Another Comment from Our Semi-Retired Critical Care Doctor on Fluids and the Lymphatics


If you hadn’t already read John (Last Name Not Given), go immediately to this post and read it.

A physiology master comments on the sepsis talks

The comment was in response to the two podcasts on Dr. Paul Marik’s Fluids in Sepsis Talk

The Role of the Lymphatics

In the light of our ‘improved’ understanding of the capillary fluid dynamics of which lymphatics play a significant part (I know, I am sounding like a broken record when it comes to the role of lymphatics!), a few points need to be addressed…..

Optimal fluid resuscitation involves the maintenance of adequate microcirculatory flow coupled with prevention of development of interstitial edema. Edema develops when the capillary hydrostatic pressure increases, coupled with a reduction in removal of interstitial fluid. There is always a normal extravasation of fluid from the intracapillary space to the extracapillary (interstitial) space, otherwise the cells would starve. This extravasation happens along the entire length of the non-fenestrated, non-sinusoidal capillaries and not just at the arteriolar end, as previously thought ( Tom W’s fantastic article!!).

A normally functioning lymphatic system is crucial for returning this fluid back to the central circulation, otherwise edema would ensue.

Normal Lymphatic Function

Let us have a very brief outline of the normal lymphatic structure in this context. I find it useful to think about the arrangement as a kind of a bronchial tree in reverse ….

Initial lymphatics, rich in numbers and deeply embedded in tissue parenchyma, consist of pure endothelial channels without perivascular cells (e.g., pericytes) and smooth muscle cells. They have overlapping cell junctions forming primary valves in addition to traditional secondary lymph valves, and they rely on surrounding tissue motions to achieve periodic lymph channel expansion and compression for collection of interstitial fluid and fluid transport inside the lymphatics.
By contrast, the contractile lymphatics, (calcium dependant) are equipped with rows of bileaflet valves and contract by a specialized smooth muscle phenotype unique to the lymphatics to carry fluid from the initial lymphatics to the lymph nodes. Each pair of upstream and downstream valves in contractile lymphatics forms a lymphangion, facilitating unidirectional lymph fluid during periodic contraction. Contractile lymphatics have many of the vascular control mechanisms present in the arterioles, from classical myogenic contraction to neurogenic, purinergic, and endothelial-dependent and -independent controls.

The microenvironment surrounding collecting lymphatic vessels is a determinant of lymphatic function. Under physiological conditions, NO produced by eNOS in endothelial cells is required for periodic contraction and lymph flow; removing NO caused a reduction in contraction strength. Under inflammatory conditions, iNOS overproduces NO, overwhelms the subtle flow-dependent NO production from eNOS, and prevents contraction. At least in mouse models, higher levels of NO production stimulated by ACh evoked dilation, decreased tone, slowed contraction frequency and reduced fractional pump flow. The situation facilitates lymph edema, reduces antigen delivery into lymph nodes, and consequently, reduces antigen-presenting cells and T-cell activation. It is interesting to note that the effect of nitric oxide and therefore Nitroglycerin are completely different in normal circumstances and in inflammation!
Suppression of lymphatic function by CD11b-positive myeloid cells is a mechanism of self-protection from autoreactive responses during on-going inflammation. To initiate an immune response, antigen and antigen-presenting cells arrive in lymph nodes within hours on antigen encounter. Myeloid cells may accumulate at an inflammatory site and inhibit collecting lymphatic function, suppressing additional immune response to self-antigen by reducing antigen transport into the lymph node.

Some good references on this point are ..

Glycocalyx Protection

Now, on to the aspect of glycocalyx protection,

Injudicious fluid administration in resuscitation practices can cause edema to develop by a variety of mechanisms.
A rapid fluid bolus can cause significant shear stress on the delicate glycocalyx, disrupting it and breaking down the barriers to extravasation.

Colloids and hyperoncotic stuff can themselves cause dessication and compaction of the glycocalyx, by sucking up its water content.

Hypervolemia itself can cause atrial stretch, causing the release of ANP and BNP (evil twins of volume overload.) The actions of both peptides include natriuresis and diuresis, a decrease in systemic blood pressure, and inhibition of the renin–angiotensin–aldosterone system. Further, ANP and BNP elicit increases in blood microvessel permeability sufficient to cause protein and fluid extravasation into the interstitium to reduce the vascular volume. They have a rather differential action on the lymphatics, interms of altering either the permeability or the contractility. Notably, ANP abolishes spontaneous contraction amplitude while BNP augments both parameters by ?2-fold . In aggregate, the consensus is that an increase in collecting lymphatic permeability opposes the absorptive function of the lymphatic capillaries, and aids in the retention of protein and fluid in the interstitial space to counteract volume expansion. The works of Joshua P. Scallan, Michael J. Davis and Virginia H. Huxley, in this regard are noteworthy.

One can see the possible pitfalls of using Nitroglycerine at a micro-circulatory level….

One, by causing vasodilatation, it can aggravate edema..(increased capillary hydrostatic pressure)

Two, by knocking off lymphatics, (through the NO synthase mechanisms) it might perpetuate interstitial fluid retention.

Hope this helps.
“Semi retired critical care doc”.

It does indeed help, but…!

Now, an alternative view is to go to the actual clinical data (albeit preliminary), for instance

Spronk PE, Ince C, Gardien MJ, Mathura KR, Oudemans-van Straaten HM, Zandstra DF. Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet. 2002 Nov 2;360(9343):1395-6.

His letter of response to questions also has additional references for the mode of action that may be beneficial

These two fantastic review articles on microcirculatory resuscitation are must reads:

  • Intensive Care Med 2002;28:1208
  • Critical Care 2006;10:221

What do you think?

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  1. […] mysterious John has more great commentary on EMCrit with Another Comment from Our Semi-Retired Critical Care Doctor on Fluids and the Lymphatics. Also in Best of 2013 – Eight is Enough & Social Media Update Scott highlights some great […]

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