staff Welfare, Morale, and Burnout

Key points in Critical Care Medicine:

Managing ICU staff Welfare, Morale, and Burnout

 “Adapted from Oxford Textbook of Critical Care-Oxford University Press 2016”

  • The intensive care unit (ICU) environment exposes staff to stressful and emotionally-demanding situations, which places them at high risk for burnout.
  • Risk factors for Burnout can be found at both individual and organization levels.
  • Consequences of low morale and burnout include personal distress for clinicians, poor quality of care for patients, and highly health care costs for organizations and society.
  • Staff engagement is emerging as the antithesis of burnout.
  • We need to promote a wider recognition among ICU staff regrading risks of burnout and the consequences for both them and the patients in their care.

Potential phases of Burnout

  • The need to prove oneself: often occurring in highly motivated and ambitious individuals.
  • Working harder: high personal expectations emerge as further work commitments are undertaken.
  • Neglecting personal needs: no time or energy is reserved for activities or relationships outside the workplace.
  • Displacement of conflict: The individual is unable to identify the cause for their difficulties.
  • Revision of values: isolation from family and friends with a solely job- related value system.
  • Denial: cynicism, aggression, and intolerance of others emerge, leading to isolation.
  • Behavioral changes become more apparent to others: e.g conflict.
  • Depersonalization: loss of appreciation for self and self- worth. Cannot appreciate further success.
  • Inner emptiness: may seek an activity to full the void such as eating, drugs, etc.
  • Depression: typical affective, cognitive and somatic features are present.

Burnout ensues: complete physical and emotional collapse.